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Zhou S, Ren X, Cao Y, Mi H, Han M, Li L, Jiang C, Ye Y, Zheng C, Zhao B, Yang T, Wu N, Li Z, Wu L, Zhao X. The Spectra of Pathogenic Variants and Phenotypes in a Chinese Cohort of 298 Families with Osteogenesis Imperfecta. Genes (Basel) 2025; 16:416. [PMID: 40282376 PMCID: PMC12026677 DOI: 10.3390/genes16040416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/23/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Osteogenesis imperfecta (OI) is marked by clinical and genetic heterogeneity, and the genotype-phenotype correlation remains not very clear. We conducted a clinical and genetic study in a Chinese OI cohort to determine the spectra of phenotypes and pathogenic variants. Methods: In this study, 298 Chinese families were recruited from 2019 to 2024. Clinical phenotypes including fractures, short stature, skeletal deformities, blue sclera, dentinogenesis imperfecta, and hearing loss were recorded and analyzed. Next-generation sequencing combined with PCR-based techniques was used to detect candidate pathogenic variants. Variant pathogenicity was evaluated via conservation analysis, bioinformatics analysis, and functional studies at the cellular level. In this OI cohort, the spectra of pathogenic variants, clinical phenotypes, and genotype-phenotype correlations were analyzed. Results: Our OI cohort included 71 type I (23.83%), 122 type III (40.94%), 90 type IV (30.20%), and 15 type V (5.03%) probands. The cohort consisted of 196 children (65.77%) and 102 adults (34.23%). For the first time, phenotypic differences between different age groups were confirmed. In total, we identified 231 variants, including 47 novel pathogenic variants. Notable variants include two atypical splicing variants, one small deletion, two small duplications, one gross deletion, and one gross duplication. New genotype-phenotype correlations were observed: patients with SERPINF1 variants had the highest fracture frequency, followed by those with WNT1 variants, compared to patients with other gene variants. Conclusions: We performed the clinical and genetic analysis in a large Chinese OI cohort. The expanded spectra of genetic variants and clinical phenotypes were constructed by identifying 47 novel pathogenic variants and summarizing the skeletal and extra-skeletal manifestations. The current paper will provide important evidence for the precise diagnosis of the disease.
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Affiliation(s)
- Siji Zhou
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
| | - Xiuzhi Ren
- Key Laboratory in Science and Technology Development Project of Suzhou (CN), Pediatric Orthopedics, Children’s Hospital of Soochow University, No. 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, China
| | - Yixuan Cao
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
| | - Huan Mi
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
| | - Mingchen Han
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
| | - Lulu Li
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
| | - Chendan Jiang
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
| | - Yuqian Ye
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
| | - Chaoqun Zheng
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
| | - Binshan Zhao
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
| | - Tao Yang
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
| | - Nan Wu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Shuai Fu Community, Dongcheng District, Beijing 100730, China
| | - Zhen Li
- Department of Stomatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Shuai Fu Community, Dongcheng District, Beijing 100730, China
| | - Lingqian Wu
- Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, No. 172 Tongzipo Road, Changsha 410017, China
| | - Xiuli Zhao
- State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5# Dongdan San Tiao, Beijing 100005, China; (S.Z.)
- Key Laboratory in Science and Technology Development Project of Suzhou (CN), Pediatric Orthopedics, Children’s Hospital of Soochow University, No. 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, China
- Center for Rare Diseases, State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuai Fu Community, Dongcheng District, Beijing 100730, China
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Trieb K, Huber T, Senck S, Landauer F. The role of heat shock proteins in fracture healing-a narrative review. Eur J Trauma Emerg Surg 2025; 51:154. [PMID: 40140003 DOI: 10.1007/s00068-025-02838-2] [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: 06/21/2024] [Accepted: 03/13/2025] [Indexed: 03/28/2025]
Abstract
Fracture healing is a physiological process that is always accompanied by an immunologically mediated inflammatory reaction, resulting in primary bone healing. Heat shock proteins (HSPs) are omnipresent stress proteins produced by cells in response to exposure to stressful conditions, which function as intracellular proteins that accomplish protein folding and transport intracellularly. This narrative review aims to shed light on the underlying molecular mechanisms of HSPs with respect to the currently available Medline literature. The initial search for "heat shock protein AND fracture" identified 70 studies; after reviewing the texts and checking for content, 9 studies remained. The second search for "heat shock protein AND trauma AND bone" identified 67 studies. After manually searching through the titles and abstracts, six articles remained, three of which were already found in the first search. One study was excluded because it did not include HSPs or fractures, resulting in two additional papers being included. The third search for "heat shock protein AND osteogenesis imperfecta AND fracture" resulted in nine studies. After reviewing the texts, three articles that were already included from the first search remained. This review highlights the significant potential of HSPs and the established HSP investigations related to fracture healing. Our review indicates that, despite the few studies available, those that were selected are very important for identifying research approaches and areas that require further study.
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Affiliation(s)
- Klemens Trieb
- Division for Orthopaedics and Traumatology, Center for Clinical Medicine, Department of Medicine, Faculty of Medicine and Dentistry, Danube Private University, Krems, Austria.
- Department of Orthopaedic and Trauma Surgery, Paracelsus Medical University Salzburg, Salzburg, Austria.
| | - T Huber
- Department of Orthopaedic, Klinikum Wels-Grieskirchen, Wels, Austria
| | - S Senck
- University of Applied Sciences Upper Austria, Wels, Austria
| | - Franz Landauer
- Department of Orthopaedic and Trauma Surgery, Paracelsus Medical University Salzburg, Salzburg, Austria
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3
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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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Stasek S, Zaucke F, Hoyer-Kuhn H, Etich J, Reincke S, Arndt I, Rehberg M, Semler O. Osteogenesis imperfecta: shifting paradigms in pathophysiology and care in children. J Pediatr Endocrinol Metab 2025; 38:1-15. [PMID: 39670712 DOI: 10.1515/jpem-2024-0512] [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: 10/25/2024] [Accepted: 11/19/2024] [Indexed: 12/14/2024]
Abstract
The formation of functional bone requires a delicate interplay between osteogenesis and osteolysis. Disturbances in this subtle balance result in an increased risk for fractures. Besides its mechanical function, bone tissue represents a key player in the regulation of calcium homeostasis. Impaired bone formation results in bone fragility, which is especially pronounced in osteogenesis imperfecta (OI). This rare genetic disorder is characterized by frequent fractures as well as extraskeletal manifestations. The current classification of OI includes 23 distinct types. In recent years, several new mutations in different genes have been identified, although the exact pathomechanisms leading to the clinical presentation of OI often remain unclear. While bisphosphonates are still the standard of care, novel therapeutic approaches are emerging. Especially, targeted antibody therapies, originally developed for osteoporosis, are increasingly being investigated in children with OI and represent a promising approach to alleviate the consequences of impaired osteogenesis and improve quality of life in OI patients. This review aims to provide insight into the pathophysiology of OI and the consequences of distinct disease-causing mutations affecting the regulation of bone homeostasis. In this context, we describe the four most recently identified OI-causing genes and provide an update on current approaches for diagnosis and treatment.
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Affiliation(s)
- Stefanie Stasek
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Frank Zaucke
- Department of Trauma Surgery and Orthopedics, Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany
| | - Heike Hoyer-Kuhn
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Julia Etich
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Susanna Reincke
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Isabell Arndt
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Mirko Rehberg
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Oliver Semler
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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Jovanovic M, Marini JC. Update on the Genetics of Osteogenesis Imperfecta. Calcif Tissue Int 2024; 115:891-914. [PMID: 39127989 PMCID: PMC11607015 DOI: 10.1007/s00223-024-01266-5] [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: 05/31/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024]
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal dysplasia characterized by bone fragility and deformity, growth deficiency, and other secondary connective tissue defects. OI is now understood as a collagen-related disorder caused by defects of genes whose protein products interact with collagen for folding, post-translational modification, processing and trafficking, affecting bone mineralization and osteoblast differentiation. This review provides the latest updates on genetics of OI, including new developments in both dominant and rare OI forms, as well as the signaling pathways involved in OI pathophysiology. There is a special emphasis on discoveries of recessive mutations in TENT5A, MESD, KDELR2 and CCDC134 whose causality of OI types XIX, XX, XXI and XXI, respectively, is now established and expends the complexity of mechanisms underlying OI to overlap LRP5/6 and MAPK/ERK pathways. We also review in detail new discoveries connecting the known OI types to each other, which may underlie an eventual understanding of a final common pathway in OI cellular and bone biology.
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Affiliation(s)
- Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
- Section on Adolescent Bone and Body Composition, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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Will PA, Kilian K, Bieback K, Fricke F, Berner JE, Kneser U, Hirche C. Lymphedema-Associated Fibroblasts Are Related to Fibrosis and Stage Progression in Patients and a Murine Microsurgical Model. Plast Reconstr Surg 2024; 154:688e-700e. [PMID: 37832143 DOI: 10.1097/prs.0000000000011141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2023]
Abstract
BACKGROUND The driver of secondary lymphedema (SL) progression is chronic inflammation, which promotes fibrosis. Despite advances in preclinical research, a specific effector cell subpopulation as a biomarker for therapy response or stage progression is still missing for SL. METHODS Whole skin samples of 35 murine subjects of a microsurgically induced SL model and 12 patients with SL were collected and their fibroblasts were isolated. These lymphedema-associated fibroblasts (LAFs) were cultured in a collagen I-poly-D-lysine 3-dimensional hydrogel to mimic skin conditions. Fibroblasts from nonlymphedema skin were used as negative control and transforming growth factor β (TGF-β)-stimulated fibroblasts were used to recreate profibrotic myofibroblasts. Quantitative immunocytofluorescence confocal microscopy analysis and invasion functional assays were performed in all subpopulations and statistically compared. RESULTS In contrast to normal skin fibroblasts, LAFs exhibit α-smooth muscle actin-positive stress fibers and a reduced number of tight junctions in 3-dimensional hydrogel conditions. The switch from normal E-cadherin high phenotype to an N-cadherin high -E-cadherin low morphology suggests epithelial-to-mesenchymal transition for expansion and proliferation. This pathologic behavior of LAF was confirmed by live cell imaging analysis of invasion assays. The significant activation of markers of the TGF-β receptor 2-Smad pathway and collagen synthesis (HSP-47 [heat shock protein 47]) in LAFs supports epithelial-to-mesenchymal transition phenotypic changes and previous findings relating to TGF-β1 and fibrosis with lymphedema. CONCLUSIONS A characteristic SL myofibroblast subpopulation was identified and translationally related to fibrosis and TGF-β1-associated stage progression. This SL-related subpopulation was termed LAFs. A comprehensive stage-related characterization is required to validate LAFs as a reliable biomarker for SL disease progression. CLINICAL RELEVANCE STATEMENT The authors identify a cellular effector for fibrosis and stage progression of secondary lymphedema as a possible biomarker for surgical indication and therapy response.
