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Lafaver BN, Lee L, Derocher CE, Levin LF, Carter EM, Sardesai K, Vallejo JA, McAllister-Day A, Crawford TK, Chapman IM, Wacker MJ, Raggio CL, Ma L, Krenz M, Phillips CL. Cardiac health, type I collagen, and aging in the oim/oim mouse model of osteogenesis imperfecta and a cohort of adults with OI. Am J Physiol Heart Circ Physiol 2025; 328:H565-H580. [PMID: 39902996 DOI: 10.1152/ajpheart.00535.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 08/30/2024] [Accepted: 01/12/2025] [Indexed: 02/06/2025]
Abstract
Osteogenesis imperfecta (OI) is a heritable connective tissue disorder with marked skeletal fragility and increased recognition as a pleiotropic type I collagenopathy. The impact of OI-causing gene variants on cardiac health and lifespan is just beginning to be understood. To begin to investigate cardiac manifestations of OI-causing type I collagen variants, we utilized the osteogenesis imperfecta murine (oim/oim) model to examine survival with increased age, as well as cardiac function and collagen expression at 4 and 18 mo of age. We determined male oim/oim mice had 50% decreased survival by 18 mo of age compared with wild-type (WT) littermates. Cardiac magnetic resonance imaging and echocardiography revealed 18-mo-old male oim/oim mice had increased left ventricular end-diastolic and end-systolic volumes concomitant with decreased function, as well as the presence of aortic stenosis in a subset of 4- and 18-mo-old male oim/oim mice compared with WT littermates. Female oim/oim survival and cardiac function were equivalent to their WT counterparts. Cardiac evaluations of an adult patient cohort with OI corroborated increased incidences of valvular dysfunction in the patient population with OI, with much of the male cohort also presenting with altered left ventricular function. Little is known concerning the impact of OI-causing variants on patient cardiac health and the influence of sex and age. Using an OI mouse model, we determined that 18-mo-old male oim/oim mice have cardiac dysfunction with decreased lifespan, confirming the need for further investigations to understand pleiotropic extraskeletal manifestations and disease progression in osteogenesis imperfecta.NEW & NOTEWORTHY The heritable skeletal dysplasia, osteogenesis imperfecta (OI), recently recognized as a pleiotropic collagenopathy, shows growing evidence of cardiac involvement impacting lifespan. Evaluating cardiac function (magnetic resonance imaging and echocardiography) using an OI mouse model revealed increased left ventricular end-diastolic and end-systolic volumes concomitant with decreased function and reduced survival in 18-mo-old male OI mice. Additional cardiac evaluations of an adult patient cohort with OI corroborated increased incidences of valvular dysfunction in the patient population with OI.
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Affiliation(s)
- Brittany N Lafaver
- Department of Biochemistry, University of Missouri School of Medicine, Columbia, Missouri, United States
| | - Li Lee
- Department of Radiology, University of Missouri School of Medicine, Columbia, Missouri, United States
- VA-Biomolecular Imaging Center, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri, United States
| | | | | | - Erin M Carter
- Hospital for Special Surgery, New York, New York, United States
| | - Krish Sardesai
- Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, United States
| | - Julian A Vallejo
- Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, United States
| | - Ali McAllister-Day
- College of Veterinary Medicine, University of Missouri School of Medicine, Columbia, Missouri, United States
| | - Tara K Crawford
- Department of Biochemistry, University of Missouri School of Medicine, Columbia, Missouri, United States
| | - Isabel M Chapman
- Department of Biochemistry, University of Missouri School of Medicine, Columbia, Missouri, United States
| | - Michael J Wacker
- Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, United States
| | | | - Lixin Ma
- Department of Radiology, University of Missouri School of Medicine, Columbia, Missouri, United States
- VA-Biomolecular Imaging Center, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri, United States
| | - Maike Krenz
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, United States
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, United States
| | - Charlotte L Phillips
- Department of Biochemistry, University of Missouri School of Medicine, Columbia, Missouri, United States
- Department of Child Health, University of Missouri School of Medicine, Columbia, Missouri, United States
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2
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Moody M, Zainadine N, Doktorski T, Trivedi R, Schmidt TA, Deymier A. Potassium bicarbonate, not sodium bicarbonate, maintains acidosis-mediated bone dissolution. Bone 2025; 192:117369. [PMID: 39674389 DOI: 10.1016/j.bone.2024.117369] [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: 04/02/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 12/16/2024]
Abstract
Treatments for metabolic acidosis are not well studied; however, one treatment that is commonly used is sodium bicarbonate administration. Sodium bicarbonate has been shown to help reduce symptoms of metabolic acidosis, but its benefits for bone health remain uncertain. Potassium bicarbonate has become a potential new treatment due to its reduction in bone resorption markers, unlike sodium bicarbonate. However, very few studies have looked at the connection between bone functionality and potassium bicarbonate supplementation, especially under the influence of an acidic challenge. To determine the impact of potassium bicarbonate and sodium bicarbonate on the mechanical, structural, compositional, and cellular properties of bone, acidotic mice were given either potassium bicarbonate or sodium bicarbonate for seven days. Blood gas analysis was conducted to evaluate their acidotic states throughout the study. After experimentation, the mice were euthanized, and their femurs excised for further analysis. Before bicarbonate supplementation, the acidotic mice given sodium bicarbonate were in acidosis while the acidotic mice given potassium bicarbonate were in acidemia. The bicarbonate treatment somewhat rescued the blood gas parameters in both acidosis groups, but acidemia and bone dissolution continued occurring in the acidotic mice given potassium bicarbonate, as made evident by the continuous elevation in blood sodium levels compared to the control. The acidosis group given potassium bicarbonate group also had worsened composition and structure, while the acidosis group given sodium bicarbonate had no changes in bone metrics. In this study, potassium bicarbonate was not effective at reducing bone dissolution under acidotic conditions.
