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1
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Anastasilakis AD, Tsourdi E. Τhe story of sclerostin inhibition: the past, the present, and the future. Hormones (Athens) 2025; 24:41-58. [PMID: 38170438 DOI: 10.1007/s42000-023-00521-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024]
Abstract
Sclerostin inhibits osteoblast activity by hampering activation of the canonical Wnt signaling pathway and simultaneously stimulates osteoclastogenesis through upregulation of the receptor activator of NFκB ligand (RANKL). Thus, antibodies against sclerostin (Scl-Abs), besides promoting bone formation, suppress bone resorption and dissociate bone formation from resorption. This dual action results in remarkable increases of bone mineral density which are of a greater magnitude compared to the other antiosteoporotic treatments and are accompanied by decreases of fracture risk at all skeletal sites. The anabolic effect subsides after the first few months of treatment and a predominantly antiresorptive effect remains after this period, limiting its use to 12 months. Furthermore, these effects are largely reversible upon discontinuation; therefore, subsequent treatment with antiresorptives is indicated to maintain or further increase the bone gains achieved. Romosozumab is currently the only Scl-Ab approved for the treatment of severe postmenopausal osteoporosis. Indications for use in other populations, such as males, premenopausal women, and patients with glucocorticoid-induced osteoporosis, are pending. Additionally, the efficacy of Scl-Abs in other bone diseases, such as osteogenesis imperfecta, hypophosphatasia, X-linked hypophosphatemia, and bone loss associated with malignancies, is under thorough investigation. Cardiovascular safety concerns currently exclude patients at high cardiovascular risk from this treatment.
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Affiliation(s)
- Athanasios D Anastasilakis
- Department of Endocrinology, 424 Military General Hospital, Ring Road, 564 29 N. Efkarpia, Thessaloniki, Greece.
| | - Elena Tsourdi
- Department of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
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2
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Besio R, Garibaldi N, Sala A, Tonelli F, Aresi C, Maffioli E, Casali C, Torriani C, Biggiogera M, Villani S, Rossi A, Tedeschi G, Forlino A. The administration of exogenous HSP47 as a collagen-specific therapeutic approach. JCI Insight 2025; 10:e181570. [PMID: 39913197 PMCID: PMC11949040 DOI: 10.1172/jci.insight.181570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 02/05/2025] [Indexed: 03/25/2025] Open
Abstract
The proof of principle of the therapeutic potential of heat shock protein 47 (HSP47) for diseases characterized by defects in collagen I synthesis is here demonstrated in osteogenesis imperfecta (OI), a prototype of collagen disorders. Most of the OI mutations delay collagen I chain folding, increasing their exposure to posttranslational modifications that affect collagen secretion and impact extracellular matrix fibril assembly. As a model, we used primary fibroblasts from OI individuals with a defect in the collagen prolyl 3-hydroxylation complex, since they are characterized by the synthesis of homogeneously overmodified collagen molecules. We demonstrated that exogenous recombinant HSP47 (rHSP47) is taken up by the cells and localizes at the ER exit sites and ER-Golgi intermediate compartment. rHSP47 treatment increased collagen secretion, reduced collagen posttranslational modifications and intracellular collagen retention, and ameliorated general ER proteostasis, leading to improved cellular homeostasis and vitality. These positive changes were also mirrored by an increased collagen content in the OI matrix. A mutation-dependent effect was found in fibroblasts from 3 probands with collagen I mutations, for which rHSP47 was effective only in cells with the most N-terminal defect. A beneficial effect on bone mineralization was demonstrated in vivo in the zebrafish p3h1-/- OI model.
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Affiliation(s)
- Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Nadia Garibaldi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Alessandra Sala
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Francesca Tonelli
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Carla Aresi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Elisa Maffioli
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
- CIMAINA, University of Milan, Milano, Italy
| | | | - Camilla Torriani
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Italy
| | | | - Simona Villani
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Italy
| | - Antonio Rossi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Gabriella Tedeschi
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
- CIMAINA, University of Milan, Milano, Italy
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
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3
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Misof BM, Fratzl-Zelman N. Bone Quality and Mineralization and Effects of Treatment in Osteogenesis Imperfecta. Calcif Tissue Int 2024; 115:777-804. [PMID: 39231826 DOI: 10.1007/s00223-024-01263-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 07/10/2024] [Indexed: 09/06/2024]
Abstract
Osteogenesis imperfecta (OI) is a rare congenital bone dysplasia characterized by high fracture rates and broad variations in clinical manifestations ranging from mild to increasingly severe and perinatal lethal forms. The underlying mutations affect either the synthesis or processing of the type I procollagen molecule itself or proteins that are involved in the formation and mineralization of the collagen matrix. Consequently, the collagen forming cells, the osteoblasts, become broadly dysfunctional in OI. Strikingly, hypermineralized bone matrix seems to be a frequent feature in OI, despite the variability in clinical severity and mutations in the so far studied different forms of human OI. While the causes of the increased mineral content of the bone matrix are not fully understood yet, there is evidence that the descendants of the osteoblasts, the osteocytes, which play a critical role not only in bone remodeling, but also in mineralization and sensing of mechanical loads, are also highly dysregulated and might be of major importance in the pathogenesis of OI. In this review article, we firstly summarize findings of cellular abnormalities in osteoblasts and osteocytes, alterations of the organic matrix, as well as of the microstructural organization of bone. Secondly, we focus on the hypermineralization of the bone matrix in OI as observed in several different forms of human OI as well as in animal models, its measurement and potential mechanical implications and its effect on the bone mineral density measured by dual X-ray absorptiometry. Thirdly, we give an overview of established medication treatments of OI and new approaches with a focus of their known or possible effects on the bone material, particularly on bone matrix mineralization.
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Affiliation(s)
- Barbara M Misof
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
- Vienna Bone and Growth Center, Vienna, Austria
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria.
- Vienna Bone and Growth Center, Vienna, Austria.
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4
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Rummler M, Schemenz V, McCluskey S, Davydok A, Rauch F, Glorieux FH, Harrington MJ, Wagermaier W, Willie BM, Zimmermann EA. Bone matrix properties in adults with osteogenesis imperfecta are not adversely affected by setrusumab-a sclerostin neutralizing antibody. J Bone Miner Res 2024; 39:1229-1239. [PMID: 38982734 DOI: 10.1093/jbmr/zjae108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 06/04/2024] [Accepted: 06/27/2024] [Indexed: 07/11/2024]
Abstract
Osteogenesis imperfecta (OI) is a skeletal dysplasia characterized by low bone mass and frequent fractures. Children with OI are commonly treated with bisphosphonates to reduce fracture rate, but treatment options for adults are limited. In the Phase 2b ASTEROID trial, setrusumab (a sclerostin neutralizing antibody, SclAb) improved bone density and strength in adults with type I, III, and IV OI. Here, we investigate bone matrix material properties in tetracycline-labeled trans iliac biopsies from 3 groups: (1) control: individuals with no metabolic bone disease, (2) OI: individuals with OI, (3) SclAb-OI: individuals with OI after 6 mo of setrusumab treatment (as part of the ASTEROID trial). In addition to bone histomorphometry, bone mineral and matrix properties were evaluated with nanoindentation, Raman spectroscopy, second harmonic generation imaging, quantitative backscatter electron imaging, and small-angle X-ray scattering. Spatial locations of fluorochrome labels were identified to differentiate inter-label bone of the same tissue age and intra-cortical bone. No difference in collagen orientation was found between the groups. The bone mineral density distribution and analysis of Raman spectra indicate that OI groups have greater mean mineralization, greater relative mineral content, and lower crystallinity than the control group, which was not altered by SclAb treatment. Finally, a lower modulus and hardness were measured in the inter-label bone of the OI-SclAb group compared to the OI group. Previous studies suggest that even though bone from OI has a higher mineral content, the extracellular matrix (ECM) has comparable mechanical properties. Therefore, fragility in OI may stem from contributions from other yet unexplored aspects of bone organization at higher length scales. We conclude that SclAb treatment leads to increased bone mass while not adversely affecting bone matrix properties in individuals with OI.
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Affiliation(s)
- Maximilian Rummler
- Research Centre, Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada
- Department of Experimental Surgery, McGill University, Montreal, QC H3A 0G4, Canada
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam 14476, Germany
| | - Victoria Schemenz
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam 14476, Germany
- Department for Operative, Preventive and Pediatric Dentistry, Centrum für Zahn-, Mund- und Kieferheilkunde, Charité - Universitätsmedizin, Berlin 14197, Germany
| | - Samantha McCluskey
- Research Centre, Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
| | - Anton Davydok
- Institute of Material Physics, Helmholtz Zentrum Hereon, Hamburg 22607, Germany
| | - Frank Rauch
- Research Centre, Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada
- Department of Pediatrics, McGill University, Montreal, QC H3A 0G4, Canada
| | - Francis H Glorieux
- Research Centre, Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada
- Department of Pediatrics, McGill University, Montreal, QC H3A 0G4, Canada
| | | | - Wolfgang Wagermaier
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam 14476, Germany
| | - Bettina M Willie
- Research Centre, Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada
- Department of Experimental Surgery, McGill University, Montreal, QC H3A 0G4, Canada
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
| | - Elizabeth A Zimmermann
- Research Centre, Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
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5
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Sung HH, Kwon HH, Stephan C, Reynolds SM, Dai Z, Van der Kraan PM, Caird MS, Blaney Davidson EN, Kozloff KM. Sclerostin antibody enhances implant osseointegration in bone with Col1a1 mutation. Bone 2024; 186:117167. [PMID: 38876270 PMCID: PMC11243590 DOI: 10.1016/j.bone.2024.117167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/06/2024] [Accepted: 06/10/2024] [Indexed: 06/16/2024]
Abstract
We evaluated the potential of sclerostin antibody (SclAb) therapy to enhance osseointegration of dental and orthopaedic implants in a mouse model (Brtl/+) mimicking moderate to severe Osteogenesis Imperfecta (OI). To address the challenges in achieving stable implant integration in compromised bone conditions, our aim was to determine the effectiveness of sclerostin antibody (SclAb) at improving bone-to-implant contact and implant fixation strength. Utilizing a combination of micro-computed tomography, mechanical push-in testing, immunohistochemistry, and Western blot analysis, we observed that SclAb treatment significantly enhances bone volume fraction (BV/TV) and bone-implant contact (BIC) in Brtl/+ mice, suggesting a normalization of bone structure toward WT levels. Despite variations in implant survival rates between the maxilla and tibia, SclAb treatment consistently improved implant stability and resistance to mechanical forces, highlighting its potential to overcome the inherent challenges of OI in dental and orthopaedic implant integration. These results suggest that SclAb could be a valuable therapeutic approach for enhancing implant success in compromised bone conditions.
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Affiliation(s)
- Hsiao H Sung
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, MI, USA; Experimental Rheumatology, Department of Rheumatology, Radboud Medical Centre, Nijmegen, the Netherlands
| | - Hanna H Kwon
- Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Chris Stephan
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Skylar M Reynolds
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Zongrui Dai
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Peter M Van der Kraan
- Experimental Rheumatology, Department of Rheumatology, Radboud Medical Centre, Nijmegen, the Netherlands
| | - Michelle S Caird
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | | | - Kenneth M Kozloff
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.
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Xiaohui T, Wang L, Yang X, Jiang H, Zhang N, Zhang H, Li D, Li X, Zhang Y, Wang S, Zhong C, Yu S, Ren M, Sun M, Li N, Chen T, Ma Y, Li F, Liu J, Yu Y, Yue H, Zhang Z, Zhang G. Sclerostin inhibition in rare bone diseases: Molecular understanding and therapeutic perspectives. J Orthop Translat 2024; 47:39-49. [PMID: 39007037 PMCID: PMC11245887 DOI: 10.1016/j.jot.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 04/09/2024] [Accepted: 05/09/2024] [Indexed: 07/16/2024] Open
Abstract
Sclerostin emerges as a novel target for bone anabolic therapy in bone diseases. Osteogenesis imperfecta (OI) and X-linked hypophosphatemia (XLH) are rare bone diseases in which therapeutic potential of sclerostin inhibition cannot be ignored. In OI, genetic/pharmacologic sclerostin inhibition promoted bone formation of mice, but responses varied by genotype and age. Serum sclerostin levels were higher in young OI-I patients, while lower in adult OI-I/III/IV. It's worth investigating whether therapeutic response of OI to sclerostin inhibition could be clinically predicted by genotype and age. In XLH, preclinical/clinical data suggested factors other than identified FGF23 contributing to XLH. Higher levels of circulating sclerostin were detected in XLH. Sclerostin inhibition promoted bone formation in Hyp mice, while restored phosphate homeostasis in age-/gender-dependent manner. The role of sclerostin in regulating phosphate metabolism deserves investigation. Sclerostin/FGF23 levels of XLH patients with/without response to FGF23-antibody warrants study to develop precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy. Notably, OI patients were associated with cardiovascular abnormalities, so were XLH patients receiving conventional therapy. Targeting sclerostin loop3 promoted bone formation without cardiovascular risks. Further, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety. The Translational Potential of this Article. Preclinical data on the molecular understanding of sclerostin inhibition in OI and therapeutic efficacy in mouse models of different genotypes, as well as clinical data on serum sclerostin levels in patients with different phenotypes of OI, were reviewed and discussed. Translationally, it would facilitate to develop clinical prediction strategies (e.g. based on genotype and age, not just phenotype) for OI patients responsive to sclerostin inhibition. Both preclinical and clinical data suggested sclerostin as another factor contributing to XLH, in addition to the identified FGF23. The molecular understanding and therapeutic effects of sclerostin inhibition on both promoting bone anabolism and improving phosphate homostasis in Hyp mice were reviewed and discussed. Translationaly, it would facilitate the development of precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy for the treatment of XLH. Cardiovascular risk could not be ruled out during sclerostin inhibition treatment, especially for OI and XLH patients with cardiovascular diseases history and cardiovascular abnormalities. Studies on the role of sclerostin in inhiting bone formation and protecting cardiovascular system were reviewed and discussed. Translationaly, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.