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Affiliation(s)
- Patrick A Will
- From the Department of Plastic and Hand Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden
- Department of Hand, Plastic, and Reconstructive Surgery, Microsurgery, Burn Centre BG Klinik Ludwigshafen
- Plastic Surgery and Hand Surgery
| | - Katja Kilian
- Department of Hand, Plastic, and Reconstructive Surgery, Microsurgery, Burn Centre BG Klinik Ludwigshafen
- Plastic Surgery and Hand Surgery
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Mannheim Institute of Innate Immunoscience
- FlowCore Mannheim, Medical Faculty Mannheim, Heidelberg University
- German Red Cross Blood Donor Service Baden-Württemberg-Hessen
| | - Fabia Fricke
- Applied Tumor Biology, German Cancer Research Center
| | - Juan Enrique Berner
- Kellogg College, University of Oxford
- Division of Plastic Surgery. University of Texas Health Science Center at San Antonio
| | - Ulrich Kneser
- Department of Hand, Plastic, and Reconstructive Surgery, Microsurgery, Burn Centre BG Klinik Ludwigshafen
- Plastic Surgery and Hand Surgery
| | - Christoph Hirche
- Department of Hand, Plastic, and Reconstructive Surgery, Microsurgery, Burn Centre BG Klinik Ludwigshafen
- Plastic Surgery and Hand Surgery
- Department of Plastic, Hand, and Reconstructive Microsurgery, BG Unfallklinik Frankfurt am Main, Affiliated Hospital of Goethe-University
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Aliyeva L, Ongen YD, Eren E, Sarisozen MB, Alemdar A, Temel SG, Sag SO. Genotype and Phenotype Correlation of Patients with Osteogenesis Imperfecta. J Mol Diagn 2024; 26:754-769. [PMID: 39025364 DOI: 10.1016/j.jmoldx.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 04/17/2024] [Accepted: 05/16/2024] [Indexed: 07/20/2024] Open
Abstract
Osteogenesis imperfecta (OI) is the most common inherited connective tissue disease of the bone, characterized by recurrent fractures and deformities. In patients displaying the OI phenotype, genotype-phenotype correlation is used to screen multiple genes swiftly, identify new variants, and distinguish between differential diagnoses and mild subtypes. This study evaluated variants identified through next-generation sequencing in 58 patients with clinical characteristics indicative of OI. The cohort included 18 adults, 37 children, and 3 fetuses. Clinical classification revealed 25 patients as OI type I, three patients as OI type II, 18 as OI type III, and 10 as OI type IV. Fifteen variants in COL1A1 were detected in 19 patients, 9 variants in COL1A2 (n = 19), 5 variants in LEPRE1/P3H1 (n = 7), 3 variants in FKBP10 (n = 4), 3 variants in SERPINH1 (n = 2), 1 variant in IFITM5 (n = 1), and 1 variant in PLS3 (n = 1). In total, 37 variants (18 pathogenic, 14 likely pathogenic, and 5 variants of uncertain significance), including 16 novel variants, were identified in 43 (37 probands, 6 family members) of the 58 patients analyzed. This study highlights the efficacy of panel testing in the molecular diagnosis of OI, the significance of the next-generation sequencing technique, and the importance of genotype-phenotype correlation.
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Affiliation(s)
- Lamiya Aliyeva
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey; Department of Medical Genetics, Atakent Hospital, Acibadem Health Group, Istanbul, Türkiye
| | - Yasemin Denkboy Ongen
- Department of Pediatric Endocrinology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Erdal Eren
- Department of Pediatric Endocrinology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Mehmet B Sarisozen
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Adem Alemdar
- Department of Translational Medicine, Health Sciences Institute, Bursa Uludag University, Bursa, Türkiye
| | - Sehime G Temel
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey; Department of Histology and Embryology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey; Department of Translational Medicine, Health Sciences Institute, Bursa Uludag University, Bursa, Türkiye.
| | - Sebnem Ozemri Sag
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey.
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Herbert A. Osteogenesis imperfecta type 10 and the cellular scaffolds underlying common immunological diseases. Genes Immun 2024; 25:265-276. [PMID: 38811682 DOI: 10.1038/s41435-024-00277-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 05/15/2024] [Accepted: 05/21/2024] [Indexed: 05/31/2024]
Abstract
Osteogenesis imperfecta type 10 (OI10) is caused by loss of function codon variants in the gene SERPINH1 that encodes heat shock protein 47 (HSP47), rather than in a gene specifying bone formation. The HSP47 variants disrupt the folding of both collagen and the endonuclease IRE1α (inositol-requiring enzyme 1α) that splices X-Box Binding Protein 1 (XBP1) mRNA. Besides impairing bone development, variants likely affect osteoclast differentiation. Three distinct biochemical scaffold play key roles in the differentiation and regulated cell death of osteoclasts. These scaffolds consist of non-templated protein modifications, ordered lipid arrays, and protein filaments. The scaffold components are specified genetically, but assemble in response to extracellular perturbagens, pathogens, and left-handed Z-RNA helices encoded genomically by flipons. The outcomes depend on interactions between RIPK1, RIPK3, TRIF, and ZBP1 through short interaction motifs called RHIMs. The causal HSP47 nonsynonymous substitutions occur in a novel variant leucine repeat region (vLRR) that are distantly related to RHIMs. Other vLRR protein variants are causal for a variety of different mendelian diseases. The same scaffolds that drive mendelian pathology are associated with many other complex disease outcomes. Their assembly is triggered dynamically by flipons and other context-specific switches rather than by causal, mendelian, codon variants.
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Affiliation(s)
- Alan Herbert
- InsideOutBio, 42 8th Street, Charlestown, MA, USA.
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9
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Khan ES, Däinghaus T. HSP47 in human diseases: Navigating pathophysiology, diagnosis and therapy. Clin Transl Med 2024; 14:e1755. [PMID: 39135385 PMCID: PMC11319607 DOI: 10.1002/ctm2.1755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 06/12/2024] [Accepted: 06/17/2024] [Indexed: 08/16/2024] Open
Abstract
Heat shock protein 47 (HSP47) is a chaperone protein responsible for regulating collagen maturation and transport, directly impacting collagen synthesis levels. Aberrant HSP47 expression or malfunction has been associated with collagen-related disorders, most notably fibrosis. Recent reports have uncovered new functions of HSP47 in various cellular processes. Hsp47 dysregulation in these alternative roles has been linked to various diseases, such as cancer, autoimmune and neurodegenerative disorders, thereby highlighting its potential as both a diagnostic biomarker and a therapeutic target. In this review, we discuss the pathophysiological roles of HSP47 in human diseases, its potential as a diagnostic tool, clinical screening techniques and its role as a target for therapeutic interventions.
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Affiliation(s)
- Essak. S. Khan
- Posttranscriptional Gene RegulationCancer Research and Experimental HemostasisUniversity Medical Center Mainz (UMCM)MainzGermany
- Center for Thrombosis and Hemostasis (CTH)UMCMMainzGermany
- German Consortium for Translational Cancer Research (DKTK)DKFZ Frankfurt‐MainzFrankfurt am MainGermany
| | - Tobias Däinghaus
- Posttranscriptional Gene RegulationCancer Research and Experimental HemostasisUniversity Medical Center Mainz (UMCM)MainzGermany
- Center for Thrombosis and Hemostasis (CTH)UMCMMainzGermany
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10
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Martínez-Montoya V, Fonseca-Sánchez MA, Fabian-Morales G, Vega-Gamas R, Queipo-García GE, León-Madero LF, Sánchez-Sánchez LM. IFITM5-related (type V) osteogenesis imperfecta with evidence of perinatal involvement: A case report. Bone Rep 2024; 21:101766. [PMID: 38681748 PMCID: PMC11052912 DOI: 10.1016/j.bonr.2024.101766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 05/01/2024] Open
Abstract
Osteogenesis imperfecta (OI) is a rare hereditary disorder characterized by bone fragility and frequent fractures. While most cases are attributed to variations in collagen-coding genes COL1A1 and COL1A2, other genes such as IFITM5 have also been associated with the disease, accounting for up to 5 % of cases. Here, we report a case of a 3-month-old female with a femur fracture and limb deformity. X-rays revealed evidence of osteopenia and previous fractures in the arms, clavicle, ribs, and left limb, alongside prenatal bone deformities detected by ultrasound. Initial clinical evaluation suggested progressively deforming (Sillence's type III) osteogenesis imperfecta (OI). Molecular testing led to the diagnosis of IFITM5-related OI, identifying the c.-14C>T (rs587776916) variant. Although this variant has been previously reported in patients with IFITM5-related OI, prenatal involvement had not been associated with this variant.
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Affiliation(s)
- Valentina Martínez-Montoya
- Medical Genetics Service, NanoLab Next Generation Diagnostics, Mexico City, Mexico
- Genetics Service, Instituto Médico de la Visión, Mexico City, Mexico
| | | | | | - Ramiro Vega-Gamas
- Medical Genetics Service, NanoLab Next Generation Diagnostics, Mexico City, Mexico
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Merkuryeva ES, Markova TV, Kenis VM, Agranovich OE, Dan IM, Kotalevskaya YY, Shchagina OA, Ryzhkova OP, Fomenko SS, Dadali EL, Kutsev SI. Presentation of Rare Phenotypes Associated with the FKBP10 Gene. Genes (Basel) 2024; 15:674. [PMID: 38927610 PMCID: PMC11202786 DOI: 10.3390/genes15060674] [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: 04/22/2024] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 06/28/2024] Open
Abstract
Pathogenic variants in the FKBP10 gene lead to a spectrum of rare autosomal recessive phenotypes, including osteogenesis imperfecta (OI) Type XI, Bruck syndrome Type I (BS I), and the congenital arthrogryposis-like phenotype (AG), each with variable clinical manifestations that are crucial for diagnosis. This study analyzed the clinical-genetic characteristics of patients with these conditions, focusing on both known and newly identified FKBP10 variants. We examined data from 15 patients, presenting symptoms of OI and joint contractures. Diagnostic methods included genealogical analysis, clinical assessments, radiography, whole exome sequencing, and direct automated Sanger sequencing. We diagnosed 15 patients with phenotypes due to biallelic FKBP10 variants-4 with OI Type XI, 10 with BS I, and 1 with the AG-like phenotype-demonstrating polymorphism in disease severity. Ten pathogenic FKBP10 variants were identified, including three novel ones, c.1373C>T (p.Pro458Leu), c.21del (p.Pro7fs), and c.831_832insCG (p.Gly278Argfs), and a recurrent variant, c.831dup (p.Gly278Argfs). Variant c.1490G>A (p.Trp497Ter) was found in two unrelated patients, causing OI XI in one and BS I in the other. Additionally, two unrelated patients with BS I and epidermolysis bullosa shared identical homozygous FKBP10 and KRT14 variants. This observation illustrates the diversity of FKBP10-related pathology and the importance of considering the full spectrum of phenotypes in clinical diagnostics.
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Affiliation(s)
| | | | - Vladimir M. Kenis
- The Turner Scientific Research Institute for Children’s Orthopedics, 196603 Saint Petersburg, Russia
| | - Olga E. Agranovich
- The Turner Scientific Research Institute for Children’s Orthopedics, 196603 Saint Petersburg, Russia
| | - Ivan M. Dan
- The National Medical Research Center of Traumatology and Orthopedics Named after N.N. Priorov, 127299 Moscow, Russia
| | - Yulia Y. Kotalevskaya
- Vladimirsky Moscow Regional Research and Clinical Institute, 61/2, Schepkina St., 129110 Moscow, Russia
- Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, 10, St. Ushaika River Embankment, 634050 Tomsk, Russia
- Charitable Foundation «BELA. Butterfly Children», Building 3, Room 1, Furmanny Lane, 105062 Moscow, Russia
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12
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Jacobson KR, Saleh AM, Lipp SN, Tian C, Watson AR, Luetkemeyer CM, Ocken AR, Spencer SL, Kinzer-Ursem TL, Calve S. Extracellular matrix protein composition dynamically changes during murine forelimb development. iScience 2024; 27:108838. [PMID: 38303699 PMCID: PMC10831947 DOI: 10.1016/j.isci.2024.108838] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 10/02/2023] [Accepted: 01/03/2024] [Indexed: 02/03/2024] Open
Abstract
The extracellular matrix (ECM) is an integral part of multicellular organisms, connecting different cell layers and tissue types. During morphogenesis and growth, tissues undergo substantial reorganization. While it is intuitive that the ECM remodels in concert, little is known regarding how matrix composition and organization change during development. Here, we quantified ECM protein dynamics in the murine forelimb during appendicular musculoskeletal morphogenesis (embryonic days 11.5-14.5) using tissue fractionation, bioorthogonal non-canonical amino acid tagging, and mass spectrometry. Our analyses indicated that ECM protein (matrisome) composition in the embryonic forelimb changed as a function of development and growth, was distinct from other developing organs (brain), and was altered in a model of disease (osteogenesis imperfecta murine). Additionally, the tissue distribution for select matrisome was assessed via immunohistochemistry in the wild-type embryonic and postnatal musculoskeletal system. This resource will guide future research investigating the role of the matrisome during complex tissue development.