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Affiliation(s)
- Mikayla Moody
- Dept of Biomedical Engineering, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - Nayara Zainadine
- Dept of Biomedical Engineering, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - Trey Doktorski
- Dept of Biomedical Engineering, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - Ruchir Trivedi
- Department of Nephrology, School of Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - Tannin A Schmidt
- Dept of Biomedical Engineering, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - Alix Deymier
- Dept of Biomedical Engineering, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, USA.
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Dev I, Mehmood S, Pleshko N, Obeid I, Querido W. Assessment of submicron bone tissue composition in plastic-embedded samples using optical photothermal infrared (O-PTIR) spectral imaging and machine learning. J Struct Biol X 2024; 10:100111. [PMID: 39507318 PMCID: PMC11539169 DOI: 10.1016/j.yjsbx.2024.100111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2024] Open
Abstract
Understanding the composition of bone tissue at the submicron level is crucial to elucidate factors contributing to bone disease and fragility. Here, we introduce a novel approach utilizing optical photothermal infrared (O-PTIR) spectroscopy and imaging coupled with machine learning analysis to assess bone tissue composition at 500 nm spatial resolution. This approach was used to evaluate thick bone samples embedded in typical poly(methyl methacrylate) (PMMA) blocks, eliminating the need for cumbersome thin sectioning. We demonstrate the utility of O-PTIR imaging to assess the distribution of bone tissue mineral and protein, as well as to explore the structure-composition relationship surrounding microporosity at a spatial resolution unattainable by conventional infrared imaging modalities. Using bone samples from wildtype (WT) mice and from a mouse model of osteogenesis imperfecta (OIM), we further showcase the application of O-PTIR spectroscopy to quantify mineral content, crystallinity, and carbonate content in spatially defined regions across the cortical bone. Notably, we show that machine learning analysis using support vector machine (SVM) was successful in identifying bone phenotypes (typical in WT, fragile in OIM) based on input of spectral data, with over 86 % of samples correctly identified when using the collagen spectral range. Our findings highlight the potential of O-PTIR spectroscopy and imaging as valuable tools for exploring bone submicron composition.
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Affiliation(s)
- Isha Dev
- Department of Bioengineering, Temple University, Philadelphia, PA, 19122, USA
| | - Sofia Mehmood
- Department of Bioengineering, Temple University, Philadelphia, PA, 19122, USA
| | - Nancy Pleshko
- Department of Bioengineering, Temple University, Philadelphia, PA, 19122, USA
| | - Iyad Obeid
- Department of Electrical and Computer Engineering, Temple University, Philadelphia, PA 19122, USA
| | - William Querido
- Department of Bioengineering, Temple University, Philadelphia, PA, 19122, USA
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Dzubanova M, Benova A, Ferencakova M, Coupeau R, Tencerova M. Nutrition and Bone Marrow Adiposity in Relation to Bone Health. Physiol Res 2024; 73:S107-S138. [PMID: 38752771 PMCID: PMC11412336 DOI: 10.33549/physiolres.935293] [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: 12/02/2023] [Accepted: 04/29/2024] [Indexed: 09/04/2024] Open
Abstract
Bone remodeling is energetically demanding process. Energy coming from nutrients present in the diet contributes to function of different cell type including osteoblasts, osteocytes and osteoclasts in bone marrow participating in bone homeostasis. With aging, obesity and osteoporosis the function of key building blocks, bone marrow stromal cells (BMSCs), changes towards higher accumulation of bone marrow adipose tissue (BMAT) and decreased bone mass, which is affected by diet and sex dimorphism. Men and women have unique nutritional needs based on physiological and hormonal changes across the life span. However, the exact molecular mechanisms behind these pathophysiological conditions in bone are not well-known. In this review, we focus on bone and BMAT physiology in men and women and how this approach has been taken by animal studies. Furthermore, we discuss the different diet interventions and impact on bone and BMAT in respect to sex differences. We also discuss the future perspective on precision nutrition with a consideration of sex-based differences which could bring better understanding of the diet intervention in bone health and weight management.