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Affiliation(s)
- Tao Xiaohui
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Luyao Wang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Xin Yang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Hewen Jiang
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ning Zhang
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Huarui Zhang
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Dijie Li
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Xiaofei Li
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yihao Zhang
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Shenghang Wang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Chuanxin Zhong
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Sifan Yu
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Meishen Ren
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Meiheng Sun
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Nanxi Li
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Tienan Chen
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yuan Ma
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Fangfei Li
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Jin Liu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yuanyuan Yu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Hua Yue
- Shanghai Clinical Research Center of Bone Diseases, Department of Osteoporosis and Bone Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Zhenlin Zhang
- Shanghai Clinical Research Center of Bone Diseases, Department of Osteoporosis and Bone Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
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7
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Dinulescu A, Păsărică AS, Carp M, Dușcă A, Dijmărescu I, Pavelescu ML, Păcurar D, Ulici A. New Perspectives of Therapies in Osteogenesis Imperfecta-A Literature Review. J Clin Med 2024; 13:1065. [PMID: 38398378 PMCID: PMC10888533 DOI: 10.3390/jcm13041065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/26/2024] [Accepted: 01/31/2024] [Indexed: 02/25/2024] Open
Abstract
(1) Background: Osteogenesis imperfecta (OI) is a rare skeletal dysplasia characterized as a heterogeneous disorder group with well-defined phenotypic and genetic features that share uncommon bone fragility. The current treatment options, medical and orthopedic, are limited and not efficient enough to improve the low bone density, bone fragility, growth, and mobility of the affected individuals, creating the need for alternative therapeutic agents. (2) Methods: We searched the medical database to find papers regarding treatments for OI other than conventional ones. We included 45 publications. (3) Results: In reviewing the literature, eight new potential therapies for OI were identified, proving promising results in cells and animal models or in human practice, but further research is still needed. Bone marrow transplantation is a promising therapy in mice, adults, and children, decreasing the fracture rate with a beneficial effect on structural bone proprieties. Anti-RANKL antibodies generated controversial results related to the therapy schedule, from no change in the fracture rate to improvement in the bone mineral density resorption markers and bone formation, but with adverse effects related to hypercalcemia. Sclerostin inhibitors in murine models demonstrated an increase in the bone formation rate and trabecular cortical bone mass, and a few human studies showed an increase in biomarkers and BMD and the downregulation of resorption markers. Recombinant human parathormone and TGF-β generated good results in human studies by increasing BMD, depending on the type of OI. Gene therapy, 4-phenylbutiric acid, and inhibition of eIF2α phosphatase enzymes have only been studied in cell cultures and animal models, with promising results. (4) Conclusions: This paper focuses on eight potential therapies for OI, but there is not yet enough data for a new, generally accepted treatment. Most of them showed promising results, but further research is needed, especially in the pediatric field.
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Affiliation(s)
- Alexandru Dinulescu
- Departament of Pediatrics and Department of Pediatric Orthopedics, “Carol Davila“ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.D.); (M.C.); (A.D.); (I.D.); (M.L.P.); (A.U.)
- Departament of Pediatrics and Department of Pediatric Orthopedics, Emergency Hospital for Children ‘’Grigore Alexandrescu’’, 011743 Bucharest, Romania;
| | - Alexandru-Sorin Păsărică
- Departament of Pediatrics and Department of Pediatric Orthopedics, Emergency Hospital for Children ‘’Grigore Alexandrescu’’, 011743 Bucharest, Romania;
| | - Mădălina Carp
- Departament of Pediatrics and Department of Pediatric Orthopedics, “Carol Davila“ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.D.); (M.C.); (A.D.); (I.D.); (M.L.P.); (A.U.)
- Departament of Pediatrics and Department of Pediatric Orthopedics, Emergency Hospital for Children ‘’Grigore Alexandrescu’’, 011743 Bucharest, Romania;
| | - Andrei Dușcă
- Departament of Pediatrics and Department of Pediatric Orthopedics, “Carol Davila“ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.D.); (M.C.); (A.D.); (I.D.); (M.L.P.); (A.U.)
- Departament of Pediatrics and Department of Pediatric Orthopedics, Emergency Hospital for Children ‘’Grigore Alexandrescu’’, 011743 Bucharest, Romania;
| | - Irina Dijmărescu
- Departament of Pediatrics and Department of Pediatric Orthopedics, “Carol Davila“ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.D.); (M.C.); (A.D.); (I.D.); (M.L.P.); (A.U.)
- Departament of Pediatrics and Department of Pediatric Orthopedics, Emergency Hospital for Children ‘’Grigore Alexandrescu’’, 011743 Bucharest, Romania;
| | - Mirela Luminița Pavelescu
- Departament of Pediatrics and Department of Pediatric Orthopedics, “Carol Davila“ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.D.); (M.C.); (A.D.); (I.D.); (M.L.P.); (A.U.)
- Departament of Pediatrics and Department of Pediatric Orthopedics, Emergency Hospital for Children ‘’Grigore Alexandrescu’’, 011743 Bucharest, Romania;
| | - Daniela Păcurar
- Departament of Pediatrics and Department of Pediatric Orthopedics, “Carol Davila“ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.D.); (M.C.); (A.D.); (I.D.); (M.L.P.); (A.U.)
- Departament of Pediatrics and Department of Pediatric Orthopedics, Emergency Hospital for Children ‘’Grigore Alexandrescu’’, 011743 Bucharest, Romania;
| | - Alexandru Ulici
- Departament of Pediatrics and Department of Pediatric Orthopedics, “Carol Davila“ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.D.); (M.C.); (A.D.); (I.D.); (M.L.P.); (A.U.)
- Departament of Pediatrics and Department of Pediatric Orthopedics, Emergency Hospital for Children ‘’Grigore Alexandrescu’’, 011743 Bucharest, Romania;
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8
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Sung HH, Spresser WJ, Hoffmann JP, Dai Z, Van der Kraan PM, Caird MS, Davidson EB, Kozloff KM. Collagen mutation and age contribute to differential craniofacial phenotypes in mouse models of osteogenesis imperfecta. JBMR Plus 2024; 8:ziad004. [PMID: 38690127 PMCID: PMC11059998 DOI: 10.1093/jbmrpl/ziad004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/23/2023] [Accepted: 11/01/2023] [Indexed: 05/02/2024] Open
Abstract
Craniofacial and dentoalveolar abnormalities are present in all types of osteogenesis imperfecta (OI). Mouse models of the disorder are critical to understand these abnormalities and underlying OI pathogenesis. Previous studies on severely affected OI mice report a broad spectrum of craniofacial phenotypes, exhibiting some similarities to the human disorder. The Brtl/+ and G610c/+ are moderately severe and mild-type IV OI, respectively. Little is known about the aging effects on the craniofacial bones of these models and their homology to human OI. This study aimed to analyze the Brtl/+ and G610c/+ craniofacial morphometries during aging to establish suitability for further OI craniofacial bone intervention studies. We performed morphological measurements on the micro-CT-scanned heads of 3-wk-old, 3-mo-old, and 6-mo-old female Brtl/+ and G610c/+ mice. We observed that Brtl/+ skulls are shorter in length than WT (P < .05), whereas G610c/+ skulls are similar in length to their WT counterparts. The Brtl/+ mice exhibit alveolar bone with a porotic-like appearance that is not observed in G610c/+. As they age, Brtl/+ mice show severe bone resorption in both the maxilla and mandible (P < .05). By contrast, G610c/+ mice experience mandibular resorption consistently across all ages, but maxillary resorption is only evident at 6 mo (P < .05). Western blot shows high osteoclastic activities in the Brtl/+ maxilla. Both models exhibit delayed pre-functional eruptions of the third molars (P < .05), which are similar to those observed in some bisphosphonate-treated OI subjects. Our study shows that the Brtl/+ and G610c/+ mice display clear features found in type IV OI patients; both show age-related changes in the craniofacial growth phenotype. Therefore, understanding the craniofacial features of these models and how they age will allow us to select the most accurate mouse model, mouse age, and bone structure for the specific craniofacial bone treatment of differing OI groups.
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Affiliation(s)
- Hsiao H Sung
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI 48109, United States
- Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, MI 48109, United States
- Experimental Rheumatology, Department of Rheumatology, Radboud Medical Centre, Nijmegen, The Netherlands, 6525 GA
| | - Wyatt J Spresser
- Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, MI 48109, United States
| | - Joseph P Hoffmann
- Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, MI 48109, United States
| | - Zongrui Dai
- Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, United States
| | - Peter M Van der Kraan
- Experimental Rheumatology, Department of Rheumatology, Radboud Medical Centre, Nijmegen, The Netherlands, 6525 GA
| | - Michelle S Caird
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI 48109, United States
| | - Esmeralda Blaney Davidson
- Experimental Rheumatology, Department of Rheumatology, Radboud Medical Centre, Nijmegen, The Netherlands, 6525 GA
| | - Kenneth M Kozloff
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI 48109, United States
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Indermaur M, Casari D, Kochetkova T, Willie BM, Michler J, Schwiedrzik J, Zysset P. Tensile Mechanical Properties of Dry Cortical Bone Extracellular Matrix: A Comparison Among Two Osteogenesis Imperfecta and One Healthy Control Iliac Crest Biopsies. JBMR Plus 2023; 7:e10826. [PMID: 38130764 PMCID: PMC10731133 DOI: 10.1002/jbm4.10826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 08/22/2023] [Accepted: 09/14/2023] [Indexed: 12/23/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a genetic, collagen-related bone disease that increases the incidence of bone fractures. Still, the origin of this brittle mechanical behavior remains unclear. The extracellular matrix (ECM) of OI bone exhibits a higher degree of bone mineralization (DBM), whereas compressive mechanical properties at the ECM level do not appear to be inferior to healthy bone. However, it is unknown if collagen defects alter ECM tensile properties. This study aims to quantify the tensile properties of healthy and OI bone ECM. In three transiliac biopsies (healthy n = 1, OI type I n = 1, OI type III n = 1), 23 microtensile specimens (gauge dimensions 10 × 5 × 2 μm3) were manufactured and loaded quasi-statically under tension in vacuum condition. The resulting loading modulus and ultimate strength were extracted. Interestingly, tensile properties in OI bone ECM were not inferior compared to controls. All specimens revealed a brittle failure behavior. Fracture surfaces were graded according to their mineralized collagen fibers (MCF) orientation into axial, mixed, and transversal fracture surface types (FST). Furthermore, tissue mineral density (TMD) of the biopsy cortices was extracted from micro-computed tomogra[hy (μCT) images. Both FST and TMD are significant factors to predict loading modulus and ultimate strength with an adjusted R 2 of 0.556 (p = 2.65e-05) and 0.46 (p = 2.2e-04), respectively. The influence of MCF orientation and DBM on the mechanical properties of the neighboring ECM was further verified with quantitative polarized Raman spectroscopy (qPRS) and site-matched nanoindentation. MCF orientation and DBM were extracted from the qPRS spectrum, and a second mechanical model was developed to predict the indentation modulus with MCF orientation and DBM (R 2 = 67.4%, p = 7.73e-07). The tensile mechanical properties of the cortical bone ECM of two OI iliac crest biopsies are not lower than the one from a healthy and are primarily dependent on MCF orientation and DBM. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Michael Indermaur
- ARTORG Center for Biomedical EngineeringUniversity of BernBernSwitzerland
| | - Daniele Casari
- ARTORG Center for Biomedical EngineeringUniversity of BernBernSwitzerland
- Swiss Federal Laboratories for Material Science and TechnologyThunSwitzerland
| | - Tatiana Kochetkova
- Swiss Federal Laboratories for Material Science and TechnologyThunSwitzerland
| | - Bettina M. Willie
- Research Centre, Shriners Hospital for Children‐Canada, Department of Pediatric SurgeryMcGill UniversityMontrealQCCanada
| | - Johann Michler
- Swiss Federal Laboratories for Material Science and TechnologyThunSwitzerland
| | - Jakob Schwiedrzik
- Swiss Federal Laboratories for Material Science and TechnologyThunSwitzerland
| | - Philippe Zysset
- ARTORG Center for Biomedical EngineeringUniversity of BernBernSwitzerland
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10
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Marulanda J, Tauer JT, Boraschi-Diaz I, Bardai G, Rauch F. Effect of sclerostin inactivation in a mouse model of severe dominant osteogenesis imperfecta. Sci Rep 2023; 13:5010. [PMID: 36973504 PMCID: PMC10043013 DOI: 10.1038/s41598-023-32221-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a rare bone disease that is associated with fractures and low bone mass. Sclerostin inhibition is being evaluated as a potential approach to increase bone mass in OI. We had previously found that in Col1a1Jrt/+ mice, a model of severe OI, treatment with an anti-sclerostin antibody had a minor effect on the skeletal phenotype. In the present study, we assessed the effect of genetic sclerostin inactivation in the Col1a1Jrt/+ mouse. We crossed Col1a1Jrt/+ mice with Sost knockout mice to generate Sost-deficient Col1a1Jrt/+ mice and assessed differences between Col1a1Jrt/+ mice with homozygous Sost deficiency and Col1a1Jrt/+ mice with heterozygous Sost deficiency. We found that Col1a1Jrt/+ mice with homozygous Sost deficiency had higher body mass, femur length, trabecular bone volume, cortical thickness and periosteal diameter as well as increased biomechanical parameters of bone strength. Differences between genotypes were larger at the age of 14 weeks than at 8 weeks of age. Transcriptome analysis of RNA extracted from the tibial diaphysis revealed only 5 differentially regulated genes. Thus, genetic inactivation of Sost increased bone mass and strength in the Col1a1Jrt/+ mouse. It appears from these observations that the degree of Sost suppression that is required for eliciting a beneficial response can vary with the genetic cause of OI.