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Affiliation(s)
- Kathryn R. Jacobson
- Purdue University Interdisciplinary Life Science Program, Purdue University, West Lafayette, IN 47907, USA
- Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Aya M. Saleh
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Sarah N. Lipp
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
- The Indiana University Medical Scientist/Engineer Training Program, Indiana University, Indianapolis, IN 46202, USA
| | - Chengzhe Tian
- Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA
- BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA
- Research Center for Molecular Medicine (CEMM) of the Austrian Academy of Sciences, Vienna, Austria
| | - Audrey R. Watson
- Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA
- BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA
| | - Callan M. Luetkemeyer
- Paul M. Rady Department of Mechanical Engineering, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Alexander R. Ocken
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Sabrina L. Spencer
- Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA
- BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA
| | - Tamara L. Kinzer-Ursem
- Purdue University Interdisciplinary Life Science Program, Purdue University, West Lafayette, IN 47907, USA
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Sarah Calve
- Purdue University Interdisciplinary Life Science Program, Purdue University, West Lafayette, IN 47907, USA
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
- BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA
- Paul M. Rady Department of Mechanical Engineering, University of Colorado Boulder, Boulder, CO 80309, USA
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13
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Ruf M, Cunningham S, Wandersee A, Brox R, Achenbach S, Strobel J, Hackstein H, Schneider S. SERPINC1 c.1247dupC: a novel SERPINC1 gene mutation associated with familial thrombosis results in a secretion defect and quantitative antithrombin deficiency. Thromb J 2024; 22:19. [PMID: 38347553 PMCID: PMC10860291 DOI: 10.1186/s12959-024-00589-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 02/01/2024] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Antithrombin (AT) is an important anticoagulant in hemostasis. We describe here the characterization of a novel AT mutation associated with clinically relevant thrombosis. A pair of sisters with confirmed type I AT protein deficiency was genetically analyzed on suspicion of an inherited SERPINC1 mutation. A frameshift mutation, c.1247dupC, was identified and the effect of this mutation was examined on the cellular and molecular level. METHODS Plasmids for the expression of wild-type (WT) and mutated SERPINC1 coding sequence (CDS) fused to green fluorescent protein (GFP) or hemagglutinin (HA) tag were transfected into HEK293T cells. Subcellular localization and secretion of the respective fusion proteins were analyzed by confocal laser scanning microscopy and Western blot. RESULTS The c.1247dupC mutation results in a frameshift in the CDS of the SERPINC1 gene and a subsequently altered amino acid sequence (p.Ser417LysfsTer48). This alteration affects the C-terminus of the AT antigen and results in impaired secretion as confirmed by GFP- and HA-tagged mutant AT analyzed in HEK293T cells. CONCLUSION The p.Ser417LysfsTer48 mutation leads to impaired secretion, thus resulting in a quantitative AT deficiency. This is in line with the type I AT deficiency observed in the patients.
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Affiliation(s)
- Maximilian Ruf
- Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany
| | - Sarah Cunningham
- Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany
| | - Alexandra Wandersee
- Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany
| | - Regine Brox
- Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany
| | - Susanne Achenbach
- Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany
| | - Julian Strobel
- Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany
| | - Holger Hackstein
- Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany
| | - Sabine Schneider
- Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany.
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14
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Ignatz EH, Hall JR, Eslamloo K, Kurt Gamperl A, Rise ML. Characterization and transcript expression analyses of four Atlantic salmon (Salmo salar) serpinh1 paralogues provide evidence of evolutionary divergence. Gene 2024; 894:147984. [PMID: 37952747 DOI: 10.1016/j.gene.2023.147984] [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: 08/09/2023] [Revised: 11/08/2023] [Accepted: 11/09/2023] [Indexed: 11/14/2023]
Abstract
Atlantic salmon (Salmo salar) are not only the world's most economically important farmed fish in terms of total value, but also a salmonid, which means that they are invaluable for studies of the evolutionary fate of genes following multiple whole-genome duplication (WGD) events. In this study, four paralogues of the molecular chaperone serpinh1 were characterized in Atlantic salmon, as while this gene is considered to be a sensitive biomarker of heat stress in salmonids, mammalian studies have also identified it as being essential for collagen structural assembly and integrity. The four salmon paralogues were cloned and sequenced so that in silico analyses at the nucleotide and deduced amino acid levels could be performed. In addition, qPCR was used to measure: paralogue- and sex-specific constitutive serpinh1 expression across 17 adult tissues; and their expression in the liver and head kidney of male Atlantic salmon as affected by stress phenotype (high vs. low responder), increased temperature, and injection with a multi-valent vaccine. Compared to the other three paralogues, serpinh1a-2 had a unique constitutive expression profile across the 17 tissues. Although stress phenotype had minimal impact on the transcript expression of the four paralogues, injection with a commercial vaccine containing several formalin inactivated bacterins increased the expression of most paralogues (by 1.1 to 4.5-fold) across both tissues. At 20 °C, the expression levels of serpinh1a-1 and serpinh1a-2 were generally lower (by -1.1- to -1.6-fold), and serpinh1b-1 and serpinh1b-2 were 10.2- to 19.0-fold greater, in comparison to salmon held at 12 °C. With recent studies suggesting a putative link between serpinh1 and upper thermal tolerance in salmonids, the current research is a valuable first step in elucidating the potential mechanisms involved. This research: supports the use of serpinh1b-1 and serpinh1b-2 as a biomarkers of heat stress in salmon; and provides evidence of neo- and/or subfunctionalization between the paralogues, and important insights into how multiple genome duplication events can potentially lead to evolutionary divergence.
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Affiliation(s)
- Eric H Ignatz
- Department of Ocean Sciences, Memorial University of Newfoundland and Labrador, 0 Marine Lab Road, St. John's, NL A1C 5S7, Canada.
| | - Jennifer R Hall
- Aquatic Research Cluster, CREAIT Network, Ocean Sciences Centre, Memorial University of Newfoundland and Labrador, 0 Marine Lab Road, St. John's, NL A1C 5S7, Canada
| | - Khalil Eslamloo
- Department of Ocean Sciences, Memorial University of Newfoundland and Labrador, 0 Marine Lab Road, St. John's, NL A1C 5S7, Canada
| | - A Kurt Gamperl
- Department of Ocean Sciences, Memorial University of Newfoundland and Labrador, 0 Marine Lab Road, St. John's, NL A1C 5S7, Canada
| | - Matthew L Rise
- Department of Ocean Sciences, Memorial University of Newfoundland and Labrador, 0 Marine Lab Road, St. John's, NL A1C 5S7, Canada.
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15
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Sun Y, Li L, Wang J, Liu H, Wang H. Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches. ACS Pharmacol Transl Sci 2024; 7:72-96. [PMID: 38230285 PMCID: PMC10789133 DOI: 10.1021/acsptsci.3c00324] [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: 11/12/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 01/18/2024]
Abstract
Osteogenesis imperfecta (OI) is an uncommon genetic disorder characterized by shortness of stature, hearing loss, poor bone mass, recurrent fractures, and skeletal abnormalities. Pathogenic variations have been found in over 20 distinct genes that are involved in the pathophysiology of OI, contributing to the disorder's clinical and genetic variability. Although medications, surgical procedures, and other interventions can partially alleviate certain symptoms, there is still no known cure for OI. In this Review, we provide a comprehensive overview of genetic pathogenesis, existing treatment modalities, and new developments in biotechnologies such as gene editing, stem cell reprogramming, functional differentiation, and transplantation for potential future OI therapy.
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Affiliation(s)
- Yu Sun
- PET
Center, Chongqing University Three Gorges
Hospital, Chongqing 404000, China
| | - Lin Li
- PET
Center, Chongqing University Three Gorges
Hospital, Chongqing 404000, China
| | - Jiajun Wang
- Medical
School of Hubei Minzu University, Enshi 445000, China
| | - Huiting Liu
- PET
Center, Chongqing University Three Gorges
Hospital, Chongqing 404000, China
| | - Hu Wang
- Department
of Neurology, Johns Hopkins University School
of Medicine, Baltimore, Maryland 21205, United States
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16
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Botor M, Auguściak-Duma A, Lesiak M, Sieroń Ł, Dziedzic-Kowalska A, Witecka J, Asman M, Madetko-Talowska A, Bik-Multanowski M, Galicka A, Sieroń AL, Gawron K. Analysis of miRNAs in Osteogenesis imperfecta Caused by Mutations in COL1A1 and COL1A2: Insights into Molecular Mechanisms and Potential Therapeutic Targets. Pharmaceuticals (Basel) 2023; 16:1414. [PMID: 37895885 PMCID: PMC10609877 DOI: 10.3390/ph16101414] [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: 09/11/2023] [Revised: 09/29/2023] [Accepted: 10/01/2023] [Indexed: 10/29/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a group of connective tissue disorders leading to abnormal bone formation, mainly due to mutations in genes encoding collagen type I (Col I). Osteogenesis is regulated by a number of molecules, including microRNAs (miRNAs), indicating their potential as targets for OI therapy. The goal of this study was to identify and analyze the expression profiles of miRNAs involved in bone extracellular matrix (ECM) regulation in patients diagnosed with OI type I caused by mutations in COL1A1 or COL1A2. Primary skin fibroblast cultures were used for DNA purification and sequence analysis, followed by analysis of miRNA expression. Sequencing analysis revealed mutations of the COL1A1 or COL1A2 genes in all OI patients, including four previously unreported. Amongst the 40 miRNAs analyzed, 9 were identified exclusively in OI cells and 26 in both OI patients and the controls. In the latter case, the expression of six miRNAs (hsa-miR-10b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, has-miR-204-5p, has-miR-216a-5p, and hsa-miR-449a) increased, while four (hsa-miR-129-5p, hsa-miR-199b-5p, hsa-miR-664a-5p, and hsa-miR-30a-5p) decreased significantly in OI cells in comparison to their expression in the control cells. The identified mutations and miRNA expression profiles shed light on the intricate processes governing bone formation and ECM regulation, paving the way for further research and potential therapeutic advancements in OI and other genetic diseases related to bone abnormality management.