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Affiliation(s)
- M Dzubanova
- Laboratory of Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Prague 4, Czech Republic.
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Lee SY, Kim SJ, Park KH, Lee G, Oh Y, Ryu JH, Huh YH. Differential but complementary roles of HIF-1α and HIF-2α in the regulation of bone homeostasis. Commun Biol 2024; 7:892. [PMID: 39039245 PMCID: PMC11263705 DOI: 10.1038/s42003-024-06581-z] [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: 10/19/2023] [Accepted: 07/11/2024] [Indexed: 07/24/2024] Open
Abstract
Bone is a highly dynamic tissue undergoing continuous formation and resorption. Here, we investigated differential but complementary roles of hypoxia-inducible factor (HIF)-1α and HIF-2α in regulating bone remodeling. Using RNA-seq analysis, we identified that specific genes involved in regulating osteoblast differentiation were similarly but slightly differently governed by HIF-1α and HIF-2α. We found that increased HIF-1α expression inhibited osteoblast differentiation via inhibiting RUNX2 function by upregulation of Twist2, confirmed using Hif1a conditional knockout (KO) mouse. Ectopic expression of HIF-1α via adenovirus transduction resulted in the increased expression and activity of RANKL, while knockdown of Hif1a expression via siRNA or osteoblast-specific depletion of Hif1a in conditional KO mice had no discernible effect on osteoblast-mediated osteoclast activation. The unexpected outcome was elucidated by the upregulation of HIF-2α upon Hif1a overexpression, providing evidence that Hif2a is a transcriptional target of HIF-1α in regulating RANKL expression, verified through an experiment of HIF-2α knockdown after HIF-1α overexpression. The above results were validated in an ovariectomized- and aging-induced osteoporosis model using Hif1a conditional KO mice. Our findings conclude that HIF-1α plays an important role in regulating bone homeostasis by controlling osteoblast differentiation, and in influencing osteoclast formation through the regulation of RANKL secretion via HIF-2α modulation.
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Affiliation(s)
- Sun Young Lee
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Su-Jin Kim
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea
- Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Ka Hyon Park
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea
- Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Gyuseok Lee
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Youngsoo Oh
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Je-Hwang Ryu
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
- Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
| | - Yun Hyun Huh
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
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Shao C, Liu Y, Zhao Y, Jing Y, Li J, Lv Z, Fu T, Wang Z, Li G. DNA methyltransferases inhibitor azacitidine improves the skeletal phenotype of mild osteogenesis imperfecta by reversing the impaired osteogenesis and excessive osteoclastogenesis. Bone 2023; 170:116706. [PMID: 36822490 DOI: 10.1016/j.bone.2023.116706] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 02/06/2023] [Accepted: 02/12/2023] [Indexed: 02/24/2023]
Abstract
BACKGROUND Osteogenesis imperfecta (OI), as a disease of congenital bone dysplasia, is often accompanied by the abnormal alteration of bone absorption and bone formation. DNA methyltransferases (Dnmts) can regulate the gene expression involved in osteogenesis and osteoclastogenesis. Dnmts changes and their effects on bone cells under OI is poorly understood. METHODS The Dnmts expression in adipose derived mesenchymal stem cells (ADSCs), bone marrow derived pre-osteoclasts (pre-Ocs) and femurs of Col1a2oim/+ and Col1a1+/-365 mice, both modeling mild OI types, were determined. The effects of azacitidine (Aza) administration and Dnmt3a knockdown by ShRNA on the osteogenic differentiation of ADSCs together with osteoclasts (Ocs) production of pre-Ocs were studied in vitro. The synthesis and secretion of collagen fibers of OI derived ADSCs were examined. The therapeutic outcomes of intraperitoneal (i.p.) infused Aza (1 mg/kg/2d) for 30 days were evaluated in OI mice. RESULTS Obviously elevated expression of Dnmts, especially Dnmt3a, existed in ADSCs, pre-Ocs, and femurs isolated from OI modeled mice. Much more collagen molecules of mutant ADSCs were secreted into the extracellular medium post Aza addition. Both Aza administration and Dnmt3a knockdown effectively enhanced the bone-forming capacity of affected ADSCs and reduced Ocs formation of OI mice in vitro. Aza treatment apparently improved the femora microstructure and biomechanical properties, increased bone formation and decreased the number of Ocs in mice with OI. CONCLUSION Highly expressed Dnmt3a contributed to the impaired osteogenesis and enhanced osteoclastogenesis of collagen defect-related OI. Aza medication effectively improved the femora phenotype of the two types of OI modeled mice partly by Dnmts inhibition and modulating cell stress response. These findings facilitated understanding the role of Dnmts alteration in skeletal pathological development of mild OI and preliminary confirmed the therapeutic potential of Dnmts depressants in mild OI treatment. Still, further researches are needed to explore the specific function of Dnmts in OI bones and clarify the benefits of Aza administration in OI treatment.