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Affiliation(s)
- Juliana Marulanda
- Shriners Hospital for Children, 1003 Decarie, Montreal, QC, H4A 0A9, Canada
- Department of Pediatrics, McGill University, Montreal, QC, Canada
| | - Josephine T Tauer
- Shriners Hospital for Children, 1003 Decarie, Montreal, QC, H4A 0A9, Canada
| | | | - Ghalib Bardai
- Shriners Hospital for Children, 1003 Decarie, Montreal, QC, H4A 0A9, Canada
| | - Frank Rauch
- Shriners Hospital for Children, 1003 Decarie, Montreal, QC, H4A 0A9, Canada.
- Department of Pediatrics, McGill University, Montreal, QC, Canada.
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11
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Marini F, Giusti F, Palmini G, Brandi ML. Role of Wnt signaling and sclerostin in bone and as therapeutic targets in skeletal disorders. Osteoporos Int 2023; 34:213-238. [PMID: 35982318 DOI: 10.1007/s00198-022-06523-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 08/01/2022] [Indexed: 01/24/2023]
Abstract
UNLABELLED Wnt signaling and its bone tissue-specific inhibitor sclerostin are key regulators of bone homeostasis. The therapeutic potential of anti-sclerostin antibodies (Scl-Abs), for bone mass recovery and fragility fracture prevention in low bone mass phenotypes, has been supported by animal studies. The Scl-Ab romosozumab is currently used for osteoporosis treatment. INTRODUCTION Wnt signaling is a key regulator of skeletal development and homeostasis; germinal mutations affecting genes encoding components, inhibitors, and enhancers of the Wnt pathways were shown to be responsible for the development of rare congenital metabolic bone disorders. Sclerostin is a bone tissue-specific inhibitor of the Wnt/β-catenin pathway, secreted by osteocytes, negatively regulating osteogenic differentiation and bone formation, and promoting osteoclastogenesis and bone resorption. PURPOSE AND METHODS Here, we reviewed current knowledge on the role of sclerostin and Wnt pathways in bone metabolism and skeletal disorders, and on the state of the art of therapy with sclerostin-neutralizing antibodies in low-bone-mass diseases. RESULTS Various in vivo studies on animal models of human low-bone-mass diseases showed that targeting sclerostin to recover bone mass, restore bone strength, and prevent fragility fracture was safe and effective in osteoporosis, osteogenesis imperfecta, and osteoporosis pseudoglioma. Currently, only treatment with romosozumab, a humanized monoclonal anti-sclerostin antibody, has been approved in human clinical practice for the treatment of osteoporosis, showing a valuable capability to increase BMD at various skeletal sites and reduce the occurrence of new vertebral, non-vertebral, and hip fragility fractures in treated male and female osteoporotic patients. CONCLUSIONS Preclinical studies demonstrated safety and efficacy of therapy with anti-sclerostin monoclonal antibodies in the preservation/restoration of bone mass and prevention of fragility fractures in low-bone-mass clinical phenotypes, other than osteoporosis, to be validated by clinical studies for their approved translation into prevalent clinical practice.
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Affiliation(s)
- Francesca Marini
- Fondazione FIRMO Onlus, Italian Foundation for the Research on Bone Diseases, Via San Gallo 123, 50129, Florence, Italy
| | - Francesca Giusti
- Donatello Bone Clinic, Villa Donatello Hospital, Sesto Fiorentino, Florence, Italy
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Gaia Palmini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Maria Luisa Brandi
- Fondazione FIRMO Onlus, Italian Foundation for the Research on Bone Diseases, Via San Gallo 123, 50129, Florence, Italy.
- Donatello Bone Clinic, Villa Donatello Hospital, Sesto Fiorentino, Florence, Italy.
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Alcorta-Sevillano N, Infante A, Macías I, Rodríguez CI. Murine Animal Models in Osteogenesis Imperfecta: The Quest for Improving the Quality of Life. Int J Mol Sci 2022; 24:ijms24010184. [PMID: 36613624 PMCID: PMC9820162 DOI: 10.3390/ijms24010184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/25/2022] Open
Abstract
Osteogenesis imperfecta is a rare genetic disorder characterized by bone fragility, due to alterations in the type I collagen molecule. It is a very heterogeneous disease, both genetically and phenotypically, with a high variability of clinical phenotypes, ranging from mild to severe forms, the most extreme cases being perinatal lethal. There is no curative treatment for OI, and so great efforts are being made in order to develop effective therapies. In these attempts, the in vivo preclinical studies are of paramount importance; therefore, serious analysis is required to choose the right murine OI model able to emulate as closely as possible the disease of the target OI population. In this review, we summarize the features of OI murine models that have been used for preclinical studies until today, together with recently developed new murine models. The bone parameters that are usually evaluated in order to determine the relevance of new developing therapies are exposed, and finally, current and innovative therapeutic strategies attempts considered in murine OI models, along with their mechanism of action, are reviewed. This review aims to summarize the in vivo studies developed in murine models available in the field of OI to date, in order to help the scientific community choose the most accurate OI murine model when developing new therapeutic strategies capable of improving the quality of life.
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Affiliation(s)
- Natividad Alcorta-Sevillano
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
- Department of Cell Biology and Histology, University of Basque Country UPV/EHU, 48940 Leioa, Spain
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
| | - Iratxe Macías
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
| | - Clara I. Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
- Correspondence:
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Lv F, Cai X, Ji L. An Update on Animal Models of Osteogenesis Imperfecta. Calcif Tissue Int 2022; 111:345-366. [PMID: 35767009 DOI: 10.1007/s00223-022-00998-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 06/01/2022] [Indexed: 11/02/2022]
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous disorder characterized by bone fragility, multiple fractures, bone deformity, and short stature. In recent years, the application of next generation sequencing has triggered the discovery of many new genetic causes for OI. Until now, more than 25 genetic causes of OI and closely related disorders have been identified. However, the mechanisms of many genes on skeletal fragility in OI are not entirely clear. Animal models of OI could help to understand the cellular, signaling, and metabolic mechanisms contributing to the disease, and how targeting these pathways can provide therapeutic targets. To date, a lot of animal models, mainly mice and zebrafish, have been described with defects in 19 OI-associated genes. In this review, we summarize the known genetic causes and animal models that recapitulate OI with a main focus on engineered mouse and zebrafish models. Additionally, we briefly discuss domestic animals with naturally occurring OI phenotypes. Knowledge of the specific molecular basis of OI will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches.
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Affiliation(s)
- Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Xizhimen South Street No.11, Beijing, 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Xizhimen South Street No.11, Beijing, 100044, China.
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Xizhimen South Street No.11, Beijing, 100044, China.
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Scheiber AL, Wilkinson KJ, Suzuki A, Enomoto-Iwamoto M, Kaito T, Cheah KS, Iwamoto M, Leikin S, Otsuru S. 4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts. JCI Insight 2022; 7:149636. [PMID: 34990412 PMCID: PMC8855815 DOI: 10.1172/jci.insight.149636] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 12/21/2021] [Indexed: 11/17/2022] Open
Abstract
Short stature is a major skeletal phenotype in osteogenesis imperfecta (OI), a genetic disorder mainly caused by mutations in genes encoding type I collagen. However, the underlying mechanism is poorly understood, and no effective treatment is available. In OI mice that carry a G610C mutation in COL1A2, we previously found that mature hypertrophic chondrocytes (HCs) are exposed to cell stress due to accumulation of misfolded mutant type I procollagen in the endoplasmic reticulum (ER). By fate mapping analysis of HCs in G610C OI mice, we found that HCs stagnate in the growth plate, inhibiting translocation of HC descendants to the trabecular area and their differentiation to osteoblasts. Treatment with 4-phenylbutyric acid (4PBA), a chemical chaperone, restored HC ER structure and rescued this inhibition, resulting in enhanced longitudinal bone growth in G610C OI mice. Interestingly, the effects of 4PBA on ER dilation were limited in osteoblasts, and the bone fragility was not ameliorated. These results highlight the importance of targeting HCs to treat growth deficiency in OI. Our findings demonstrate that HC dysfunction induced by ER disruption plays a critical role in the pathogenesis of OI growth deficiency, which lays the foundation for developing new therapies for OI.
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Affiliation(s)
- Amanda L Scheiber
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
| | - Kevin J Wilkinson
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
| | - Akiko Suzuki
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
| | - Motomi Enomoto-Iwamoto
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
| | - Takashi Kaito
- Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Kathryn Se Cheah
- School of Biomedical Sciences, University of Hong Kong, Hong Kong, China
| | - Masahiro Iwamoto
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
| | - Sergey Leikin
- Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health & Human Developme, Bethesda, United States of America
| | - Satoru Otsuru
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
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15
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Liu C, Bai Z, Lin J, Jiang K, Huang S, Zheng W, Chen R, Xiang Y, Wang X, Liu L. 3D printing silk-gelatin-propanediol scaffold with enhanced osteogenesis properties through p-Smad1/5/8 activated Runx2 pathway. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2021; 32:1515-1529. [PMID: 33830881 DOI: 10.1080/09205063.2021.1912977] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The application of 3 D printing technology in tissue engineering has become increasingly important. However, due to the limitations of bio-ink, there are still some remaining problems. For example, the major challenge for ideal bio-ink is to maintain stable 3 D structure and good biocompatibility in the meantime while conventional gels are week and nearly unprintable. So, the development of new bio-ink material with improved rheological and mechanical properties is highly demanded to avoid compromising biocompatibility for tissue engineering. Silk fibroin (SF), a natural degradable polymer, is considered to be a proper material for the preparation of bio-inks. We used SF, gelatin, and polyols as raw materials to fabricate bio-inks and scaffolds. We evaluated the rheological properties and printability of bio-inks with a rotational rheometer and a 3 D printer. The scaffolds were prepared by crosslinking and freeze-drying technologies. The biocompatibility and osteoinductive functions of scaffolds were investigated by evaluating proliferation, osteogenic differentiation and related cell signaling of cultured MC3T3-E1 cells. The results showed that the scaffolds using SF, Gel and propanediol (PG) not only had good rheological properties and storage modulus, but also could better enhance osteogenic specific genes expression mediated by Smad1/5/8 and Runx2 pathways. What is more, morphological characterization showed that α-mem incubation could help scaffold form porous structure on its surface, which could shed a light on a new 3 D bio-printed bone repair scaffold with both naturally emerged and CAD-designed porous structure. Our findings provide a potential biomaterial for the treatment of bone tissue regeneration.
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Affiliation(s)
- Caiyun Liu
- Department of Biology and Chemistry, College of Liberal Arts and Sciences, National University of Defense Technology, Changsha, Hunan, PR China.,School of Chemistry and Biological Engineering, Changsha University of Science and Technology, Changsha, Hunan, PR China
| | - Zhenzu Bai
- Department of Biology and Chemistry, College of Liberal Arts and Sciences, National University of Defense Technology, Changsha, Hunan, PR China
| | - Jiayu Lin
- Department of Biology and Chemistry, College of Liberal Arts and Sciences, National University of Defense Technology, Changsha, Hunan, PR China
| | - Kai Jiang
- Department of Biology and Chemistry, College of Liberal Arts and Sciences, National University of Defense Technology, Changsha, Hunan, PR China
| | - Shan Huang
- Department of Biology and Chemistry, College of Liberal Arts and Sciences, National University of Defense Technology, Changsha, Hunan, PR China
| | - Weijia Zheng
- Department of Biology and Chemistry, College of Liberal Arts and Sciences, National University of Defense Technology, Changsha, Hunan, PR China
| | - Ruifen Chen
- Joint Logistic Support Force 921th Hospital, Changsha, Hunan, PR China
| | - Yang Xiang
- School of Chemistry and Biological Engineering, Changsha University of Science and Technology, Changsha, Hunan, PR China
| | - Xiaoyan Wang
- Department of Biology and Chemistry, College of Liberal Arts and Sciences, National University of Defense Technology, Changsha, Hunan, PR China
| | - Long Liu
- Department of Biology and Chemistry, College of Liberal Arts and Sciences, National University of Defense Technology, Changsha, Hunan, PR China
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Abstract
Osteogenesis imperfecta (OI) is a disease characterised by altered bone tissue material properties together with abnormal micro and macro-architecture and thus bone fragility, increased bone turnover and hyperosteocytosis. Increasingly appreciated are the soft tissue changes, sarcopenia in particular. Approaches to treatment are now multidisciplinary, with bisphosphonates having been the primary pharmacological intervention over the last 20 years. Whilst meta-analyses suggest that anti-fracture efficacy across the life course is equivocal, there is good evidence that for children bisphosphonates reduce fracture risk, increase vertebral size and improve vertebral shape, as well as improving motor function and mobility. The genetics of OI continues to provide insights into the molecular pathogenesis of the disease, although the pathophysiology is less clear. The complexity of the multi-scale interactions of bone tissue with cellular function are gradually being disentangled, but the fundamental question of why increased tissue brittleness should be associated with so many other changes is unclear; ER stress, pro-inflammatory cytokines, accelerated senesence and altered matrix component release might all contribute, but a unifying hypothesis remains elusive. New approaches to therapy are focussed on increasing bone mass, following the paradigm established by the treatment of postmenopausal osteoporosis. For adults, this brings the prospect of restoring previously lost bone - for children, particularly at the severe end of the spectrum, the possibility of further reducing fracture frequency and possibly altering growth and long term function are attractive. The alternatives that might affect tissue brittleness are autophagy enhancement (through the removal of abnormal type I collagen aggregates) and stem cell transplantation - both still at the preclinical stage of assessment. Preclinical assessment is not supportive of targeting inflammatory pathways, although understanding why TGFb signalling is increased, and whether that presents a treatment target in OI, remains to be established.
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Affiliation(s)
- Fawaz Arshad
- Academic Unit of Child Health, Sheffield Children's Hospital, Department of Oncology and Metabolism, University of Sheffield, S10 2TH, UK
| | - Nick Bishop
- Academic Unit of Child Health, Sheffield Children's Hospital, Department of Oncology and Metabolism, University of Sheffield, S10 2TH, UK.