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Affiliation(s)
- Malwina Botor
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Aleksandra Auguściak-Duma
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Marta Lesiak
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Łukasz Sieroń
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Agata Dziedzic-Kowalska
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Joanna Witecka
- Department of Parasitology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland;
| | - Marek Asman
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-808 Zabrze, Poland;
| | - Anna Madetko-Talowska
- Department of Medical Genetics, Jagiellonian University Medical College, 30-663 Krakow, Poland; (A.M.-T.); (M.B.-M.)
| | - Mirosław Bik-Multanowski
- Department of Medical Genetics, Jagiellonian University Medical College, 30-663 Krakow, Poland; (A.M.-T.); (M.B.-M.)
| | - Anna Galicka
- Department of Medical Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland;
| | - Aleksander L. Sieroń
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Katarzyna Gawron
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
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17
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Grover SP, Mackman N, Bendapudi PK. Heat shock protein 47 and venous thrombosis: letting sleeping bears lie. J Thromb Haemost 2023; 21:2648-2652. [PMID: 37473845 DOI: 10.1016/j.jtha.2023.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/22/2023]
Affiliation(s)
- Steven P Grover
- University of North Carolina Blood Research Center, The University of North Carolina at Chapel Hill, North Carolina, USA; Division of Hematology, Department of Medicine, The University of North Carolina at Chapel Hill, North Carolina, USA.
| | - Nigel Mackman
- University of North Carolina Blood Research Center, The University of North Carolina at Chapel Hill, North Carolina, USA; Division of Hematology, Department of Medicine, The University of North Carolina at Chapel Hill, North Carolina, USA
| | - Pavan K Bendapudi
- Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Division of Hematology and Blood Transfusion Service, Massachusetts General Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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18
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Aida N, Saito A, Azuma T. Current Status of Next-Generation Sequencing in Bone Genetic Diseases. Int J Mol Sci 2023; 24:13802. [PMID: 37762102 PMCID: PMC10530486 DOI: 10.3390/ijms241813802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
The development of next-generation sequencing (NGS) has dramatically increased the speed and volume of genetic analysis. Furthermore, the range of applications of NGS is rapidly expanding to include genome, epigenome (such as DNA methylation), metagenome, and transcriptome analyses (such as RNA sequencing and single-cell RNA sequencing). NGS enables genetic research by offering various sequencing methods as well as combinations of methods. Bone tissue is the most important unit supporting the body and is a reservoir of calcium and phosphate ions, which are important for physical activity. Many genetic diseases affect bone tissues, possibly because metabolic mechanisms in bone tissue are complex. For instance, the presence of specialized immune cells called osteoclasts in the bone tissue, which absorb bone tissue and interact with osteoblasts in complex ways to support normal vital functions. Moreover, the many cell types in bones exhibit cell-specific proteins for their respective activities. Mutations in the genes encoding these proteins cause a variety of genetic disorders. The relationship between age-related bone tissue fragility (also called frailty) and genetic factors has recently attracted attention. Herein, we discuss the use of genomic, epigenomic, transcriptomic, and metagenomic analyses in bone genetic disorders.
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Affiliation(s)
- Natsuko Aida
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kandamisaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; (A.S.); (T.A.)
| | - Akiko Saito
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kandamisaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; (A.S.); (T.A.)
| | - Toshifumi Azuma
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kandamisaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; (A.S.); (T.A.)
- Oral Health Science Center, Tokyo Dental College, 2-9-18 Kandamisaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan
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19
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Sakamoto N, Okuno D, Tokito T, Yura H, Kido T, Ishimoto H, Tanaka Y, Mukae H. HSP47: A Therapeutic Target in Pulmonary Fibrosis. Biomedicines 2023; 11:2387. [PMID: 37760828 PMCID: PMC10525413 DOI: 10.3390/biomedicines11092387] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/19/2023] [Accepted: 08/23/2023] [Indexed: 09/29/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by a progressive decline in lung function and poor prognosis. The deposition of the extracellular matrix (ECM) by myofibroblasts contributes to the stiffening of lung tissue and impaired oxygen exchange in IPF. Type I collagen is the major ECM component and predominant collagen protein deposited in chronic fibrosis, suggesting that type I collagen could be a target of drugs for fibrosis treatment. Heat shock protein 47 (HSP47), encoded by the serpin peptidase inhibitor clade H, member 1 gene, is a stress-inducible collagen-binding protein. It is an endoplasmic reticulum-resident molecular chaperone essential for the correct folding of procollagen. HSP47 expression is increased in cellular and animal models of pulmonary fibrosis and correlates with pathological manifestations in human interstitial lung diseases. Various factors affect HSP47 expression directly or indirectly in pulmonary fibrosis models. Overall, understanding the relationship between HSP47 expression and pulmonary fibrosis may contribute to the development of novel therapeutic strategies.
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Affiliation(s)
- Noriho Sakamoto
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Daisuke Okuno
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Takatomo Tokito
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Hirokazu Yura
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Takashi Kido
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Hiroshi Ishimoto
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Yoshimasa Tanaka
- Center for Medical Innovation, Nagasaki University, Nagasaki 852-8588, Japan
| | - Hiroshi Mukae
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
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20
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Legrand M, Jourdan ML, de Pinieux G. Histopathogenesis of bone- and soft-tissue tumor spectrum with USP6 gene rearrangement: multiple partners involved in the tissue repair process. Histol Histopathol 2023; 38:247-260. [PMID: 36205240 DOI: 10.14670/hh-18-532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
Primary aneurysmal bone cyst, nodular fasciitis, myositis ossificans and related lesions as well as fibroma of tendon sheath are benign tumors that share common histological features and a chromosomal rearrangement involving the ubiquitin-specific peptidase 6 (USP6) gene. The tumorigenesis of this tumor spectrum has become complex with the identification of an increasing number of new partners involved in USP6 rearrangements. Because traumatic involvement has long been mentioned in the histogenesis of most lesions in the USP6 spectrum and they morphologically resemble granulation tissue or callus, we attempted to shed light on the function and role USP6 partners play in tissue remodelling and the repair process and, to a lesser extent, bone metabolism.
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Affiliation(s)
- Mélanie Legrand
- University Hospital of Tours, Department of Pathology, Tours, France
| | - Marie-Lise Jourdan
- University Hospital of Tours, Platform of Molecular Genetics, Tours, France
| | - Gonzague de Pinieux
- University Hospital of Tours, Department of Pathology, Tours, France.,University of Tours, Tours, France.
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21
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Ghosh DK, Udupa P, Shrikondawar AN, Bhavani GS, Shah H, Ranjan A, Girisha KM. Mutant MESD links cellular stress to type I collagen aggregation in osteogenesis imperfecta type XX. Matrix Biol 2023; 115:81-106. [PMID: 36526215 PMCID: PMC7615836 DOI: 10.1016/j.matbio.2022.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/19/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022]
Abstract
Aberrant forms of endoplasmic reticulum (ER)-resident chaperones are implicated in loss of protein quality control in rare diseases. Here we report a novel mutation (p.Asp233Asn) in the ER retention signal of MESD by whole exome sequencing of an individual diagnosed with osteogenesis imperfecta (OI) type XX. While MESDD233N has similar stability and chaperone activity as wild-type MESD, its mislocalization to cytoplasm leads to imbalance of ER proteostasis, resulting in improper folding and aggregation of proteins, including LRP5 and type I collagen. Aggregated LRP5 loses its plasma membrane localization to disrupt the expression of WNT-responsive genes, such as BMP2, BMP4, in proband fibroblasts. We show that MESD is a direct chaperone of pro-α1(I) [COL1A1], and absence of MESDD233N in ER results in cytosolic type I collagen aggregates that remain mostly not secreted. While cytosolic type I collagen aggregates block the intercellular nanotubes, decreased extracellular type I collagen also results in loss of interaction of ITGB1 with type I collagen and weaker attachment of fibroblasts to matrix. Although proband fibroblasts show increased autophagy to degrade the aggregated type I collagen, an overall cellular stress overwhelms the proband fibroblasts. In summary, we present an essential chaperone function of MESD for LRP5 and type I collagen and demonstrating how the D233N mutation in MESD correlates with impaired WNT signaling and proteostasis in OI.
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Affiliation(s)
- Debasish Kumar Ghosh
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
| | - Prajna Udupa
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Akshaykumar Nanaji Shrikondawar
- Computational and Functional Genomics Group, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, Telangana, India
| | - Gandham SriLakshmi Bhavani
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Hitesh Shah
- Department of Pediatric Orthopedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Akash Ranjan
- Computational and Functional Genomics Group, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, Telangana, India
| | - Katta M Girisha
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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22
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Abstract
Glioblastoma (GBM) is a malignant tumor. The long-term prognosis of the patients is poor. Therefore, it is of important clinical value to further explore the pathogenesis and look for molecular markers for early diagnosis and targeted treatment. Two expression profiling datasets [GSE50161 (GPL570 platform), GSE116520 (GPL10558 platform)] were respectively downloaded from the gene expression omnibus database. Volcano diagrams show the Differently expressed genes (DEGs) of GSE50161 and GSE116520. A Venn diagram revealed 467 common DEGs between the 2 datasets. Lysyl oxidase (LOX), serpin family H member 1 (SERPINH1) and transforming growth factor beta induced (TGFBI) were negatively correlated with the overall survival rate in patients with GBM. The hub genes are high in GBM tumor tissues. The relative expression levels of LOX, SERPINH1 and TGFBI were significantly higher in GBM samples, compared with the normal brain tissues groups. Bioinformatics technology could be a useful tool to predict progression of GBM and to explore the mechanism of GBM.LOX, SERPINH1 and TGFBI may be involved in the mechanism of the occurrence and development of GBM, and may be used as molecular targets for early diagnosis and specific treatment. DEGs identified using GEO2R. Functional annotation of DEGs using Kyoto Encyclopedia of Genes and Genomes and gene body pathway enrichment analysis. Construction of a protein-protein interaction network. The pathway and process enrichment analysis of the hub genes were performed by Metascape. Survival analysis was performed in gene expression profiling interactive analysis. Real-time fluorescent quantitative polymerase chain reaction assay was performed to verify. The animal model was established for western blot test analysis.
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Affiliation(s)
- Shuyuan Zhang
- Department of Neurosurgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, China
| | - Weiwei Zhang
- Department of Operating Theater, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Bin Wu
- Department of Neurosurgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, China
| | - Liang Xia
- Department of Neurosurgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, China
| | - Liwen Li
- Department of Neurosurgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, China
| | - Kai Jin
- Department of Neurosurgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, China
| | - Yangfan Zou
- Department of Neurosurgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, China
| | - Caixing Sun
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, China
- * Correspondence: Caixing Sun, Department of Neurosurgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China (e-mail: )
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23
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Thornley P, Bishop N, Baker D, Brock J, Arundel P, Burren C, Smithson S, DeVile C, Crowe B, Allgrove J, Saraff V, Shaw N, Balasubramanian M. Non-collagen pathogenic variants resulting in the osteogenesis imperfecta phenotype in children: a single-country observational cohort study. Arch Dis Child 2022; 107:486-490. [PMID: 34750202 DOI: 10.1136/archdischild-2021-322911] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 10/21/2021] [Indexed: 11/03/2022]
Abstract
BACKGROUND/OBJECTIVES In England, children (0-18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a 'Highly Specialised Service' (HSS OI); affected children with a genetic origin for their disease that is not in COL1A1 or COL1A2 form the majority of the 'atypical' group, which has set criteria for entry into the service. We have used the data from the service to assess the range and frequency of non-collagen pathogenic variants resulting in OI in a single country. METHODS Children with atypical OI were identified through the HSS OI service database. All genetic testing for children with OI in the service were undertaken at the Sheffield Diagnostic Genetics Service. Variant data were extracted and matched to individual patients. This study was done as part of a service evaluation project registered with the Sheffield Children's Hospital Clinical Governance Department. RESULTS One hundred of 337 children in the HSS met the 'atypical' criteria. Eighty have had genetic testing undertaken; 72 had genetic changes detected, 67 in 13 genes known to be causative for OI. The most frequently affected genes were IFITM5 (22), P3H1 (12), SERPINF1 (8) and BMP1 (6). CONCLUSION Among children with more severe forms of OI (approximately one-third of all children with OI), around 20% have pathogenic variants in non-collagen genes. IFITM5 was the most commonly affected gene, followed by genes within the P3H1 complex. These data provide additional information regarding the likelihood of different genetic origins of the disease in children with OI, which may influence clinical care.