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17
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Zhu L, Tang Y, Li XY, Keller ET, Yang J, Cho JS, Feinberg TY, Weiss SJ. Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases. Sci Transl Med 2021; 12:12/529/eaaw6143. [PMID: 32024800 DOI: 10.1126/scitranslmed.aaw6143] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 10/03/2019] [Accepted: 01/02/2020] [Indexed: 12/11/2022]
Abstract
Osteoclasts actively remodel both the mineral and proteinaceous components of bone during normal growth and development as well as pathologic states ranging from osteoporosis to bone metastasis. The cysteine proteinase cathepsin K confers osteoclasts with potent type I collagenolytic activity; however, cathepsin K-null mice, as well as cathepsin K-mutant humans, continue to remodel bone and degrade collagen by as-yet-undefined effectors. Here, we identify a cathepsin K-independent collagenolytic system in osteoclasts that is composed of a functionally redundant network of the secreted matrix metalloproteinase MMP9 and the membrane-anchored matrix metalloproteinase MMP14. Unexpectedly, whereas deleting either of the proteinases individually leaves bone resorption intact, dual targeting of Mmp9 and Mmp14 inhibited the resorptive activity of mouse osteoclasts in vitro and in vivo and human osteoclasts in vitro. In vivo, Mmp9/Mmp14 conditional double-knockout mice exhibited marked increases in bone density and displayed a highly protected status against either parathyroid hormone- or ovariectomy-induced pathologic bone loss. Together, these studies characterize a collagenolytic system operative in mouse and human osteoclasts and identify the MMP9/MMP14 axis as a potential target for therapeutic interventions for bone-wasting disease states.
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Affiliation(s)
- Lingxin Zhu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China. .,Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.,Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yi Tang
- Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.,Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xiao-Yan Li
- Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.,Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Evan T Keller
- Department of Pathology, Department of Urology and the Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jingwen Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China.,School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jung-Sun Cho
- Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.,Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Tamar Y Feinberg
- Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.,Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Stephen J Weiss
- Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. .,Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
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18
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Tauer JT, Boraschi-Diaz I, Al Rifai O, Rauch F, Ferron M, Komarova SV. Male but not female mice with severe osteogenesis imperfecta are partially protected from high-fat diet-induced obesity. Mol Genet Metab 2021; 133:211-221. [PMID: 33814269 DOI: 10.1016/j.ymgme.2021.03.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/16/2021] [Accepted: 03/24/2021] [Indexed: 01/07/2023]
Abstract
Previously we have shown that young mice with a dominant severe form of osteogenesis imperfecta (OI), caused by mutated collagen type I, exhibit an altered glucose/insulin metabolism and energy expenditure along with elevated levels of osteocalcin, a bone-derived hormone involved in the regulation of whole-body metabolism. This study aimed to examine the long-term effects of a western diet in these OI mice. Male and female OI mice and wild type littermates (WT) were fed a high-fat diet (HFD) or a matched low-fat diet (LFD) for 26 weeks. HFD-induced obesity was observed in male and female WT and female OI mice, but not in male OI mice. HFD-fed WT and OI mice of both sexes developed hyperglycemia and glucose intolerance, but the degree of glucose intolerance was significantly lower in male and female OI mice compared to sex- and diet-matched WT mice. Indirect calorimetry revealed increased movement of male OI mice on HFD compared to LFD and, while HFD lowered energy expenditure in WT mice, energy expenditure was not changed in OI mice. Further, HFD-fed male OI mice demonstrated a diet-induced increased expression of the thermogenesis genes, Ucp1 and Pgc1α, in brown adipose tissue. On LFD, total and Gla-13 osteocalcin levels were similar in 30-week-old WT and OI mice, but on HFD, both were significantly higher in OI mice than WT. Thus, male OI mice respond to HFD with increased movement, energy expenditure, brown adipose tissue thermogenesis, and higher levels of osteocalcin, resulting in partial protection against HFD-induced obesity.
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Affiliation(s)
- Josephine T Tauer
- Faculty of Dentistry, McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children-Canada, Montreal, Quebec, Canada.
| | - Iris Boraschi-Diaz
- Shriners Hospital for Children-Canada, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Omar Al Rifai
- Unité de Recherche en Physiologie Moléculaire, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada
| | - Frank Rauch
- Shriners Hospital for Children-Canada, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Mathieu Ferron
- Unité de Recherche en Physiologie Moléculaire, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada; Départements de Médecine et de Biochimie et Médecine Moléculaire, Université de Montréal, Montreal, Quebec, Canada
| | - Svetlana V Komarova
- Faculty of Dentistry, McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children-Canada, Montreal, Quebec, Canada
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19
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Zaripova AR, Khusainova RI. Modern classification and molecular-genetic aspects of osteogenesis imperfecta. Vavilovskii Zhurnal Genet Selektsii 2021; 24:219-227. [PMID: 33659802 PMCID: PMC7716575 DOI: 10.18699/vj20.614] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Osteogenesis imperfecta (imperfect osteogenesis in the Russian literature) is the most common hereditary form of bone fragility, it is a genetically and clinically heterogeneous disease with a wide range of clinical severity, often leading to disability from early childhood. It is based on genetic disorders leading to a violation of the structure of bone tissue, which leads to frequent fractures, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, renal impairment, hearing loss. Osteogenesis imperfecta occurs in both men and women, the disease is inherited in both autosomal dominant and autosomal recessive types, there are sporadic cases of the disease due to de novo mutations, as well as X-linked forms. The term "osteogenesis imperfecta" was coined by W. Vrolick in the 1840s. The first classification of the disease was made in 1979 and has been repeatedly reviewed due to the identification of the molecular cause of the disease and the discovery of new mechanisms for the development of osteogenesis imperfecta. In the early 1980s, mutations in two genes of collagen type I (COL1A1 and COL1A2) were first associated with an autosomal dominant inheritance type of osteogenesis imperfecta. Since then, 18 more genes have been identified whose products are involved in the formation and mineralization of bone tissue. The degree of genetic heterogeneity of the disease has not yet been determined, researchers continue to identify new genes involved in its pathogenesis, the number of which has reached 20. In the last decade, it has become known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes, encoding proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells, cause imperfect osteogenesis. A large number of causative genes complicated the classical classification of the disease and, due to new advances in the molecular basis of the disease, the classification of the disease is constantly being improved. In this review, we systematized and summarized information on the results of studies in the field of clinical and genetic aspects of osteogenesis imperfecta and reflected the current state of the classification criteria for diagnosing the disease.
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Affiliation(s)
- A R Zaripova
- Institute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia
| | - R I Khusainova
- Institute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia Republican Medical-Genetic Center, Ufa, Russia
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20
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Osteoporosis Treatment with Anti-Sclerostin Antibodies-Mechanisms of Action and Clinical Application. J Clin Med 2021; 10:jcm10040787. [PMID: 33669283 PMCID: PMC7920044 DOI: 10.3390/jcm10040787] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 01/30/2021] [Accepted: 02/13/2021] [Indexed: 12/13/2022] Open
Abstract
Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures and significant long-term disability. Although both anti-resorptive treatments and osteoanabolic drugs, such as parathyroid hormone analogues, are effective in fracture prevention, limitations exist due to lack of compliance or contraindications to these drugs. Thus, there is a need for novel potent therapies, especially for patients at high fracture risk. Romosozumab is a monoclonal antibody against sclerostin with a dual mode of action. It enhances bone formation and simultaneously suppresses bone resorption, resulting in a large anabolic window. In this opinion-based narrative review, we highlight the role of sclerostin as a critical regulator of bone mass and present human diseases of sclerostin deficiency as well as preclinical models of genetically modified sclerostin expression, which led to the development of anti-sclerostin antibodies. We review clinical studies of romosozumab in terms of bone mass accrual and anti-fracture activity in the setting of postmenopausal and male osteoporosis, present sequential treatment regimens, and discuss its safety profile and possible limitations in its use. Moreover, an outlook comprising future translational applications of anti-sclerostin antibodies in diseases other than osteoporosis is given, highlighting the clinical significance and future scopes of Wnt signaling in these settings.
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21
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New therapeutic options for bone diseases. Wien Med Wochenschr 2021; 171:120-125. [PMID: 33512621 DOI: 10.1007/s10354-020-00810-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 12/28/2020] [Indexed: 02/07/2023]
Abstract
In recent years, new treatment options for both common and rare bone diseases have become available. The sclerostin antibody romosozumab is the most recently approved drug for the therapy of postmenopausal osteoporosis. Its anabolic capacity makes it a promising treatment option for severe osteoporosis. Other sclerostin antibodies for the treatment of rare bone diseases such as osteogenesis imperfecta are currently being investigated. For rare bone diseases such as X‑linked hypophosphatemia (XLH) and hypophosphatasia (HPP), specific therapies are now also available, showing promising data in children and adults with a severe disease course. However, long-term data are needed to assess a sustained benefit for patients.
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22
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Abstract
One of the primary functions of bone is to support the skeleton by withstanding load. In the diseased state, bone's ability to perform this function is altered. Quantification of the features of bone that support its functional behavior, and how they may change with disease, is accomplished through mechanical testing. As such, mechanical testing is a useful tool for scientists studying orthopedic-related diseases. Furthermore, a common animal model used to investigate disease and its treatment is the mouse. Therefore, in this chapter we (1) describe central concepts of mechanical testing, (2) describe factors that influence the mechanical behavior of bone, and (3) describe the application of a widely used mechanical testing technique, four-point bending, to the mouse bone for characterization of its structural properties.
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23
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Etich J, Rehberg M, Eckes B, Sengle G, Semler O, Zaucke F. Signaling pathways affected by mutations causing osteogenesis imperfecta. Cell Signal 2020; 76:109789. [PMID: 32980496 DOI: 10.1016/j.cellsig.2020.109789] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 12/17/2022]
Abstract
Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility and skeletal deformity. To maintain skeletal strength and integrity, bone undergoes constant remodeling of its extracellular matrix (ECM) tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. There are at least 20 recognized OI-forms caused by mutations in the two collagen type I-encoding genes or genes implicated in collagen folding, posttranslational modifications or secretion of collagen, osteoblast differentiation and function, or bone mineralization. The underlying disease mechanisms of non-classical forms of OI that are not caused by collagen type I mutations are not yet completely understood, but an altered ECM structure as well as disturbed intracellular homeostasis seem to be the main defects. The ECM orchestrates local cell behavior in part by regulating bioavailability of signaling molecules through sequestration, release and activation during the constant bone remodeling process. Here, we provide an overview of signaling pathways that are associated with known OI-causing genes and discuss the impact of these genes on signal transduction. These pathways include WNT-, RANK/RANKL-, TGFβ-, MAPK- and integrin-mediated signaling as well as the unfolded protein response.
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Affiliation(s)
- Julia Etich
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, Frankfurt/Main, 60528, Germany.
| | - Mirko Rehberg
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany
| | - Beate Eckes
- Translational Matrix Biology, Faculty of Medicine, University of Cologne, Cologne 50931, Germany
| | - Gerhard Sengle
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne 50931, Germany; Cologne Center for Musculoskeletal Biomechanics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany
| | - Oliver Semler
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Center for Rare Diseases, University Hospital Cologne, University of Cologne, Cologne 50931, Germany
| | - Frank Zaucke
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, Frankfurt/Main, 60528, Germany
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24
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Surowiec RK, Battle LF, Schlecht SH, Wojtys EM, Caird MS, Kozloff KM. Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone. JBMR Plus 2020; 4:e10377. [PMID: 32803109 PMCID: PMC7422710 DOI: 10.1002/jbm4.10377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 05/19/2020] [Indexed: 12/31/2022] Open
Abstract
Sclerostin antibody (SclAb) therapy has been suggested as a novel therapeutic approach toward addressing the fragility phenotypic of osteogenesis imperfecta (OI). Observations of cellular and transcriptional responses to SclAb in OI have been limited to mouse models of the disorder, leaving a paucity of data on the human OI osteoblastic cellular response to the treatment. Here, we explore factors associated with response to SclAb therapy in vitro and in a novel xenograft model using OI bone tissue derived from pediatric patients. Bone isolates (approximately 2 mm3) from OI patients (OI type III, type III/IV, and type IV, n = 7; non-OI control, n = 5) were collected to media, randomly assigned to an untreated (UN), low-dose SclAb (TRL, 2.5 μg/mL), or high-dose SclAb (TRH, 25 μg/mL) group, and maintained in vitro at 37°C. Treatment occurred on days 2 and 4 and was removed on day 5 for TaqMan qPCR analysis of genes related to the Wnt pathway. A subset of bone was implanted s.c. into an athymic mouse, representing our xenograft model, and treated (25 mg/kg s.c. 2×/week for 2/4 weeks). Implanted OI bone was evaluated using μCT and histomorphometry. Expression of Wnt/Wnt-related targets varied among untreated OI bone isolates. When treated with SclAb, OI bone showed an upregulation in osteoblast and osteoblast progenitor markers, which was heterogeneous across tissue. Interestingly, the greatest magnitude of response generally corresponded to samples with low untreated expression of progenitor markers. Conversely, samples with high untreated expression of these markers showed a lower response to treatment. in vivo implanted OI bone showed a bone-forming response to SclAb via μCT, which was corroborated by histomorphometry. SclAb induced downstream Wnt targets WISP1 and TWIST1, and elicited a compensatory response in Wnt inhibitors SOST and DKK1 in OI bone with the greatest magnitude from OI cortical bone. Understanding patients' genetic, cellular, and morphological bone phenotypes may play an important role in predicting treatment response. This information may aid in clinical decision-making for pharmacological interventions designed to address fragility in OI. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Rachel K Surowiec
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMIUSA
- Department of Orthopaedic SurgeryUniversity of MichiganAnn ArborMIUSA
| | - Lauren F Battle
- Department of Orthopaedic SurgeryUniversity of MichiganAnn ArborMIUSA
| | - Stephen H Schlecht
- Department of Orthopaedic SurgeryUniversity of MichiganAnn ArborMIUSA
- Department of Mechanical EngineeringUniversity of MichiganAnn ArborMIUSA
| | - Edward M Wojtys
- Department of Orthopaedic SurgeryUniversity of MichiganAnn ArborMIUSA
| | - Michelle S Caird
- Department of Orthopaedic SurgeryUniversity of MichiganAnn ArborMIUSA
| | - Kenneth M Kozloff
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMIUSA
- Department of Orthopaedic SurgeryUniversity of MichiganAnn ArborMIUSA
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25
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Cardinal M, Dessain A, Roels T, Lafont S, Ominsky MS, Devogelaer JP, Chappard D, Mabilleau G, Ammann P, Nyssen-Behets C, Manicourt DH. Sclerostin-Antibody Treatment Decreases Fracture Rates in Axial Skeleton and Improves the Skeletal Phenotype in Growing oim/oim Mice. Calcif Tissue Int 2020; 106:494-508. [PMID: 32025752 DOI: 10.1007/s00223-019-00655-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 12/28/2019] [Indexed: 12/11/2022]
Abstract
In osteogenesis imperfecta (OI), vertebrae brittleness causes thorax deformations and leads to cardiopulmonary failure. As sclerostin-neutralizing antibodies increase bone mass and strength in animal models of osteoporosis, their administration in two murine models of severe OI enhanced the strength of vertebrae in growing female Crtap-/- mice but not in growing male Col1a1Jrt/+ mice. However, these two studies ignored the impact of antibodies on spine growth, fracture rates, and compressive mechanical properties. Here, we conducted a randomized controlled trial in oim/oim mice, an established model of human severe OI type III due to a mutation in Col1a2. Five-week-old female WT and oim/oim mice received either PBS or sclerostin antibody (Scl-Ab) for 9 weeks. Analyses included radiography, histomorphometry, pQCT, microcomputed tomography, and biomechanical testing. Though it did not modify vertebral axial growth, Scl-Ab treatment markedly reduced the fracture prevalence in the pelvis and caudal vertebrae, enhanced osteoblast activity (L4), increased cervico-sacral spine BMD, and improved the lumbosacral spine bone cross-sectional area. Scl-Ab did not impact vertebral height and body size but enhanced the cortical thickness and trabecular bone volume significantly in the two Scl-Ab groups. At lumbar vertebrae and tibial metaphysis, the absolute increase in cortical and trabecular bone mass was higher in Scl-Ab WT than in Scl-Ab oim/oim. The effects on trabecular bone mass were mainly due to changes in trabecular number at vertebrae and in trabecular thickness at metaphyses. Additionally, Scl-Ab did not restore a standard trabecular network, but improved bone compressive ultimate load with more robust effects at vertebrae than at metaphysis. Overall, Scl-Ab treatment may be beneficial for reducing vertebral fractures and spine deformities in patients with severe OI.