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Affiliation(s)
- Patrick Thornley
- The University of Sheffield Faculty of Medicine Dentistry and Health, Sheffield, UK
| | - Nicholas Bishop
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK.,Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
| | - Duncan Baker
- Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Joanna Brock
- Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Paul Arundel
- Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
| | - Christine Burren
- Department of Paediatric Endocrinology and Diabetes, Bristol Royal Hospital for Children, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Sarah Smithson
- Department of Clinical Genetics, St Michaels Hospital, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Catherine DeVile
- Department of Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Belinda Crowe
- Department of Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Jeremy Allgrove
- Department of Endocrinology, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK
| | - Vrinda Saraff
- Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Nick Shaw
- Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.,Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Meena Balasubramanian
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK .,Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.,Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
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24
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Schindeler A, Lee LR, O'Donohue AK, Ginn SL, Munns CF. Curative Cell and Gene Therapy for Osteogenesis Imperfecta. J Bone Miner Res 2022; 37:826-836. [PMID: 35306687 PMCID: PMC9324990 DOI: 10.1002/jbmr.4549] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/03/2022] [Accepted: 02/27/2022] [Indexed: 11/17/2022]
Abstract
Osteogenesis imperfecta (OI) describes a series of genetic bone fragility disorders that can have a substantive impact on patient quality of life. The multidisciplinary approach to management of children and adults with OI primarily involves the administration of antiresorptive medication, allied health (physiotherapy and occupational therapy), and orthopedic surgery. However, advances in gene editing technology and gene therapy vectors bring with them the promise of gene-targeted interventions to provide an enduring or perhaps permanent cure for OI. This review describes emergent technologies for cell- and gene-targeted therapies, major hurdles to their implementation, and the prospects of their future success with a focus on bone disorders. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Aaron Schindeler
- Bioengineering and Molecular Medicine Laboratorythe Children's Hospital at Westmead and the Westmead Institute for Medical ResearchWestmeadAustralia
- Children's Hospital Westmead Clinical SchoolUniversity of SydneyCamperdownAustralia
| | - Lucinda R Lee
- Bioengineering and Molecular Medicine Laboratorythe Children's Hospital at Westmead and the Westmead Institute for Medical ResearchWestmeadAustralia
- Children's Hospital Westmead Clinical SchoolUniversity of SydneyCamperdownAustralia
| | - Alexandra K O'Donohue
- Bioengineering and Molecular Medicine Laboratorythe Children's Hospital at Westmead and the Westmead Institute for Medical ResearchWestmeadAustralia
- Children's Hospital Westmead Clinical SchoolUniversity of SydneyCamperdownAustralia
| | - Samantha L Ginn
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and HealthThe University of Sydney and Sydney Children's Hospitals NetworkWestmeadAustralia
| | - Craig F Munns
- Faculty of MedicineThe University of QueenslandBrisbaneQLDAustralia
- Department of Endocrinology and DiabetesQueensland Children's HospitalBrisbaneQLDAustralia
- Child Health Research Centre and Faculty of MedicineThe University of QueenslandBrisbaneQueenslandAustralia
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25
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Duran I, Zieba J, Csukasi F, Martin JH, Wachtell D, Barad M, Dawson B, Fafilek B, Jacobsen CM, Ambrose CG, Cohn DH, Krejci P, Lee BH, Krakow D. 4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta. J Bone Miner Res 2022; 37:675-686. [PMID: 34997935 PMCID: PMC9018561 DOI: 10.1002/jbmr.4501] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 12/01/2022]
Abstract
Osteogenesis imperfecta (OI) is a genetically heterogenous disorder most often due to heterozygosity for mutations in the type I procollagen genes, COL1A1 or COL1A2. The disorder is characterized by bone fragility leading to increased fracture incidence and long-bone deformities. Although multiple mechanisms underlie OI, endoplasmic reticulum (ER) stress as a cellular response to defective collagen trafficking is emerging as a contributor to OI pathogenesis. Herein, we used 4-phenylbutiric acid (4-PBA), an established chemical chaperone, to determine if treatment of Aga2+/- mice, a model for moderately severe OI due to a Col1a1 structural mutation, could attenuate the phenotype. In vitro, Aga2+/- osteoblasts show increased protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation protein levels, which improved upon treatment with 4-PBA. The in vivo data demonstrate that a postweaning 5-week 4-PBA treatment increased total body length and weight, decreased fracture incidence, increased femoral bone volume fraction (BV/TV), and increased cortical thickness. These findings were associated with in vivo evidence of decreased bone-derived protein levels of the ER stress markers binding immunoglobulin protein (BiP), CCAAT/-enhancer-binding protein homologous protein (CHOP), and activating transcription factor 4 (ATF4) as well as increased levels of the autophagosome marker light chain 3A/B (LC3A/B). Genetic ablation of CHOP in Aga2+/- mice resulted in increased severity of the Aga2+/- phenotype, suggesting that the reduction in CHOP observed in vitro after treatment is a consequence rather than a cause of reduced ER stress. These findings suggest the potential use of chemical chaperones as an adjunct treatment for forms of OI associated with ER stress. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Ivan Duran
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, University of Málaga, Institute of Biomedical Research in Malaga (IBIMA), Málaga, Spain.,Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain
| | - Jennifer Zieba
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
| | - Fabiana Csukasi
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, University of Málaga, Institute of Biomedical Research in Malaga (IBIMA), Málaga, Spain.,Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain
| | - Jorge H Martin
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
| | - Davis Wachtell
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
| | - Maya Barad
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
| | - Brian Dawson
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Bohumil Fafilek
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - 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
| | - Catherine G Ambrose
- Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Daniel H Cohn
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Department of Molecular Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, CA, USA
| | - Pavel Krejci
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Brendan H Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Deborah Krakow
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Department of Human Genetics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Department of Pediatrics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
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26
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Choi Y, Hwang S, Kim GH, Lee BH, Yoo HW, Choi JH. Genotype-phenotype correlations and long-term efficacy of pamidronate therapy in patients with osteogenesis imperfecta. Ann Pediatr Endocrinol Metab 2022; 27:22-29. [PMID: 35073670 PMCID: PMC8984751 DOI: 10.6065/apem.2142144.072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 11/07/2021] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Osteogenesis imperfecta (OI) is a rare bone fragility disorder caused by defects in type 1 collagen biosynthesis. This study investigated the genotype-phenotype correlations and the efficacy of pamidronate therapy in patients with OI in a single academic center. METHODS This study included 24 patients with OI. A clinical scoring system was used to evaluate disorder severity. COL1A1 and COL1A2 genes were analyzed in 13 patients using Sanger sequencing. Genotype-phenotype correlations and the efficacy of pamidronate therapy were analyzed through a retrospective medical chart review. RESULTS Of the 24 patients, 18 (75%) were classified as type I (12 with type Ia and 6 with type Ib), 2 as type III (8.4%), and 4 as type IV (16.7%). Type Ia patients showed relatively higher lumbar bone mineral density (BMD) standard deviation scores (SDS) and lower clinical scores than those with other types. Seven patients with qualitative mutations had lower lumbar BMD-SDS (P=0.015) and higher clinical scores (P=0.008) than 6 patients with quantitative mutations. The annual fracture frequency and lumbar BMD-SDS improved in patients with qualitative mutations after pamidronate treatment. CONCLUSION This study demonstrated that OI patients with qualitative mutations in COL1A1/2 had a more severe phenotype than those with quantitative mutations. Patients with qualitative mutations showed a significant reduction in fracture frequency and an increase in lumbar BMD-SDS after pamidronate treatment. Clinical score and genotype might be helpful for predicting phenotype and response to pamidronate therapy in OI patients.
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Affiliation(s)
- Yunha Choi
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soojin Hwang
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gu-Hwan Kim
- Medical Genetics Center, Asan Medical Center, Seoul, Korea
| | - Beom Hee Lee
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Han-Wook Yoo
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin-Ho Choi
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,Address for correspondence: Jin-Ho Choi Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
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27
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Fujii KK, Taga Y, Takagi YK, Masuda R, Hattori S, Koide T. The Thermal Stability of the Collagen Triple Helix Is Tuned According to the Environmental Temperature. Int J Mol Sci 2022; 23:ijms23042040. [PMID: 35216155 PMCID: PMC8877210 DOI: 10.3390/ijms23042040] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 12/24/2022] Open
Abstract
Triple helix formation of procollagen occurs in the endoplasmic reticulum (ER) where the single-stranded α-chains of procollagen undergo extensive post-translational modifications. The modifications include prolyl 4- and 3-hydroxylations, lysyl hydroxylation, and following glycosylations. The modifications, especially prolyl 4-hydroxylation, enhance the thermal stability of the procollagen triple helix. Procollagen molecules are transported to the Golgi and secreted from the cell, after the triple helix is formed in the ER. In this study, we investigated the relationship between the thermal stability of the collagen triple helix and environmental temperature. We analyzed the number of collagen post-translational modifications and thermal melting temperature and α-chain composition of secreted type I collagen in zebrafish embryonic fibroblasts (ZF4) cultured at various temperatures (18, 23, 28, and 33 °C). The results revealed that thermal stability and other properties of collagen were almost constant when ZF4 cells were cultured below 28 °C. By contrast, at a higher temperature (33 °C), an increase in the number of post-translational modifications and a change in α-chain composition of type I collagen were observed; hence, the collagen acquired higher thermal stability. The results indicate that the thermal stability of collagen could be autonomously tuned according to the environmental temperature in poikilotherms.
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Affiliation(s)
- Kazunori K. Fujii
- Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan; (K.K.F.); (Y.K.T.)
| | - Yuki Taga
- Nippi Research Institute of Biomatrix, 520-11 Kuwabara, Toride 302-0017, Japan; (Y.T.); (S.H.)
| | - Yusuke K. Takagi
- Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan; (K.K.F.); (Y.K.T.)
| | - Ryo Masuda
- Waseda Research Institute for Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan;
| | - Shunji Hattori
- Nippi Research Institute of Biomatrix, 520-11 Kuwabara, Toride 302-0017, Japan; (Y.T.); (S.H.)
| | - Takaki Koide
- Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan; (K.K.F.); (Y.K.T.)
- Waseda Research Institute for Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan;
- Correspondence: ; Tel.: +81-3-5286-2569
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28
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Wang Y, Gu W, Wen W, Zhang X. SERPINH1 is a Potential Prognostic Biomarker and Correlated With Immune Infiltration: A Pan-Cancer Analysis. Front Genet 2022; 12:756094. [PMID: 35058967 PMCID: PMC8764125 DOI: 10.3389/fgene.2021.756094] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/06/2021] [Indexed: 01/14/2023] Open
Abstract
Background: Serpin peptidase inhibitor clade H, member 1 (SERPINH1) is a gene encoding a member of the serpin superfamily of serine proteinase inhibitors. The upregulated of SERPINH1 was associated with poor prognosis in breast cancer, stomach adenocarcinoma, and esophageal carcinoma. However, the role of SERPINH1 in pan-cancer is largely unexplored. Methods: SERPINH1 expression and the correlation with prognosis in human pan-cancer were analyzed by the Cancer Genome Atlas and the Genotype-Tissue Expression dataset. Pearson correlation analysis was applied to evaluate the role of SERPINH1 expression in tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), DNA methyltransferase, and common immunoregulators. Spearman’s correlation test was used to analysis SERPINH1 expression in tumor immune infiltration and infiltrating immune cells via the Tumor Immune Evaluation Resource database. Furtherly, immunohistochemistry staining of SERPINH1 was acquired from the Human Protein Atlas database for validation. Results: SERPINH1 was abnormally expressed in fourteen cancers. The high expression of SERPINH1 significantly reduced the overall survival (OS), disease-specific survival, and progression free interval in eleven cancers. Moreover, SERPINH1 expression was correlated with MMR, MSI, TMB, and DNA methylation in multiple types of cancer. Also, SERPINH1 expression showed strong association with immunoregulators and immune checkpoint markers in testicular germ cell tumors, brain lower grade glioma (LGG), pheochromocytoma and paraganglioma. In addition, SERPINH1 expression was related to immune cell infiltration in multiple cancers, particularly in breast invasive carcinoma, LGG, and liver hepatocellular carcinoma. The result of immunohistochemistry verification shown that SERPINH1 staining was higher in tumor samples than in normal tissue in colon adenocarcinoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma and cervical squamous cell carcinoma, which was consistent with the result of OS. Conclusion: Overall, these results indicate that SERPINH1 may serve as an important prognostic biomarker and correlate with tumor immunity in human pan-cancer.
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Affiliation(s)
- Yu Wang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Hangzhou Institute of Digestive Diseases, Hangzhou, China.,Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Weigang Gu
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Hangzhou Institute of Digestive Diseases, Hangzhou, China.,Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Weiwei Wen
- Department of Dermatology, Third People's Hospital of Hangzhou, Hangzhou, China
| | - Xiaofeng Zhang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Hangzhou Institute of Digestive Diseases, Hangzhou, China.,Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
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29
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Rusu-Nastase EG, Lupan AM, Marinescu CI, Neculachi CA, Preda MB, Burlacu A. MiR-29a Increase in Aging May Function as a Compensatory Mechanism Against Cardiac Fibrosis Through SERPINH1 Downregulation. Front Cardiovasc Med 2022; 8:810241. [PMID: 35118144 PMCID: PMC8804242 DOI: 10.3389/fcvm.2021.810241] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 12/17/2021] [Indexed: 12/13/2022] Open
Abstract
Deregulation of microRNA (miRNA) profile has been reportedly linked to the aging process, which is a dominant risk factor for many pathologies. Among the miRNAs with documented roles in aging-related cardiac diseases, miR-18a, -21a, -22, and -29a were mainly associated with hypertrophy and/or fibrosis; however, their relationship to aging was not fully addressed before. The purpose of this paper was to evaluate the variations in the expression levels of these miRNAs in the aging process. To this aim, multiple organs were harvested from young (2–3-months-old), old (16–18-months-old), and very old (24–25-months-old) mice, and the abundance of the miRNAs was evaluated by quantitative real-time (RT)-PCR. Our studies demonstrated that miR-21a, miR-22, and miR-29a were upregulated in the aged heart. Among them, miR-29a was highly expressed in many other organs, i.e., the brain, the skeletal muscle, the pancreas, and the kidney, and its expression was further upregulated during the natural aging process. Western blot, immunofluorescence, and xCELLigence analyses concurrently indicated that overexpression of miR-29a in the muscle cells decreased the collagen levels as well as cell migration and proliferation. Computational prediction analysis and overexpression studies identified SERPINH1, a specific chaperone of procollagens, as a potential miR-29a target. Corroborating to this, significantly downregulated SERPINH1 levels were found in the skeletal muscle, the heart, the brain, the kidney, and the pancreas harvested from very old animals, thereby indicating the role of the miR-29a-SERPINH1 axis in the aging process. In vitro analysis of miR-29a effects on fibroblast and cardiac muscle cells pointed toward a protective role of miR-29a on aging-related fibrosis, by reducing cell migration and proliferation. In conclusion, our study indicates an adaptive increase of miR-29 in the natural aging process and suggests its role as a transcriptional repressor of SERPINH1, with a potential therapeutic value against adverse matrix remodeling and aging-associated tissue fibrosis.
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Staab-Weijnitz CA. Fighting the Fiber: Targeting Collagen in Lung Fibrosis. Am J Respir Cell Mol Biol 2021; 66:363-381. [PMID: 34861139 DOI: 10.1165/rcmb.2021-0342tr] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Organ fibrosis is characterized by epithelial injury and aberrant tissue repair, where activated effector cells, mostly fibroblasts and myofibroblasts, excessively deposit collagen into the extracellular matrix. Fibrosis frequently results in organ failure and has been estimated to contribute to at least one third of all global deaths. Also lung fibrosis, in particular idiopathic pulmonary fibrosis (IPF), is a fatal disease with rising incidence worldwide. As current treatment options targeting fibrogenesis are insufficient, there is an urgent need for novel therapeutic strategies. During the last decade, several studies have proposed to target intra- and extracellular components of the collagen biosynthesis, maturation, and degradation machinery. This includes intra- and extracellular targets directly acting on collagen gene products, but also such that anabolize essential building blocks of collagen, in particular glycine and proline biosynthetic enzymes. Collagen, however, is a ubiquitous molecule in the body and fulfils essential functions as a macromolecular scaffold, growth factor reservoir, and receptor binding site in virtually every tissue. This review summarizes recent advances and future directions in this field. Evidence for the proposed therapeutic targets and where they currently stand in terms of clinical drug development for treatment of fibrotic disease is provided. The drug targets are furthermore discussed in light of (1) specificity for collagen biosynthesis, maturation and degradation, and (2) specificity for disease-associated collagen. As therapeutic success and safety of these drugs may largely depend on targeted delivery, different strategies for specific delivery to the main effector cells and to the extracellular matrix are discussed.
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Affiliation(s)
- Claudia A Staab-Weijnitz
- Helmholtz Zentrum Munchen Deutsches Forschungszentrum fur Gesundheit und Umwelt, 9150, Comprehensive Pneumology Center/Institute of Lung Biology and Disease, Member of the German Center of Lung Research (DZL), München, Germany;
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Abraham ET, Oecal S, Mörgelin M, Schmid PWN, Buchner J, Baumann U, Gebauer JM. Collagen's primary structure determines collagen:HSP47 complex stoichiometry. J Biol Chem 2021; 297:101169. [PMID: 34487762 PMCID: PMC8626583 DOI: 10.1016/j.jbc.2021.101169] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/27/2021] [Accepted: 09/02/2021] [Indexed: 11/21/2022] Open
Abstract
Collagens play important roles in development and homeostasis in most higher organisms. In order to function, collagens require the specific chaperone HSP47 for proper folding and secretion. HSP47 is known to bind to the collagen triple helix, but the exact positions and numbers of binding sites are not clear. Here, we employed a collagen II peptide library to characterize high-affinity binding sites for HSP47. We show that many previously predicted binding sites have very low affinities due to the presence of a negatively charged amino acid in the binding motif. In contrast, large hydrophobic amino acids such as phenylalanine at certain positions in the collagen sequence increase binding strength. For further characterization, we determined two crystal structures of HSP47 bound to peptides containing phenylalanine or leucine. These structures deviate significantly from previously published ones in which different collagen sequences were used. They reveal local conformational rearrangements of HSP47 at the binding site to accommodate the large hydrophobic side chain from the middle strand of the collagen triple helix and, most surprisingly, possess an altered binding stoichiometry in the form of a 1:1 complex. This altered stoichiometry is explained by steric collisions with the second HSP47 molecule present in all structures determined thus far caused by the newly introduced large hydrophobic residue placed on the trailing strand. This exemplifies the importance of considering all three sites of homotrimeric collagen as independent interaction surfaces and may provide insight into the formation of higher oligomeric complexes at promiscuous collagen-binding sites.
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Affiliation(s)
- Elena T Abraham
- Faculty of Mathematics and Natural Sciences, Institute of Biochemistry, University of Cologne, Cologne, Germany
| | - Sinan Oecal
- Faculty of Mathematics and Natural Sciences, Institute of Biochemistry, University of Cologne, Cologne, Germany
| | - Matthias Mörgelin
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden; Colzyx AB, Lund, Sweden
| | - Philipp W N Schmid
- Department of Chemistry, Center for Integrated Protein Science, Technische Universität München, Garching, Germany
| | - Johannes Buchner
- Department of Chemistry, Center for Integrated Protein Science, Technische Universität München, Garching, Germany
| | - Ulrich Baumann
- Faculty of Mathematics and Natural Sciences, Institute of Biochemistry, University of Cologne, Cologne, Germany.
| | - Jan M Gebauer
- Faculty of Mathematics and Natural Sciences, Institute of Biochemistry, University of Cologne, Cologne, Germany.
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Botor M, Fus-Kujawa A, Uroczynska M, Stepien KL, Galicka A, Gawron K, Sieron AL. Osteogenesis Imperfecta: Current and Prospective Therapies. Biomolecules 2021; 11:biom11101493. [PMID: 34680126 PMCID: PMC8533546 DOI: 10.3390/biom11101493] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 12/20/2022] Open
Abstract
Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI.
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Affiliation(s)
- Malwina Botor
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland; (A.F.-K.); (M.U.); (K.L.S.); (K.G.); (A.L.S.)
- Correspondence:
| | - Agnieszka Fus-Kujawa
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland; (A.F.-K.); (M.U.); (K.L.S.); (K.G.); (A.L.S.)
| | - Marta Uroczynska
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland; (A.F.-K.); (M.U.); (K.L.S.); (K.G.); (A.L.S.)
| | - Karolina L. Stepien
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland; (A.F.-K.); (M.U.); (K.L.S.); (K.G.); (A.L.S.)
| | - Anna Galicka
- Department of Medical Chemistry, Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok, Poland;
| | - Katarzyna Gawron
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland; (A.F.-K.); (M.U.); (K.L.S.); (K.G.); (A.L.S.)
| | - Aleksander L. Sieron
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland; (A.F.-K.); (M.U.); (K.L.S.); (K.G.); (A.L.S.)
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Ghatan S, Costantini A, Li R, De Bruin C, Appelman-Dijkstra NM, Winter EM, Oei L, Medina-Gomez C. The Polygenic and Monogenic Basis of Paediatric Fractures. Curr Osteoporos Rep 2021; 19:481-493. [PMID: 33945105 PMCID: PMC8551106 DOI: 10.1007/s11914-021-00680-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2021] [Indexed: 01/19/2023]
Abstract
PURPOSE OF REVIEW Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped by the individual genetic background influencing the acquisition of bone mineral density, and therefore, the skeletal fragility as shown in adults. Here, we examine paediatric fractures from the perspective of monogenic and complex trait genetics. RECENT FINDINGS Large-scale genome-wide studies in children have identified ~44 genetic loci associated with fracture or bone traits whereas ~35 monogenic diseases characterized by paediatric fractures have been described. Genetic variation can predispose to paediatric fractures through monogenic risk variants with a large effect and polygenic risk involving many variants of small effects. Studying genetic factors influencing peak bone attainment might help in identifying individuals at higher risk of developing early-onset osteoporosis and discovering drug targets to be used as bone restorative pharmacotherapies to prevent, or even reverse, bone loss later in life.