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Affiliation(s)
- Mickaël Cardinal
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium.
| | - Alicia Dessain
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium
| | - Thomas Roels
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium
| | - Sébastien Lafont
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium
| | - Michael S Ominsky
- Radius Health, Inc. (Formerly at Amgen Inc, Thousand Oaks, CA, USA), Waltham, MA, USA
| | - Jean-Pierre Devogelaer
- Pole of Rheumatology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Daniel Chappard
- GEROM, Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux, University of Angers, 49933, Angers, France
| | - Guillaume Mabilleau
- GEROM, Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux, University of Angers, 49933, Angers, France
| | - Patrick Ammann
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital, Geneva, Switzerland
| | - Catherine Nyssen-Behets
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium
| | - Daniel H Manicourt
- Pole of Rheumatology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
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26
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Varga P, Willie BM, Stephan C, Kozloff KM, Zysset PK. Finite element analysis of bone strength in osteogenesis imperfecta. Bone 2020; 133:115250. [PMID: 31981754 PMCID: PMC7383936 DOI: 10.1016/j.bone.2020.115250] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 01/17/2020] [Accepted: 01/19/2020] [Indexed: 12/11/2022]
Abstract
As a dedicated experimentalist, John Currey praised the high potential of finite element (FE) analysis but also recognized its critical limitations. The application of the FE methodology to bone tissue is reviewed in the light of his enthusiastic and colorful statements. In the past decades, FE analysis contributed substantially to the understanding of structure-function properties in the hierarchical organization of bone and to the simulation of bone adaptation. The systematic experimental validation of FE analysis of bone strength in anatomical locations at risk of fracture led to its application in clinical studies to evaluate efficacy of antiresorptive or anabolic treatment of bone fragility. Beyond the successful analyses of healthy or osteoporotic bone, FE analysis becomes increasingly involved in the investigation of other fragility-related bone diseases. The case of osteogenesis imperfecta (OI) is exposed, the multiscale alterations of the bone tissue and the effect of treatment summarized. A few FE analyses attempting to answer open questions in OI are then reported. An original study is finally presented that explored the structural properties of the Brtl/+ murine model of OI type IV subjected to sclerostin neutralizing antibody treatment using microFE analysis. The use of identical material properties in the four-point bending FE simulations of the femora reproduced not only the experimental values but also the statistical comparisons examining the effect of disease and treatment. Further efforts are needed to build upon the extraordinary legacy of John Currey and clarify the impact of different bone diseases on the hierarchical mechanical properties of bone.
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Affiliation(s)
- Peter Varga
- AO Research Institute Davos, Davos, Switzerland.
| | - Bettina M Willie
- Research Centre, Shriners Hospital for Children-Canada, Montreal, Canada; Department of Pediatric Surgery, McGill University, Montreal, Canada
| | - Chris Stephan
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, USA
| | - Kenneth M Kozloff
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, USA
| | - Philippe K Zysset
- ARTORG Centre for Biomedical Engineering Research, University of Bern, Bern, Switzerland
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27
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Cabral WA, Fratzl-Zelman N, Weis M, Perosky JE, Alimasa A, Harris R, Kang H, Makareeva E, Barnes AM, Roschger P, Leikin S, Klaushofer K, Forlino A, Backlund PS, Eyre DR, Kozloff KM, Marini JC. Substitution of murine type I collagen A1 3-hydroxylation site alters matrix structure but does not recapitulate osteogenesis imperfecta bone dysplasia. Matrix Biol 2020; 90:20-39. [PMID: 32112888 DOI: 10.1016/j.matbio.2020.02.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 02/18/2020] [Accepted: 02/18/2020] [Indexed: 01/18/2023]
Abstract
Null mutations in CRTAP or P3H1, encoding cartilage-associated protein and prolyl 3-hydroxylase 1, cause the severe bone dysplasias, types VII and VIII osteogenesis imperfecta. Lack of either protein prevents formation of the ER prolyl 3-hydroxylation complex, which catalyzes 3Hyp modification of types I and II collagen and also acts as a collagen chaperone. To clarify the role of the A1 3Hyp substrate site in recessive bone dysplasia, we generated knock-in mice with an α1(I)P986A substitution that cannot be 3-hydroxylated. Mutant mice have normal survival, growth, femoral breaking strength and mean bone mineralization. However, the bone collagen HP/LP crosslink ratio is nearly doubled in mutant mice, while collagen fibril diameter and bone yield energy are decreased. Thus, 3-hydroxylation of the A1 site α1(I)P986 affects collagen crosslinking and structural organization, but its absence does not directly cause recessive bone dysplasia. Our study suggests that the functions of the modification complex as a collagen chaperone are thus distinct from its role as prolyl 3-hydroxylase.
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Affiliation(s)
- Wayne A Cabral
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, MD, USA
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | - MaryAnn Weis
- Orthopaedic Research Laboratories, University of Washington, Seattle, WA, USA
| | - Joseph E Perosky
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Adrienne Alimasa
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Rachel Harris
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Heeseog Kang
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, MD, USA
| | - Elena Makareeva
- Section on Physical Biochemistry, NICHD, NIH, Bethesda, MD, USA
| | - Aileen M Barnes
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, MD, USA
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | - Sergey Leikin
- Section on Physical Biochemistry, NICHD, NIH, Bethesda, MD, USA
| | - Klaus Klaushofer
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Peter S Backlund
- Biomedical Mass Spectrometry Facility, NICHD, NIH, Bethesda, MD, USA
| | - David R Eyre
- Orthopaedic Research Laboratories, University of Washington, Seattle, WA, USA
| | - Kenneth M Kozloff
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, MD, USA.
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Kaupp S, Horan DJ, Lim KE, Feldman HA, Robling AG, Warman ML, Jacobsen CM. Combination therapy in the Col1a2 G610C mouse model of Osteogenesis Imperfecta reveals an additive effect of enhancing LRP5 signaling and inhibiting TGFβ signaling on trabecular bone but not on cortical bone. Bone 2020; 131:115084. [PMID: 31648079 PMCID: PMC7232829 DOI: 10.1016/j.bone.2019.115084] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 09/09/2019] [Accepted: 09/26/2019] [Indexed: 01/05/2023]
Abstract
Enhancing LRP5 signaling and inhibiting TGFβ signaling have each been reported to increase bone mass and improve bone strength in wild-type mice. Monotherapy targeting LRP5 signaling, or TGFβ signaling, also improved bone properties in mouse models of Osteogenesis Imperfecta (OI). We investigated whether additive or synergistic increases in bone properties would be attained if enhanced LRP5 signaling was combined with TGFβ inhibition. We crossed an Lrp5 high bone mass (HBM) allele (Lrp5A214V) into the Col1a2G610C/+ mouse model of OI. At 6-weeks-of-age we began treating mice with an antibody that inhibits TGFβ1, β2, and β3 (mAb 1D11), or with an isotype-matched control antibody (mAb 13C4). At 12-weeks-old, we observed that combining enhanced LRP5 signaling with inhibited TGFβ signaling produced an additive effect on femoral and vertebral trabecular bone volumes, but not on cortical bone volumes. Although enhanced LRP5 signaling increased femur strength in a 3-point bending assay in Col1a2G610C/+ mice, femur strength did not improve further with TGFβ inhibition. Neither enhanced LRP5 signaling nor TGFβ inhibition, alone or in combination, improved femur 3-point-bending post-yield displacement in Col1a2G610C/+ mice. These pre-clinical studies indicate combination therapies that target LRP5 and TGFβ signaling should increase trabecular bone mass in patients with OI more than targeting either signaling pathway alone. Whether additive increases in trabecular bone mass will occur in, and clinically benefit, patients with OI needs to be determined.
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Affiliation(s)
- Shannon Kaupp
- Orthopedic Research Laboratories, Department of Orthopedic Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Dan J Horan
- Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA
| | - Kyung-Eun Lim
- Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA
| | - Henry A Feldman
- Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA
| | - Alexander G Robling
- Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA
| | - Matthew L Warman
- Orthopedic Research Laboratories, Department of Orthopedic Surgery, Boston Children's Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Christina M Jacobsen
- Divisions of Endocrinology and Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
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29
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Surowiec RK, Battle LF, Ward FS, Schlecht SH, Khoury BM, Robbins C, Wojtys EM, Caird MS, Kozloff KM. A xenograft model to evaluate the bone forming effects of sclerostin antibody in human bone derived from pediatric osteogenesis imperfecta patients. Bone 2020; 130:115118. [PMID: 31678490 PMCID: PMC6918492 DOI: 10.1016/j.bone.2019.115118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 10/01/2019] [Accepted: 10/21/2019] [Indexed: 12/18/2022]
Abstract
Osteogenesis imperfecta (OI) is a rare and severe skeletal dysplasia marked by low bone mass and poor bone quality which is especially burdensome during childhood. Since clinical trials for pediatric OI are difficult, there is a widespread reliance on genetically modified murine models to understand the skeletal effects of emerging therapeutics. However a common model does not yet exist to understand how patient-specific genotype may influence treatment efficacy. Recently, sclerostin antibody (SclAb) has been introduced as a novel putative anabolic therapy for diseases of low bone mass, but effects in pediatric patients remain unexplored. In this study, we aim to establish a direct xenograft approach using OI patient-derived bone isolates which retain patient-specific genetic defects and cells residing in their intrinsic extracellular environment to evaluate the bone-forming effects of SclAb as a bridge to clinical trials. OI and age matched non-OI patient bone typically discarded as surgical waste during corrective orthopaedic procedures were collected, trimmed and implanted subcutaneously (s.c.) on the dorsal surface of 4-6-week athymic mice. A subset of implanted mice were evaluated at short (1 week), intermediate (4 week), and long-term (12 week) durations to assess bone cell survival and presence of donor bone cells in order to determine an appropriate treatment duration. Remaining implanted mice were randomly assigned to a two or four-week SclAb-treated (25mg/kg s.c. 2QW) or untreated control group. Immunohistochemistry determined osteocyte and osteoblast donor/host relationship, TRAP staining quantified osteoclast activity, and TUNEL assay was used to understand rates of bone cell apoptosis at each implantation timepoint. Longitudinal changes of in vivo μCT outcomes and dynamic histomorphometry were used to assess treatment response and ex vivo μCT and dynamic histomorphometry of host femora served as a positive internal control to confirm a bone forming response to SclAb. Human-derived osteocytes and lining cells were present up to 12 weeks post-implantation with nominal cell apoptosis in the implant. Sclerostin expression remained donor-derived throughout the study. Osterix expression was primarily donor-derived in treated implants and shifted in favor of the host when implants remained untreated. μCT measures of BMD, TMD, BV/TV and BV increased with treatment but response was variable and impacted by bone implant morphology (trabecular, cortical) which was corroborated by histomorphometry. There was no statistical difference between treated and untreated osteoclast number in the implants. Host femora confirmed a systemic bone forming effect of SclAb. Findings support use of the xenograft model using solid bone isolates to explore the effects of novel bone-targeted therapies. These findings will impact our understanding of SclAb therapy in pediatric OI tissue through establishing the efficacy of this treatment in human cells prior to extension to the clinic.