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Affiliation(s)
- S Ghatan
- Translational Skeletal Genomics Group, Department of Internal Medicine, Erasmus MC University Medical Centre, Doctor Molewaterplein 40, Ee-571, 3015, GD, Rotterdam, The Netherlands
- Department of Epidemiology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
| | - A Costantini
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - R Li
- Translational Skeletal Genomics Group, Department of Internal Medicine, Erasmus MC University Medical Centre, Doctor Molewaterplein 40, Ee-571, 3015, GD, Rotterdam, The Netherlands
- Department of Epidemiology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
| | - C De Bruin
- Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands
| | - N M Appelman-Dijkstra
- Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands
| | - E M Winter
- Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands
| | - L Oei
- Translational Skeletal Genomics Group, Department of Internal Medicine, Erasmus MC University Medical Centre, Doctor Molewaterplein 40, Ee-571, 3015, GD, Rotterdam, The Netherlands
- Department of Epidemiology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
- Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands
| | - Carolina Medina-Gomez
- Translational Skeletal Genomics Group, Department of Internal Medicine, Erasmus MC University Medical Centre, Doctor Molewaterplein 40, Ee-571, 3015, GD, Rotterdam, The Netherlands.
- Department of Epidemiology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.
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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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Claeys L, Storoni S, Eekhoff M, Elting M, Wisse L, Pals G, Bravenboer N, Maugeri A, Micha D. Collagen transport and related pathways in Osteogenesis Imperfecta. Hum Genet 2021; 140:1121-1141. [PMID: 34169326 PMCID: PMC8263409 DOI: 10.1007/s00439-021-02302-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/08/2021] [Indexed: 12/16/2022]
Abstract
Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although collagen type I defects are long established as the primary cause of the bone pathology, we are still far from comprehending the complete mechanism. In the last years, the advent of next generation sequencing has triggered the discovery of many new genetic causes for OI, helping to draw its molecular landscape. It has become clear that, in addition to collagen type I genes, OI can be caused by multiple proteins connected to different parts of collagen biosynthesis. The production of collagen entails a complex process, starting from the production of the collagen Iα1 and collagen Iα2 chains in the endoplasmic reticulum, during and after which procollagen is subjected to a plethora of posttranslational modifications by chaperones. After reaching the Golgi organelle, procollagen is destined to the extracellular matrix where it forms collagen fibrils. Recently discovered mutations in components of the retrograde transport of chaperones highlight its emerging role as critical contributor of OI development. This review offers an overview of collagen regulation in the context of recent gene discoveries, emphasizing the significance of transport disruptions in the OI mechanism. We aim to motivate exploration of skeletal fragility in OI from the perspective of these pathways to identify regulatory points which can hint to therapeutic targets.
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Affiliation(s)
- Lauria Claeys
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Silvia Storoni
- Department of Internal Medicine Section Endocrinology, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Marelise Eekhoff
- Department of Internal Medicine Section Endocrinology, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Mariet Elting
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Lisanne Wisse
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Gerard Pals
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Nathalie Bravenboer
- Department of Clinical Chemistry, Amsterdam /UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Alessandra Maugeri
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Dimitra Micha
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
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Serpins in cartilage and osteoarthritis: what do we know? Biochem Soc Trans 2021; 49:1013-1026. [PMID: 33843993 PMCID: PMC8106492 DOI: 10.1042/bst20201231] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/17/2021] [Accepted: 03/04/2021] [Indexed: 12/13/2022]
Abstract
Serpins (serine proteinase inhibitors) are an ancient superfamily of structurally similar proteins, the majority of which use an elegant suicide inhibition mechanism to target serine proteinases. Despite likely evolving from a single common ancestor, the 36 human serpins have established roles regulating diverse biological processes, such as blood coagulation, embryonic development and extracellular matrix (ECM) turnover. Genetic mutations in serpin genes underpin a host of monogenic disorders — collectively termed the ‘serpinopathies’ — but serpin dysregulation has also been shown to drive pathological mechanisms in many common diseases. Osteoarthritis is a degenerative joint disorder, characterised by the progressive destruction of articular cartilage. This breakdown of the cartilage is driven by the metalloproteinases, and it has long been established that an imbalance of metalloproteinases to their inhibitors is of critical importance. More recently, a role for serine proteinases in cartilage destruction is emerging; including the activation of latent matrix metalloproteinases and cell-surface receptors, or direct proteolysis of the ECM. Serpins likely regulate these processes, as well as having roles beyond serine proteinase inhibition. Indeed, serpins are routinely observed to be highly modulated in osteoarthritic tissues and fluids by ‘omic analysis, but despite this, they are largely ignored. Confusing nomenclature and an underappreciation for the role of serine proteinases in osteoarthritis (OA) being the likely causes. In this narrative review, serpin structure, biochemistry and nomenclature are introduced, and for the first time, their putative importance in maintaining joint tissues — as well as their dysregulation in OA — are explored.
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Abstract
Collagen is the most abundant protein in mammals. A unique feature of collagen is its triple-helical structure formed by the Gly-Xaa-Yaa repeats. Three single chains of procollagen make a trimer, and the triple-helical structure is then folded in the endoplasmic reticulum (ER). This unique structure is essential for collagen's functions in vivo, including imparting bone strength, allowing signal transduction, and forming basement membranes. The triple-helical structure of procollagen is stabilized by posttranslational modifications and intermolecular interactions, but collagen is labile even at normal body temperature. Heat shock protein 47 (Hsp47) is a collagen-specific molecular chaperone residing in the ER that plays a pivotal role in collagen biosynthesis and quality control of procollagen in the ER. Mutations that affect the triple-helical structure or result in loss of Hsp47 activity cause the destabilization of procollagen, which is then degraded by autophagy. In this review, we present the current state of the field regarding quality control of procollagen.
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Affiliation(s)
- Shinya Ito
- Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan;
| | - Kazuhiro Nagata
- Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan; .,Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto 603-8555, Japan; .,JT Biohistory Research Hall, Osaka, 569-1125, Japan
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Bioinformatic Analysis of Key Genes and Pathways Related to Keloids. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5897907. [PMID: 33860039 PMCID: PMC8009712 DOI: 10.1155/2021/5897907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/25/2020] [Accepted: 02/20/2021] [Indexed: 02/05/2023]
Abstract
Background The pathophysiology of keloids is complex, and the treatment for keloids is still an unmet medical need. Our study is aimed at identifying the hub genes among the differentially expressed genes (DEGs) between normal skin tissue and keloids and key pathways in the development of keloids. Materials and Methods We downloaded the GSE92566 and GSE90051 microarray data, which contain normal skin tissue and keloid gene expression data. GSE92566 was treated as a discovery dataset for summarizing the significantly DEGs, and GSE90051 served as a validation dataset. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, Reactome enrichment analysis, gene set enrichment analysis, and gene set variation analysis were performed for the key functions and pathways enriched in DEGs. Moreover, we also validated the hub genes identified from the protein-protein interaction network and predicted miRNA-hub gene interactions. Results 117 downregulated DEGs and 204 upregulated DEGs in GSE92566 were identified. Extracellular and collagen-related pathways were prominent in upregulated DEGs, while the keratinization-related pathway was associated with downregulated DEGs. The hub genes included COL5A1, COL5A2, and SERPINH1, which were also validated in GSE90051. Conclusion This study identified several hub genes and provided insights for the underlying pathways and miRNA-hub gene interactions for keloid development through bioinformatic analysis of two microarray datasets. Additionally, our results would support the development of future therapeutic strategies.
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FKBP10 Regulates Protein Translation to Sustain Lung Cancer Growth. Cell Rep 2021; 30:3851-3863.e6. [PMID: 32187554 DOI: 10.1016/j.celrep.2020.02.082] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Revised: 10/29/2019] [Accepted: 02/20/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer therapy is limited, in part, by lack of specificity. Thus, identifying molecules that are selectively expressed by, and relevant for, cancer cells is of paramount medical importance. Here, we show that peptidyl-prolyl-cis-trans-isomerase (PPIase) FK506-binding protein 10 (FKBP10)-positive cells are present in cancer lesions but absent in the healthy parenchyma of human lung. FKBP10 expression negatively correlates with survival of lung cancer patients, and its downregulation causes a dramatic diminution of lung tumor burden in mice. Mechanistically, our results from gain- and loss-of-function assays show that FKBP10 boosts cancer growth and stemness via its PPIase activity. Also, FKBP10 interacts with ribosomes, and its downregulation leads to reduction of translation elongation at the beginning of open reading frames (ORFs), particularly upon insertion of proline residues. Thus, our data unveil FKBP10 as a cancer-selective molecule with a key role in translational reprogramming, stem-like traits, and growth of lung cancer.
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Caengprasath N, Theerapanon T, Porntaveetus T, Shotelersuk V. MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders. J Transl Med 2021; 19:114. [PMID: 33743732 PMCID: PMC7981912 DOI: 10.1186/s12967-021-02779-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/08/2021] [Indexed: 12/27/2022] Open
Abstract
The MBTPS2 gene on the X-chromosome encodes the membrane-bound transcription factor protease, site-2 (MBTPS2) or site-2 protease (S2P) which cleaves and activates several signaling and regulatory proteins from the membrane. The MBTPS2 is critical for a myriad of cellular processes, ranging from the regulation of cholesterol homeostasis to unfolded protein responses. While its functional role has become much clearer in the recent years, how mutations in the MBTPS2 gene lead to several human disorders with different phenotypes including Ichthyosis Follicularis, Atrichia and Photophobia syndrome (IFAP) with or without BRESHECK syndrome, Keratosis Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis Imperfecta type XIX remains obscure. This review presents the biological role of MBTPS2 in development, summarizes its mutations and implicated disorders, and discusses outstanding unanswered questions.
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Affiliation(s)
- Natarin Caengprasath
- Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, Thailand
| | - Thanakorn Theerapanon
- Genomics and Precision Dentistry Research Unit, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Thantrira Porntaveetus
- Genomics and Precision Dentistry Research Unit, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand.
| | - Vorasuk Shotelersuk
- Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, Thailand
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Seo T, Kim J, Shin HC, Kim JG, Ju S, Nawale L, Han G, Lee HS, Bang G, Kim JY, Bang JK, Lee KH, Soung NK, Hwang J, Lee C, Kim SJ, Kim BY, Cha-Molstad H. R-catcher, a potent molecular tool to unveil the arginylome. Cell Mol Life Sci 2021; 78:3725-3741. [PMID: 33687501 PMCID: PMC8038991 DOI: 10.1007/s00018-021-03805-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 02/18/2021] [Accepted: 02/27/2021] [Indexed: 11/27/2022]
Abstract
Protein arginylation is a critical regulator of a variety of biological processes. The ability to uncover the global arginylation pattern and its associated signaling pathways would enable us to identify novel disease targets. Here, we report the development of a tool able to capture the N-terminal arginylome. This tool, termed R-catcher, is based on the ZZ domain of p62, which was previously shown to bind N-terminally arginylated proteins. Mutating the ZZ domain enhanced its binding specificity and affinity for Nt-Arg. R-catcher pulldown coupled to LC-MS/MS led to the identification of 59 known and putative arginylated proteins. Among these were a subgroup of novel ATE1-dependent arginylated ER proteins that are linked to diverse biological pathways, including cellular senescence and vesicle-mediated transport as well as diseases, such as Amyotrophic Lateral Sclerosis and Alzheimer's disease. This study presents the first molecular tool that allows the unbiased identification of arginylated proteins, thereby unlocking the arginylome and provide a new path to disease biomarker discovery.