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Affiliation(s)
- Rachel K Surowiec
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Lauren F Battle
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Ferrous S Ward
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Stephen H Schlecht
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Basma M Khoury
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Christopher Robbins
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Edward M Wojtys
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Michelle S Caird
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kenneth M Kozloff
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
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Scheiber AL, Barton DK, Khoury BM, Marini JC, Swiderski DL, Caird MS, Kozloff KM. Sclerostin Antibody-Induced Changes in Bone Mass Are Site Specific in Developing Crania. J Bone Miner Res 2019; 34:2301-2310. [PMID: 31441963 PMCID: PMC7458133 DOI: 10.1002/jbmr.3858] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 07/24/2019] [Accepted: 08/14/2019] [Indexed: 01/01/2023]
Abstract
Sclerostin antibody (Scl-Ab) is an anabolic bone agent that has been shown to increase bone mass in clinical trials of adult diseases of low bone mass, such as osteoporosis and osteogenesis imperfecta (OI). Its use to decrease bone fragility in pediatric OI has shown efficacy in several growing mouse models, suggesting translational potential to pediatric disorders of low bone mass. However, the effects of pharmacologic inhibition of sclerostin during periods of rapid growth and development have not yet been described with respect to the cranium, where lifelong deficiency of functioning sclerostin leads to patterns of excessive bone growth, cranial compression, and facial palsy. In the present study, we undertook dimensional and volumetric measurements in the skulls of growing Brtl/+ OI mice treated with Scl-Ab to examine whether therapy-induced phenotypic changes were similar to those observed clinically in patients with sclerosteosis or Van Buchem disorder. Mice treated between 3 and 14 weeks of age with high doses of Scl-Ab show significant calvarial thickening capable of rescuing OI-induced deficiencies in skull thickness. Other changes in cranial morphology, such as lengths and distances between anatomic landmarks, intracranial volume, and suture interdigitation, showed minimal effects of Scl-Ab when compared with growth-induced differences over the treatment duration. Treatment-induced narrowing of foramina was limited to sites of vascular but not neural passage, suggesting patterns of local regulation. Together, these findings reveal a site specificity of Scl-Ab action in the calvaria with no measurable cranial nerve impingement or brainstem compression. This differentiation from the observed outcomes of lifelong sclerostin deficiency complements reports of Scl-Ab treatment efficacy at other skeletal sites with the prospect of minimal cranial secondary complications. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.
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Affiliation(s)
- Amanda L Scheiber
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - David K Barton
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Basma M Khoury
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Joan C Marini
- Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Disorders, NIH, Bethesda, MD, USA
| | - Donald L Swiderski
- Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA
| | - Michelle S Caird
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kenneth M Kozloff
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
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31
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Olvera D, Stolzenfeld R, Fisher E, Nolan B, Caird MS, Kozloff KM. Pamidronate Administration During Pregnancy and Lactation Induces Temporal Preservation of Maternal Bone Mass in a Mouse Model of Osteogenesis Imperfecta. J Bone Miner Res 2019; 34:2061-2074. [PMID: 31310351 PMCID: PMC6854294 DOI: 10.1002/jbmr.3831] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 06/25/2019] [Accepted: 07/03/2019] [Indexed: 01/25/2023]
Abstract
During pregnancy and lactation, the maternal skeleton undergoes significant bone loss through increased resorption to provide the necessary calcium supply to the developing fetus and suckling neonate. This period of skeletal vulnerability has not been clearly associated with increased maternal fracture risk, but these physiological conditions can exacerbate an underlying metabolic bone condition like osteogenesis imperfecta. Although bisphosphonates (BPs) are commonly used in postmenopausal women, there are cases where premenopausal women taking BPs become pregnant. Given BPs' long half-life, there is a need to establish how BPs affect the maternal skeleton during periods of demanding metabolic bone changes that are critical for the skeletal development of their offspring. In the present study, pamidronate- (PAM-) amplified pregnancy-induced bone mass gains and lactation-induced bone loss were prevented. This preservation of bone mass was less robust when PAM was administered at late stages of lactation compared with early pregnancy and first day of lactation. Pregnancy-induced osteocyte osteolysis was also observed and was unaffected with PAM treatment. No negative skeletal effects were observed in offspring from PAM-treated dams despite lactation-induced bone loss prevention. These findings provide important insight into (1) a treatment window for when PAM is most effective in preserving maternal bone mass, and (2) the maternal changes in bone metabolism that maintain calcium homeostasis crucial for fetal and neonatal bone development. © 2019 American Society for Bone and Mineral Research.
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Affiliation(s)
- Diana Olvera
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Rachel Stolzenfeld
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Emily Fisher
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Bonnie Nolan
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Michelle S Caird
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kenneth M Kozloff
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
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Zhao Z, Liu J, Schneider A, Gao X, Ren K, Weir MD, Zhang N, Zhang K, Zhang L, Bai Y, Xu HHK. Human periodontal ligament stem cell seeding on calcium phosphate cement scaffold delivering metformin for bone tissue engineering. J Dent 2019; 91:103220. [PMID: 31678476 DOI: 10.1016/j.jdent.2019.103220] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/16/2019] [Accepted: 10/24/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES (1) develop a CPC-metformin scaffold with hPDLSC seeding for bone tissue engineering; and (2) investigate the effects of CPC-metformin scaffold on hPDLSC proliferation, osteogenic differentiation and bone matrix mineralization for the first time. METHODS hPDLSCs were harvested from extracted teeth. CPC scaffolds (with or without metformin) were prepared. Three groups were tested: (1) control group (growth medium); (2) osteogenic group (osteogenic medium); (3) metformin + osteogenic group (CPC-metformin scaffold, cultured in osteogenic medium). hPDLSC viability, osteogenic differentiation and mineralization were measured. SEM was used to examine cell morphology. RESULTS After culturing for 14 days, all three groups demonstrated excellent hPDLSC attachment and viability, as shown in live-dead staining, CCK-8 assay, and SEM examinations. The osteogenic group had 3-8 folds, 5 folds and 6 folds of increases in osteogenic gene expressions, ALP activity and mineral synthesis, compared to control group. Furthermore, the metformin + osteogenic group had 3-fold to 4-fold increases over those of the osteogenic group in osteogenic gene expressions, ALP activity and mineral synthesis. CONCLUSIONS hPDLSCs were demonstrated to be a potent cell source for bone engineering. The novel CPC-metformin-hPDLSC construct is highly promising to enhance bone repair and regeneration efficacy in dental, craniofacial and orthopedic applications.
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Affiliation(s)
- Zeqing Zhao
- Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing, China; Department of Advanced Oral Sciences and Therapeutics, University of Maryland Dental School, Baltimore, MD 21201, USA
| | - Jin Liu
- Department of Advanced Oral Sciences and Therapeutics, University of Maryland Dental School, Baltimore, MD 21201, USA; Key Laboratory of Shanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, China
| | - Abraham Schneider
- Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, MD 21201, USA
| | - Xianling Gao
- Department of Advanced Oral Sciences and Therapeutics, University of Maryland Dental School, Baltimore, MD 21201, USA; Department of Endodontics, Guanghua School and Hospital of Stomatology & Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, China
| | - Ke Ren
- Department of Neural and Pain Sciences, School of Dentistry, & Program in Neuroscience, University of Maryland, Baltimore, MD 21201, USA
| | - Michael D Weir
- Department of Advanced Oral Sciences and Therapeutics, University of Maryland Dental School, Baltimore, MD 21201, USA
| | - Ning Zhang
- Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing, China
| | - Ke Zhang
- Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing, China
| | - Li Zhang
- Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing, China
| | - Yuxing Bai
- Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing, China.
| | - Hockin H K Xu
- Department of Advanced Oral Sciences and Therapeutics, University of Maryland Dental School, Baltimore, MD 21201, USA; Member, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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Mitxitorena I, Infante A, Gener B, Rodríguez CI. Suitability and limitations of mesenchymal stem cells to elucidate human bone illness. World J Stem Cells 2019; 11:578-593. [PMID: 31616536 PMCID: PMC6789184 DOI: 10.4252/wjsc.v11.i9.578] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 07/31/2019] [Accepted: 08/27/2019] [Indexed: 02/06/2023] Open
Abstract
Functional impairment of mesenchymal stem cells (MSCs), osteoblast progenitor cells, has been proposed to be a pathological mechanism contributing to bone disorders, such as osteoporosis (the most common bone disease) and other rare inherited skeletal dysplasias. Pathological bone loss can be caused not only by an enhanced bone resorption activity but also by hampered osteogenic differentiation of MSCs. The majority of the current treatment options counteract bone loss, and therefore bone fragility by blocking bone resorption. These so-called antiresorptive treatments, in spite of being effective at reducing fracture risk, cannot be administered for extended periods due to security concerns. Therefore, there is a real need to develop osteoanabolic therapies to promote bone formation. Human MSCs emerge as a suitable tool to study the etiology of bone disorders at the cellular level as well as to be used for cell therapy purposes for bone diseases. This review will focus on the most relevant findings using human MSCs as an in vitro cell model to unravel pathological bone mechanisms and the application and outcomes of human MSCs in cell therapy clinical trials for bone disease.
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Affiliation(s)
- Izaskun Mitxitorena
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
| | - Blanca Gener
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
- Service of Genetics, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
- Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid 28005, Spain
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
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Cardinal M, Tys J, Roels T, Lafont S, Ominsky MS, Devogelaer JP, Chappard D, Mabilleau G, Ammann P, Nyssen-Behets C, Manicourt DH. Sclerostin antibody reduces long bone fractures in the oim/oim model of osteogenesis imperfecta. Bone 2019; 124:137-147. [PMID: 31051315 DOI: 10.1016/j.bone.2019.04.011] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 03/31/2019] [Accepted: 04/22/2019] [Indexed: 11/24/2022]
Abstract
Osteogenesis imperfecta type III (OI) is a serious genetic condition with poor bone quality and a high fracture rate in children. In a previous study, it was shown that a monoclonal antibody neutralizing sclerostin (Scl-Ab) increases strength and vertebral bone mass while reducing the number of axial fractures in oim/oim, a mouse model of OI type III. Here, we analyze the impact of Scl-Ab on long bones in OI mice. After 9 weeks of treatment, Scl-Ab significantly reduced long bone fractures (3.6 ± 0.3 versus 2.1 ± 0.8 per mouse, p < 0.001). In addition, the cortical thickness of the tibial midshaft was increased (+42%, p < 0.001), as well as BMD (+28%, p < 0.001), ultimate load (+86%, p < 0.05), plastic energy (+184%; p < 0.05) and stiffness (+172%; p < 0.01) in OI Scl-Ab mice compared to OI vehicle controls. Similar effects of Scl-Ab were observed in Wild type (Wt) mice. The plastic energy, which reflects the fragility of the tissue, was lower in the OI than in the Wt and significantly improved with the Scl-Ab treatment. At the tissue level by nanoindentation, Scl-Ab slightly increased the elastic modulus in bones of both OI and Wt, while moderately increasing tissue hardness (+13% compared to the vehicle; p < 0.05) in Wt bones, but not in OI bones. Although it did not change the properties of the OI bone matrix material, Scl-Ab reduced the fracture rate of the long bones by improving its bone mass, density, geometry, and biomechanical strength. These results suggest that Scl-Ab can reduce long-bone fractures in patients with OI.
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Affiliation(s)
- Mickaël Cardinal
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - Janne Tys
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - Thomas Roels
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - Sébastien Lafont
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - Michael S Ominsky
- Radius, Inc., Waltham, MA, USA, formerly at Amgen Inc, Thousand Oaks, CA, USA.
| | - Jean-Pierre Devogelaer
- Pole of Rheumatic Pathologies, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | | | | | - Patrick Ammann
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital, Geneva, Switzerland.
| | - Catherine Nyssen-Behets
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - Daniel H Manicourt
- Pole of Rheumatic Pathologies, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
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Effect of two (short-term) storage methods on load to failure testing of murine bone tissue. Sci Rep 2019; 9:5961. [PMID: 30976119 PMCID: PMC6459877 DOI: 10.1038/s41598-019-42476-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 03/27/2019] [Indexed: 11/08/2022] Open
Abstract
Since mechanical testing of bone quality is often delayed following euthanasia, the method of bone storage is of high importance in animal studies. Different storage methods may cause a change in the properties of bone tissue during mechanical testing. Therefore, the aim of this study was to investigate the biomechanical effects of two different fixation methods for bone tissue. We hypothesized that there is a difference between the load to failure values between the two groups. The tibias of fifteen 18-week-old female C57BL/6 mice were harvested and randomly allocated to three different groups with varying storage methods: (1) frozen at -80 °C, (2) paraformaldehyde working solution, and (3) native group. A storage time of two weeks prior to testing was chosen for groups 1 and 2. In group 3, referred to as the "native group", bones were immediately tested after the harvesting procedure. The comparison of the mean load to failure of all 3 groups (group 1: 28.7 N ± 6.1 N, group 2: 23.8 N ± 3.8 N and group 3: 23.7 N ± 5.7 N) did not reveal a significant difference. There was also no difference in strength or stiffness. The findings of the present study demonstrate that the two most common storage methods, do not have an influence on the biomechanical properties of murine bone over a two week period.
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Mathis NJ, Adaniya EN, Smith LM, Robling AG, Jepsen KJ, Schlecht SH. Differential changes in bone strength of two inbred mouse strains following administration of a sclerostin-neutralizing antibody during growth. PLoS One 2019; 14:e0214520. [PMID: 30947279 PMCID: PMC6448823 DOI: 10.1371/journal.pone.0214520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 03/14/2019] [Indexed: 12/02/2022] Open
Abstract
Administration of sclerostin-neutralizing antibody (Scl-Ab) treatment has been shown to elicit an anabolic bone response in growing and adult mice. Prior work characterized the response of individual mouse strains but did not establish whether the impact of Scl-Ab on whole bone strength would vary across different inbred mouse strains. Herein, we tested the hypothesis that two inbred mouse strains (A/J and C57BL/6J (B6)) will show different whole bone strength outcomes following sclerostin-neutralizing antibody (Scl-Ab) treatment during growth (4.5–8.5 weeks of age). Treated B6 femurs showed a significantly greater stiffness (S) (68.8% vs. 46.0%) and maximum load (ML) (84.7% vs. 44.8%) compared to A/J. Although treated A/J and B6 femurs showed greater cortical area (Ct.Ar) similarly relative to their controls (37.7% in A/J and 41.1% in B6), the location of new bone deposition responsible for the greater mass differed between strains and may explain the greater whole bone strength observed in treated B6 mice. A/J femurs showed periosteal expansion and endocortical infilling, while B6 femurs showed periosteal expansion. Post-yield displacement (PYD) was smaller in treated A/J femurs (-61.2%, p < 0.001) resulting in greater brittleness compared to controls; an effect not present in B6 mice. Inter-strain differences in S, ML, and PYD led to divergent changes in work-to-fracture (Work). Work was 27.2% (p = 0.366) lower in treated A/J mice and 66.2% (p < 0.001) greater in treated B6 mice relative to controls. Our data confirmed the anabolic response to Scl-Ab shown by others, and provided evidence suggesting the mechanical benefits of Scl-Ab administration may be modulated by genetic background, with intrinsic growth patterns of these mice guiding the location of new bone deposition. Whether these differential outcomes will persist in adult and elderly mice remains to be determined.