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Affiliation(s)
- Taewook Seo
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongju-si, Chungcheongbuk-do, 28116, Republic of Korea.,Department of Biomolecular Science, KRIBB School, University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Jihyo Kim
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongju-si, Chungcheongbuk-do, 28116, Republic of Korea
| | - Ho-Chul Shin
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Jung Gi Kim
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongju-si, Chungcheongbuk-do, 28116, Republic of Korea.,Department of Biomolecular Science, KRIBB School, University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Shinyeong Ju
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.,KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Laxman Nawale
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongju-si, Chungcheongbuk-do, 28116, Republic of Korea.,Department of Biomolecular Science, KRIBB School, University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Goeun Han
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongju-si, Chungcheongbuk-do, 28116, Republic of Korea.,Department of Biomolecular Science, KRIBB School, University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Hye Seon Lee
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Geul Bang
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Ochang, 28116, Republic of Korea
| | - Jin Young Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Ochang, 28116, Republic of Korea
| | - Jeong Kyu Bang
- Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, 28116, Republic of Korea
| | - Kyung Ho Lee
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongju-si, Chungcheongbuk-do, 28116, Republic of Korea
| | - Nak-Kyun Soung
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongju-si, Chungcheongbuk-do, 28116, Republic of Korea
| | - Joonsung Hwang
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongju-si, Chungcheongbuk-do, 28116, Republic of Korea
| | - Cheolju Lee
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.,KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Seung Jun Kim
- Department of Biomolecular Science, KRIBB School, University of Science and Technology, Daejeon, 34113, Republic of Korea. .,Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
| | - Bo Yeon Kim
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongju-si, Chungcheongbuk-do, 28116, Republic of Korea. .,Department of Biomolecular Science, KRIBB School, University of Science and Technology, Daejeon, 34113, Republic of Korea.
| | - Hyunjoo Cha-Molstad
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongju-si, Chungcheongbuk-do, 28116, Republic of Korea. .,Department of Biomolecular Science, KRIBB School, University of Science and Technology, Daejeon, 34113, Republic of Korea.
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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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Dynamic proteomic profiling of human periodontal ligament stem cells during osteogenic differentiation. Stem Cell Res Ther 2021; 12:98. [PMID: 33536073 PMCID: PMC7860046 DOI: 10.1186/s13287-020-02123-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/25/2020] [Indexed: 01/07/2023] Open
Abstract
Background Human periodontal ligament stem cells (hPDLSCs) are ideal seed cells for periodontal regeneration. A greater understanding of the dynamic protein profiles during osteogenic differentiation contributed to the improvement of periodontal regeneration tissue engineering. Methods Tandem Mass Tag quantitative proteomics was utilized to reveal the temporal protein expression pattern during osteogenic differentiation of hPDLSCs on days 0, 3, 7 and 14. Differentially expressed proteins (DEPs) were clustered and functional annotated by Gene Ontology (GO) terms. Pathway enrichment analysis was performed based on the Kyoto Encyclopedia of Genes and Genomes database, followed by the predicted activation using Ingenuity Pathway Analysis software. Interaction networks of redox-sensitive signalling pathways and oxidative phosphorylation (OXPHOS) were conducted and the hub protein SOD2 was validated with western blotting. Results A total of 1024 DEPs were identified and clustered in 5 distinctive clusters representing dynamic tendencies. The GO enrichment results indicated that proteins with different tendencies show different functions. Pathway enrichment analysis found that OXPHOS was significantly involved, which further predicted continuous activation. Redox-sensitive signalling pathways with dynamic activation status showed associations with OXPHOS to various degrees, especially the sirtuin signalling pathway. SOD2, an important component of the sirtuin pathway, displays a persistent increase during osteogenesis. Data are available via ProteomeXchange with identifier PXD020908. Conclusion This is the first in-depth dynamic proteomic analysis of osteogenic differentiation of hPDLSCs. It demonstrated a dynamic regulatory mechanism of hPDLSC osteogenesis and might provide a new perspective for research on periodontal regeneration. Graphical abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13287-020-02123-6.
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Syx D, Ishikawa Y, Gebauer J, Boudko SP, Guillemyn B, Van Damme T, D’hondt S, Symoens S, Nampoothiri S, Gould DB, Baumann U, Bächinger HP, Malfait F. Aberrant binding of mutant HSP47 affects posttranslational modification of type I collagen and leads to osteogenesis imperfecta. PLoS Genet 2021; 17:e1009339. [PMID: 33524049 PMCID: PMC7877763 DOI: 10.1371/journal.pgen.1009339] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 02/11/2021] [Accepted: 01/05/2021] [Indexed: 12/21/2022] Open
Abstract
Heat shock protein 47 (HSP47), encoded by the SERPINH1 gene, is a molecular chaperone essential for correct folding of collagens. We report a homozygous p.(R222S) substitution in HSP47 in a child with severe osteogenesis imperfecta leading to early demise. p.R222 is a highly conserved residue located within the collagen interacting surface of HSP47. Binding assays show a significantly reduced affinity of HSP47-R222S for type I collagen. This altered interaction leads to posttranslational overmodification of type I procollagen produced by dermal fibroblasts, with increased glycosylation and/or hydroxylation of lysine and proline residues as shown by mass spectrometry. Since we also observed a normal intracellular folding and secretion rate of type I procollagen, this overmodification cannot be explained by prolonged exposure of the procollagen molecules to the modifying hydroxyl- and glycosyltransferases, as is commonly observed in other types of OI. We found significant upregulation of several molecular chaperones and enzymes involved in procollagen modification and folding on Western blot and RT-qPCR. In addition, we showed that an imbalance in binding of HSP47-R222S to unfolded type I collagen chains in a gelatin sepharose pulldown assay results in increased binding of other chaperones and modifying enzymes. The elevated expression and binding of this molecular ensemble to type I procollagen suggests a compensatory mechanism for the aberrant binding of HSP47-R222S, eventually leading to overmodification of type I procollagen chains. Together, these results illustrate the importance of HSP47 for proper posttranslational modification and provide insights into the molecular pathomechanisms of the p.(R222S) alteration in HSP47, which leads to a severe OI phenotype. Heat shock protein 47 (HSP47) is essential for correct collagen folding. We report a homozygous p.(R222S) substitution in HSP47 in a child with severe osteogenesis imperfecta. The highly conserved p.R222 residue is located within the collagen interacting surface and HSP47-R222S shows a significantly reduced affinity for type I collagen. This altered interaction leads to posttranslational overmodification of type I procollagen. In contrast to other types of OI, this overmodification is not caused by prolonged exposure of procollagen to modifying enzymes, since the intracellular folding rate of type I procollagen appears to be normal. We show significant upregulation of several molecular chaperones and collagen-modifying enzymes and increased binding of several of these molecules to unfolded type I collagen chains upon abnormal HSP47-R222S binding. This suggests a compensatory mechanism for aberrant HSP47-R222S binding, eventually leading to overmodification of type I procollagen chains, and underscores the importance of HSP47 for proper posttranslational modification.
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Affiliation(s)
- Delfien Syx
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Yoshihiro Ishikawa
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Ophthalmology, UCSF School of Medicine, San Francisco, California, United States of America
| | - Jan Gebauer
- Institute of Biochemistry, University of Cologne, Cologne, Germany
| | - Sergei P. Boudko
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Brecht Guillemyn
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Tim Van Damme
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Sanne D’hondt
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Sofie Symoens
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Sheela Nampoothiri
- Amrita Institute of Medical Sciences and Research Center, Cochin, Kerala, India
| | - Douglas B. Gould
- Department of Ophthalmology, UCSF School of Medicine, San Francisco, California, United States of America
- Department of Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, California, United States of America
| | - Ulrich Baumann
- Institute of Biochemistry, University of Cologne, Cologne, Germany
| | - Hans Peter Bächinger
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Fransiska Malfait
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
- * E-mail:
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El-Gazzar A, Högler W. Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis. Int J Mol Sci 2021; 22:ijms22020625. [PMID: 33435159 PMCID: PMC7826666 DOI: 10.3390/ijms22020625] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/07/2021] [Accepted: 01/07/2021] [Indexed: 12/13/2022] Open
Abstract
Bone material strength is determined by several factors, such as bone mass, matrix composition, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-ß signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments.
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Affiliation(s)
| | - Wolfgang Högler
- Correspondence: ; Tel.: +43-(0)5-7680-84-22001; Fax: +43-(0)5-7680-84-22004
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van Dijk FS, Semler O, Etich J, Köhler A, Jimenez-Estrada JA, Bravenboer N, Claeys L, Riesebos E, Gegic S, Piersma SR, Jimenez CR, Waisfisz Q, Flores CL, Nevado J, Harsevoort AJ, Janus GJ, Franken AA, van der Sar AM, Meijers-Heijboer H, Heath KE, Lapunzina P, Nikkels PG, Santen GW, Nüchel J, Plomann M, Wagener R, Rehberg M, Hoyer-Kuhn H, Eekhoff EM, Pals G, Mörgelin M, Newstead S, Wilson BT, Ruiz-Perez VL, Maugeri A, Netzer C, Zaucke F, Micha D. Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2. Am J Hum Genet 2020; 107:989-999. [PMID: 33053334 DOI: 10.1016/j.ajhg.2020.09.009] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 09/22/2020] [Indexed: 12/17/2022] Open
Abstract
Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.
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47
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Omari S, Makareeva E, Gorrell L, Jarnik M, Lippincott-Schwartz J, Leikin S. Mechanisms of procollagen and HSP47 sorting during ER-to-Golgi trafficking. Matrix Biol 2020; 93:79-94. [DOI: 10.1016/j.matbio.2020.06.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 12/27/2022]
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Li L, Yang M, Jin A. COL3A1, COL6A3, and SERPINH1 Are Related to Glucocorticoid-Induced Osteoporosis Occurrence According to Integrated Bioinformatics Analysis. Med Sci Monit 2020; 26:e925474. [PMID: 32999266 PMCID: PMC7537482 DOI: 10.12659/msm.925474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Glucocorticoid-induced osteoporosis (GIOP) represents the most frequently seen type of secondary osteoporosis, a systemic skeleton disorder. Numerous factors are associated with GIOP occurrence, but there are no specific diagnostic and therapeutic biomarkers for GIOP so far. Material/Methods In this work, gene modules related to GIOP were screened through weighted gene coexpression network analysis. Moreover, protein-protein interaction (PPI) networks and gene set enrichment analysis (GSEA) were carried out for hub genes. In addition, microarray GSE30159 dataset was used as a training set to analyze gene expression within bone biopsy samples from patients with endogenous Cushing’s syndrome with GIOP and from normal controls. GSE129228 was used as the test set for investigating the hub gene involvement within GIOP. Results According to our results, the turquoise module showed clinical significance, and 10 genes (COL3A1, POSTN, COL6A3, COL14A1, SERPINH1, ASPN, OGN, THY1, NID2, and TNMD) were discovered to be the “real” hub genes within coexpression as well as PPI networks. GSEA showed that the interaction of extracellular matrix receptors together with the focal adhesion pathway had significant enrichment within samples with high COL3A1 and COL6A3 expression. After the results from both test and training sets were overlapped, SERPINH1 was also significantly altered between GIOP and normal control samples. Conclusions COL3A1, COL6A3, and SERPINH1 were identified to be the candidate biomarkers for GIOP.
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Affiliation(s)
- Liuxun Li
- Department of Spine Surgery, Zhujiang Hospital of Southern Medical University, Southern Medical University, Guangzhou, Guangdong, China (mainland)
| | - Meiling Yang
- Department of Oncology, Guangzhou University of Chinese Medicine Shenzhen Hospital, Shenzhen, Guangdong, China (mainland)
| | - Anmin Jin
- Department of Spine Surgery, Zhujiang Hospital of Southern Medical University, Southern Medical University, Guangzhou, Guangdong, China (mainland)
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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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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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