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Affiliation(s)
- Noah J. Mathis
- School of Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Emily N. Adaniya
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Lauren M. Smith
- School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Alexander G. Robling
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Karl J. Jepsen
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Stephen H. Schlecht
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America
- * E-mail:
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Scheiber AL, Guess AJ, Kaito T, Abzug JM, Enomoto-Iwamoto M, Leikin S, Iwamoto M, Otsuru S. Endoplasmic reticulum stress is induced in growth plate hypertrophic chondrocytes in G610C mouse model of osteogenesis imperfecta. Biochem Biophys Res Commun 2018; 509:235-240. [PMID: 30579604 DOI: 10.1016/j.bbrc.2018.12.111] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 12/14/2018] [Indexed: 12/21/2022]
Abstract
Osteogenesis imperfecta (OI) is a hereditary bone disorder most commonly caused by autosomal dominant mutations in genes encoding type I collagen. In addition to bone fragility, patients suffer from impaired longitudinal bone growth. It has been demonstrated that in OI, an accumulation of mutated type I collagen in the endoplasmic reticulum (ER) induces ER stress in osteoblasts, causing osteoblast dysfunction leading to bone fragility. We hypothesize that ER stress is also induced in the growth plate where bone growth is initiated, and examined a mouse model of dominant OI that carries a G610C mutation in the procollagen α2 chain. The results demonstrated that G610C OI mice had significantly shorter long bones with growth plate abnormalities including elongated total height and hypertrophic zone. Moreover, we found that mature hypertrophic chondrocytes expressed type I collagen and ER dilation was more pronounced compared to wild type littermates. The results from in vitro chondrocyte cultures demonstrated that the maturation of G610C OI hypertrophic chondrocytes was significantly suppressed and ER stress related genes were upregulated. Given that the alteration of hypertrophic chondrocyte activity often causes dwarfism, our findings suggest that hypertrophic chondrocyte dysfunction induced by ER stress may be an underlying cause of growth deficiency in G610C OI mice.
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Affiliation(s)
- Amanda L Scheiber
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Adam J Guess
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Takashi Kaito
- Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, Osaka, 565-0871, Japan
| | - Joshua M Abzug
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Motomi Enomoto-Iwamoto
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Sergey Leikin
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, 20892, USA
| | - Masahiro Iwamoto
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Satoru Otsuru
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA.
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38
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Blouin S, Fratzl-Zelman N, Roschger A, Cabral WA, Klaushofer K, Marini JC, Fratzl P, Roschger P. Cortical bone properties in the Brtl/+ mouse model of Osteogenesis imperfecta as evidenced by acoustic transmission microscopy. J Mech Behav Biomed Mater 2018; 90:125-132. [PMID: 30366302 DOI: 10.1016/j.jmbbm.2018.10.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/24/2018] [Accepted: 10/03/2018] [Indexed: 10/28/2022]
Abstract
Higher skeletal fragility has been established for the Brtl/+ mouse model of osteogenesis imperfecta at the whole bone level, but previous investigations of mechanical properties at the bone material level were inconclusive. Bone material was analyzed separately at endosteal (ER) and periosteal regions (PR) on transverse femoral midshaft sections for 2-month old mice (wild-type n = 6; Brtl/+ n = 6). Quantitative backscattered electron imaging revealed that the mass density computed from mineral density maps was higher in PR than in ER for both wild-type (+2.1%, p < 0.05) and Brtl/+ mice (+1.8%, p < 0.05). Electron induced X-ray fluorescence analysis indicated significantly lower atomic Ca/P ratios and higher Na/Ca, Mg/Ca and K/Ca ratios in PR bone compared to ER independently of genotype. Second harmonic generation microscopy indicated that the occurrence of periodically alternating collagen orientation in ER of Brtl/+ mice was strongly reduced compared to wild-type mice. Scanning acoustic microscopy in time of flight mode revealed that the sound velocity and Young's modulus (estimated based on sound velocity and mass density maps) were significantly greater in PR (respectively +6% and +15%) compared to ER in wild-type mice but not in Brtl/+ mice. ER sound velocity and Young's modulus were significantly increased in Brtl/+ mice (+9.4% and +22%, respectively) compared to wild-type mice. These data demonstrate that the Col1a1 G349C mutation in Brtl/+ mice affects the mechanical behavior of bone material predominantly in the endosteal region by altering the collagen orientation.
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Affiliation(s)
- S Blouin
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria.
| | - N Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria
| | - A Roschger
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Postdam, Germany
| | - W A Cabral
- Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
| | - K Klaushofer
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria
| | - J C Marini
- Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
| | - P Fratzl
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Postdam, Germany
| | - P Roschger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria
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Appelman-Dijkstra NM, Papapoulos SE. Clinical advantages and disadvantages of anabolic bone therapies targeting the WNT pathway. Nat Rev Endocrinol 2018; 14:605-623. [PMID: 30181608 DOI: 10.1038/s41574-018-0087-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The WNT signalling pathway is a key regulator of bone metabolism, particularly bone formation, which has helped to define the role of osteocytes - the most abundant bone cells - as orchestrators of bone remodelling. Several molecules involved in the control of the WNT signalling pathway have been identified as potential targets for the development of bone-building therapeutics for patients with osteoporosis. Several of these molecules have been investigated in animal models, but only inhibitors of sclerostin (which is produced by osteocytes) have been investigated in phase III clinical studies. Here, we review the rationale for these developments and the specificity and potential off-target actions of WNT-based therapeutics. We also describe the available preclinical and clinical studies and discuss the benefits and risks of using sclerostin inhibitors for the management of patients with osteoporosis.
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Morello R. Osteogenesis imperfecta and therapeutics. Matrix Biol 2018; 71-72:294-312. [PMID: 29540309 PMCID: PMC6133774 DOI: 10.1016/j.matbio.2018.03.010] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/08/2018] [Accepted: 03/08/2018] [Indexed: 02/08/2023]
Abstract
Osteogenesis imperfecta, or brittle bone disease, is a congenital disease that primarily causes low bone mass and bone fractures but it can negatively affect other organs. It is usually inherited in an autosomal dominant fashion, although rarer recessive and X-chromosome-linked forms of the disease have been identified. In addition to type I collagen, mutations in a number of other genes, often involved in type I collagen synthesis or in the differentiation and function of osteoblasts, have been identified in the last several years. Seldom, the study of a rare disease has delivered such a wealth of new information that have helped our understanding of multiple processes involved in collagen synthesis and bone formation. In this short review I will describe the clinical features and the molecular genetics of the disease, but then focus on how OI dysregulates all aspects of extracellular matrix biology. I will conclude with a discussion about OI therapeutics.
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Affiliation(s)
- Roy Morello
- Department of Physiology & Biophysics, Orthopaedic Surgery, and Division of Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
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Robbins A, Tom CATMB, Cosman MN, Moursi C, Shipp L, Spencer TM, Brash T, Devlin MJ. Low temperature decreases bone mass in mice: Implications for humans. AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 2018; 167:557-568. [PMID: 30187469 DOI: 10.1002/ajpa.23684] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 06/21/2018] [Accepted: 06/26/2018] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Humans exhibit significant ecogeographic variation in bone size and shape. However, it is unclear how significantly environmental temperature influences cortical and trabecular bone, making it difficult to recognize adaptation versus acclimatization in past populations. There is some evidence that cold-induced bone loss results from sympathetic nervous system activation and can be reduced by nonshivering thermogenesis (NST) via uncoupling protein (UCP1) in brown adipose tissue (BAT). Here we test two hypotheses: (1) low temperature induces impaired cortical and trabecular bone acquisition and (2) UCP1, a marker of NST in BAT, increases in proportion to degree of low-temperature exposure. METHODS We housed wildtype C57BL/6J male mice in pairs at 26 °C (thermoneutrality), 22 °C (standard), and 20 °C (cool) from 3 weeks to 6 or 12 weeks of age with access to food and water ad libitum (N = 8/group). RESULTS Cool housed mice ate more but had lower body fat at 20 °C versus 26 °C. Mice at 20 °C had markedly lower distal femur trabecular bone volume fraction, thickness, and connectivity density and lower midshaft femur cortical bone area fraction versus mice at 26 °C (p < .05 for all). UCP1 expression in BAT was inversely related to temperature. DISCUSSION These results support the hypothesis that low temperature was detrimental to bone mass acquisition. Nonshivering thermogenesis in brown adipose tissue increased in proportion to low-temperature exposure but was insufficient to prevent bone loss. These data show that chronic exposure to low temperature impairs bone architecture, suggesting climate may contribute to phenotypic variation in humans and other hominins.
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Affiliation(s)
- Amy Robbins
- Department of Anthropology, University of Michigan, Ann Arbor, Michigan
| | | | - Miranda N Cosman
- Department of Anthropology, University of Michigan, Ann Arbor, Michigan
| | - Cleo Moursi
- Department of Anthropology, University of Michigan, Ann Arbor, Michigan
| | - Lillian Shipp
- Department of Anthropology, University of Michigan, Ann Arbor, Michigan
| | - Taylor M Spencer
- Department of Anthropology, University of Michigan, Ann Arbor, Michigan
| | - Timothy Brash
- Department of Anthropology, University of Michigan, Ann Arbor, Michigan
| | - Maureen J Devlin
- Department of Anthropology, University of Michigan, Ann Arbor, Michigan
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Bailey S, Vashishth D. Mechanical Characterization of Bone: State of the Art in Experimental Approaches-What Types of Experiments Do People Do and How Does One Interpret the Results? Curr Osteoporos Rep 2018; 16:423-433. [PMID: 29915968 PMCID: PMC8078087 DOI: 10.1007/s11914-018-0454-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW The mechanical integrity of bone is determined by the direct measurement of bone mechanical properties. This article presents an overview of the current, most common, and new and upcoming experimental approaches for the mechanical characterization of bone. The key outcome variables of mechanical testing, as well as interpretations of the results in the context of bone structure and biology are also discussed. RECENT FINDINGS Quasi-static tests are the most commonly used for determining the resistance to structural failure by a single load at the organ (whole bone) level. The resistance to crack initiation or growth by fracture toughness testing and fatigue loading offers additional and more direct characterization of tissue material properties. Non-traditional indentation techniques and in situ testing are being increasingly used to probe the material properties of bone ultrastructure. Destructive ex vivo testing or clinical surrogate measures are considered to be the gold standard for estimating fracture risk. The type of mechanical test used for a particular investigation depends on the length scale of interest, where the outcome variables are influenced by the interrelationship between bone structure and composition. Advancement in the sensitivity of mechanical characterization techniques to detect changes in bone at the levels subjected to modifications by aging, disease, and/or pharmaceutical treatment is required. As such, a number of techniques are now available to aid our understanding of the factors that contribute to fracture risk.
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Affiliation(s)
- Stacyann Bailey
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, 12180, USA
| | - Deepak Vashishth
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, 12180, USA.
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Zimmerman SM, Heard-Lipsmeyer ME, Dimori M, Thostenson JD, Mannen EM, O'Brien CA, Morello R. Loss of RANKL in osteocytes dramatically increases cancellous bone mass in the osteogenesis imperfecta mouse (oim). Bone Rep 2018; 9:61-73. [PMID: 30105276 PMCID: PMC6077550 DOI: 10.1016/j.bonr.2018.06.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 05/30/2018] [Accepted: 06/29/2018] [Indexed: 12/24/2022] Open
Abstract
Osteogenesis imperfecta (OI) is characterized by osteopenia and bone fragility, and OI patients during growth often exhibit high bone turnover with the net result of low bone mass. Recent evidence shows that osteocytes significantly affect bone remodeling under physiological and pathological conditions through production of osteoclastogenic cytokines. The receptor activator of nuclear factor kappa-B ligand (RANKL) produced by osteocytes for example, is a critical mediator of bone loss caused by ovariectomy, low-calcium diet, unloading and glucocorticoid treatment. Because OI bone has increased density of osteocytes and these cells are embedded in matrix with abnormal type I collagen, we hypothesized that osteocyte-derived RANKL contributes to the OI bone phenotype. In this study, the conditional loss of RANKL in osteocytes in oim/oim mice (oim-RANKL-cKO) resulted in dramatically increased cancellous bone mass in both the femur and lumbar spine compared to oim/oim mice. Bone cortical thickness increased significantly only in spine but ultimate bone strength in the long bone and spine was minimally improved in oim-RANKL-cKO mice compared to oim/oim mice. Furthermore, unlike previous findings, we report that oim/oim mice do not exhibit high bone turnover suggesting that their low bone mass is likely due to defective bone formation and not increased bone resorption. The loss of osteocyte-derived RANKL further diminished parameters of formation in oim-RANKL-cKO. Our results indicate that osteocytes contribute significantly to the low bone mass observed in OI and the effect of loss of RANKL from these cells is similar to its systemic inhibition.
Osteocyte-specific deletion of RANKL in oim mice greatly increases cancellous bone. Skeletal effects of osteocyte RANKL deletion on OI mimic its systemic inhibition. Oim mice do not have high bone turnover. Low bone mass in oim mice is primarily caused by decreased bone formation. This study supports a potentially important role for osteocytes in OI.
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Affiliation(s)
- Sarah M. Zimmerman
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Melissa E. Heard-Lipsmeyer
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Milena Dimori
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Jeff D. Thostenson
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Erin M. Mannen
- Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Charles A. O'Brien
- Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
- Central Arkansas Veterans Healthcare System, Little Rock, AR, United States of America
- Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Roy Morello
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
- Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
- Division of Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
- Corresponding author at: Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, 4301 W. Markham St., #505, Little Rock, AR 72205-7199, United States of America.
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Olvera D, Stolzenfeld R, Marini JC, Caird MS, Kozloff KM. Low Dose of Bisphosphonate Enhances Sclerostin Antibody-Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta Mouse Model. J Bone Miner Res 2018; 33:1272-1282. [PMID: 29544018 PMCID: PMC6084801 DOI: 10.1002/jbmr.3421] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 02/27/2018] [Accepted: 03/05/2018] [Indexed: 02/01/2023]
Abstract
Osteogenesis imperfecta (OI) is a genetic disorder characterized by altered bone quality and imbalanced bone remodeling, leading to skeletal fractures that are most prominent during childhood. Treatments for OI have focused on restoring pediatric bone density and architecture to recover functional strength and consequently reduce fragility. Though antiresorptive agents like bisphosphonates (BPs) are currently the most common intervention for the treatment of OI, a number of studies have shown efficacy of sclerostin antibody (SclAb) in inducing gains in bone mass and reducing fragility in OI mouse models. In this study, the effects of the concurrent use of BP and SclAb were evaluated during bone growth in a mouse harboring an OI-causing Gly→Cys mutation on col1a1. A single dose of antiresorptive BP facilitated the anabolic action of SclAb by increasing availability of surfaces for new bone formation via retention of primary trabeculae that would otherwise be remodeled. Chronic effects of concurrent administration of BP and SclAb revealed that accumulating cycles conferred synergistic gains in trabecular mass and vertebral stiffness, suggesting a distinct advantage of both therapies combined. Cortical gains in mass and strength occurred through SclAb alone, independent of presence of BP. In conclusion, these preclinical results support the scientific hypothesis that minimal antiresorptive treatment can amplify the effects of SclAb during early stages of skeletal growth to further improve bone structure and rigidity, a beneficial outcome for children with OI. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Diana Olvera
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Rachel Stolzenfeld
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Joan C Marini
- Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Disorders, National Institutes of Health, Bethesda, MD, USA
| | - Michelle S Caird
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kenneth M Kozloff
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
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Sohail A, Sherin L, Butt SI, Javed S, Li Z, Iqbal S, Be'g OA. Role of key players in paradigm shifts of prostate cancer bone metastasis. Cancer Manag Res 2018; 10:1619-1626. [PMID: 29950899 PMCID: PMC6016588 DOI: 10.2147/cmar.s162525] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The decreased bone mineral density and compromised bone strength predispose individuals to skeletal osteoporosis. Both prostate cancer and bone metastasis caused by cancer invasion have remained a great challenge to researchers. With the advancement in the fields of biochemistry and biomechanics, the molecular mechanisms that make prostate cancer metastasize to bone have recently been identified, and they provide new molecular targets for drug development. Many biochemical by-products have been identified to help in understanding the interaction between the bone and the tumor. Enhanced clinical management of patients with bone metastases was reported during the past decade; however, the anticipated risk and the response to the therapy are still challenging to assess. In this review, the key players that play a dominant role in secondary osteoporosis are addressed. An attempt is made to provide the readers with a clear understanding of the communication pathways between each of the cell types involved in this vicious cycle. Furthermore, the role of Wnts, sclerostin, RANKL, PTHrP, and their respective clinical studies are addressed in this study.
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Affiliation(s)
- Ayesha Sohail
- Department of Mathematics, Comsats Institute of Information Technology, Lahore, Pakistan
| | - Lubna Sherin
- Department of Chemistry, Comsats Institute of Information Technology, Lahore Pakistan
| | - Saad I Butt
- Department of Mathematics, Comsats Institute of Information Technology, Lahore, Pakistan
| | - Sana Javed
- Department of Mathematics, Comsats Institute of Information Technology, Lahore, Pakistan
| | - Zhiwu Li
- Institute of Systems Engineering, Macau University of Science and Technology, Taipa, Macau.,School of Electro-Mechanical Engineering, Xidian University, Xi'an, China
| | - Sohail Iqbal
- Department of Medicine, Sir Ganga Ram Hospital, Fatima Jinnah Medical College, Lahore, Pakistan
| | - O Anwar Be'g
- Fluid Mechanics, Spray Research Group, Mechanical and Petroleum Engineering, School of Computing, Science and Engineering, University of Salford, Manchester, UK
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Abstract
Osteogenesis imperfecta (OI) is the most common inherited form of bone fragility and includes a heterogenous group of genetic disorders which most commonly result from defects associated with type 1 collagen. 85%-90% of cases are inherited in an autosomal dominant manner and are caused by mutations in the COL1A1 and COL1A2 genes, leading to quantitative or qualitative defects in type 1 collagen. In the last decade, defects in several other proteins involved in the normal processing of type 1 collagen have been described. Recent advances in genetics have called for reconsideration of the classification of OI, however, most recent classifications align with the classic clinical classification by Sillence. The hallmark of the disease is bone fragility but other tissues are also affected. Intravenous bisphosphonates (BPs) are the most widely used intervention, having significant favorable effects regarding areal bone mineral density (BMD) and vertebral reshaping following fractures in growing children. BPs have a modest effect in long bone fracture incidence, their effects in adults with OI concerns only BMD, while there are reports of subtrochanteric fractures resembling atypical femoral fractures. Other therapies showing promising results include denosumab, teriparatide, sclerostin inhibition, combination therapy with antiresorptive and anabolic drugs and TGF-β inhibition. Gene targeting approaches are under evaluation. More research is needed to delineate the best therapeutic approach in this heterogeneous disease.
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Affiliation(s)
- Symeon Tournis
- Laboratory for Research of the Musculoskeletal System 'Th. Garofalidis', KAT Hospital, University of Athens, Athens, Greece.
| | - Anastasia D Dede
- Laboratory for Research of the Musculoskeletal System 'Th. Garofalidis', KAT Hospital, University of Athens, Athens, Greece; Department of Endocrinology and Diabetes, Chelsea and Westminster Hospital, London, UK
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47
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Matthews BG, Roeder E, Wang X, Aguila HL, Lee SK, Grcevic D, Kalajzic I. Splenomegaly, myeloid lineage expansion and increased osteoclastogenesis in osteogenesis imperfecta murine. Bone 2017; 103:1-11. [PMID: 28600151 PMCID: PMC5764163 DOI: 10.1016/j.bone.2017.06.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 05/14/2017] [Accepted: 06/04/2017] [Indexed: 01/14/2023]
Abstract
Osteogenesis imperfecta (OI) is a disease caused by defects in type I collagen production that results in brittle bones. While the pathology is mainly caused by defects in the osteoblast lineage, there is also elevated bone resorption by osteoclasts resulting in high bone turnover in severe forms of the disease. Osteoclasts originate from hematopoietic myeloid cells, however changes in hematopoiesis have not been previously documented in OI. In this study, we evaluated hematopoietic lineage distribution and osteoclast progenitor cell frequency in bone marrow, spleen and peripheral blood of osteogenesis imperfecta murine (OIM) mice, a model of severe OI. We found splenomegaly in all ages examined, and expansion of myeloid lineage cells (CD11b+) in bone marrow and spleen of 7-9week old male OIM animals. OIM spleens also showed an increased frequency of purified osteoclast progenitors. This phenotype is suggestive of chronic inflammation. Isolated osteoclast precursors from both spleen and bone marrow formed osteoclasts more rapidly than wild-type controls. We found that serum TNFα levels were increased in OIM, as was IL1α in OIM females. We targeted inflammation therapeutically by treating growing animals with murine TNFR2:Fc, a compound that blocks TNFα activity. Anti-TNFα treatment marginally decreased spleen mass in OIM females, but failed to reduce bone resorption, or improve bone parameters or fracture rate in OIM animals. We have demonstrated that OIM mice have changes in their hematopoietic system, and form osteoclasts more rapidly even in the absence of OI osteoblast signals, however therapy targeting TNFα did not improve disease parameters.
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Affiliation(s)
- Brya G Matthews
- Department of Reconstructive Sciences, University of Connecticut, Farmington, CT 06030, USA.
| | - Emilie Roeder
- Department of Reconstructive Sciences, University of Connecticut, Farmington, CT 06030, USA
| | - Xi Wang
- Department of Reconstructive Sciences, University of Connecticut, Farmington, CT 06030, USA
| | | | - Sun-Kyeong Lee
- Center on Aging, University of Connecticut, Farmington, CT 06030, USA
| | - Danka Grcevic
- Department of Physiology and Immunology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Ivo Kalajzic
- Department of Reconstructive Sciences, University of Connecticut, Farmington, CT 06030, USA.
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Boraschi-Diaz I, Tauer JT, El-Rifai O, Guillemette D, Lefebvre G, Rauch F, Ferron M, Komarova SV. Metabolic phenotype in the mouse model of osteogenesis imperfecta. J Endocrinol 2017; 234:279-289. [PMID: 28716975 DOI: 10.1530/joe-17-0335] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 07/17/2017] [Indexed: 01/02/2023]
Abstract
Osteogenesis imperfecta (OI) is the most common heritable bone fragility disorder, usually caused by dominant mutations in genes coding for collagen type I alpha chains, COL1A1 or COL1A2 Osteocalcin (OCN) is now recognized as a bone-derived regulator of insulin secretion and sensitivity and glucose homeostasis. Since OI is associated with increased rates of bone formation and resorption, we hypothesized that the levels of undercarboxylated OCN are increased in OI. The objective of this study was to determine changes in OCN and to elucidate the metabolic phenotype in the Col1a1Jrt/+ mouse, a model of dominant OI caused by a Col1a1 mutation. Circulating levels of undercarboxylated OCN were higher in 4-week-old OI mice and normal by 8 weeks of age. Young OI animals exhibited a sex-dependent metabolic phenotype, including increased insulin levels in males, improved glucose tolerance in females, lower levels of random glucose and low adiposity in both sexes. The rates of O2 consumption and CO2 production, as well as energy expenditure assessed using indirect calorimetry were significantly increased in OI animals of both sexes, whereas respiratory exchange ratio was significantly higher in OI males only. Although OI mice have significant physical impairment that may contribute to metabolic differences, we specifically accounted for movement and compared OI and WT animals during the periods of similar activity levels. Taken together, our data strongly suggest that OI animals have alterations in whole body energy metabolism that are consistent with the action of undercarboxylated osteocalcin.
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Affiliation(s)
- Iris Boraschi-Diaz
- Shriners Hospital for Children-CanadaMontreal, Quebec, Canada
- Faculty of DentistryMcGill University, Montreal, Quebec, Canada
| | | | - Omar El-Rifai
- Unité de Recherche en Physiologie Intégrative et MoléculaireInstitut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
| | - Delphine Guillemette
- Shriners Hospital for Children-CanadaMontreal, Quebec, Canada
- Département de MathématiquesUniversité du Québec à Montréal, Montréal, Québec, Canada
| | - Geneviève Lefebvre
- Département de MathématiquesUniversité du Québec à Montréal, Montréal, Québec, Canada
| | - Frank Rauch
- Shriners Hospital for Children-CanadaMontreal, Quebec, Canada
| | - Mathieu Ferron
- Unité de Recherche en Physiologie Intégrative et MoléculaireInstitut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
- Départements de Médecine et de Biochimie et Médecine MoléculaireUniversité de Montréal, Montréal, Québec, Canada
| | - Svetlana V Komarova
- Shriners Hospital for Children-CanadaMontreal, Quebec, Canada
- Faculty of DentistryMcGill University, Montreal, Quebec, Canada
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49
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Abstract
Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation.
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50
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Little DG, Peacock L, Mikulec K, Kneissel M, Kramer I, Cheng TL, Schindeler A, Munns C. Combination sclerostin antibody and zoledronic acid treatment outperforms either treatment alone in a mouse model of osteogenesis imperfecta. Bone 2017; 101:96-103. [PMID: 28461254 DOI: 10.1016/j.bone.2017.04.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 04/26/2017] [Accepted: 04/27/2017] [Indexed: 10/19/2022]
Abstract
In this study, we examined the therapeutic potential of anti-Sclerostin Antibody (Scl-Ab) and bisphosphonate treatments for the bone fragility disorder Osteogenesis Imperfecta (OI). Mice with the Amish OI mutation (Col1a2 G610C mice) and control wild type littermates (WT) were treated from week 5 to week 9 of life with (1) saline (control), (2) zoledronic acid given 0.025mg/kg s.c. weekly (ZA), (3) Scl-Ab given 50mg/kg IV weekly (Scl-Ab), or (4) a combination of both (Scl-Ab/ZA). Functional outcomes were prioritized and included bone mineral density (BMD), bone microarchitecture, long bone bending strength, and vertebral compression strength. By dual-energy absorptiometry, Scl-Ab treatment alone had no effect on tibial BMD, while ZA and Scl-Ab/ZA significantly enhanced BMD by week 4 (+16% and +27% respectively, P<0.05). Scl-Ab/ZA treatment also led to increases in cortical thickness and tissue mineral density, and restored the tibial 4-point bending strength to that of control WT mice. In the spine, all treatments increased compression strength over controls, but only the combined group reached the strength of WT controls. Scl-Ab showed greater anabolic effects in the trabecular bone than in cortical bone. In summary, the Scl-Ab/ZA intervention was superior to either treatment alone in this OI mouse model, however further studies are required to establish its efficacy in other preclinical and clinical scenarios.
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Affiliation(s)
- David G Little
- Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia.
| | - Lauren Peacock
- Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Kathy Mikulec
- Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Michaela Kneissel
- Bone Unit, Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Ina Kramer
- Bone Unit, Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Tegan L Cheng
- Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia
| | - Aaron Schindeler
- Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia
| | - Craig Munns
- Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia
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