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Affiliation(s)
- Chenyi Shao
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Yi Liu
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Yuxia Zhao
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Yaqing Jing
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Jiaci Li
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Zhe Lv
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Ting Fu
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Zihan Wang
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Guang Li
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China.
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7
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Davey RA. The Importance of Sex in Preclinical Studies of Bone. J Bone Miner Res 2023; 38:3-4. [PMID: 36457148 DOI: 10.1002/jbmr.4748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 11/15/2022] [Indexed: 12/03/2022]
Affiliation(s)
- Rachel A Davey
- Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
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Sharma A, Michels LV, Pitsillides AA, Greeves J, Plotkin LI, Cardo V, Sims NA, Clarkin CE. Sexing Bones: Improving Transparency of Sex Reporting to Address Bias Within Preclinical Studies. J Bone Miner Res 2023; 38:5-13. [PMID: 36301601 PMCID: PMC10099537 DOI: 10.1002/jbmr.4729] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 10/11/2022] [Accepted: 10/20/2022] [Indexed: 01/10/2023]
Abstract
Despite knowledge that sexually dimorphic mechanisms regulate bone homeostasis, sex often remains unreported and unconsidered in preclinical experimental design. Failure to report sex could lead to inappropriate generalizations of research findings and less effective translation into clinical practice. Preclinical sex bias (preferential selection of one sex) is present across other fields, including neuroscience and immunology, but remains uninvestigated in skeletal research. For context, we first summarized key literature describing sexually dimorphic bone phenotypes in mice. We then investigated sex reporting practices in skeletal research, specifically how customary it is for murine sex to be included in journal article titles or abstracts and then determined whether any bias in sex reporting exists. Because sex hormones are important regulators of bone health (gonadectomy procedures, ie, ovariectomy [OVX] and orchidectomy [ORX], are common yet typically not reported with sex), we incorporated reporting of OVX and ORX terms, representing female and male mice, respectively, into our investigations around sex bias. Between 1999 and 2020, inclusion of sex in titles or abstracts was low in murine skeletal studies (2.6%-4.06%). Reporting of OVX and ORX terms was low (1.44%-2.64%) and reporting of OVX and ORX with sex uncommon (0.4%-0.3%). When studies were combined to include both sexes and OVX (representing female) and ORX terms (representing male), a bias toward reporting of female mice was evident. However, when the terms OVX and ORX were removed, a bias toward the use of male mice was identified. Thus, studies focusing on sex hormones are biased toward female reporting with all other studies biased in reporting of male mice. We now call upon journal editors to introduce consistent guidance for transparent and accessible reporting of murine sex in skeletal research to better monitor preclinical sex bias, to diversify development of treatments for bone health, and to enable global skeletal health equity. © 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)
- Aikta Sharma
- School of Biological Sciences, University of Southampton, Southampton, UK
| | - Lysanne V Michels
- School of Biological Sciences, University of Southampton, Southampton, UK
| | - Andrew A Pitsillides
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - Julie Greeves
- Army Health and Performance Research, Ministry of Defence, Andover, UK
| | - Lillian I Plotkin
- Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN, USA
| | - Valentina Cardo
- Winchester School of Art, University of Southampton, Winchester, UK
| | - Natalie A Sims
- Department of Medicine at St. Vincent's Hospital, St. Vincent's Institute of Medical Research and The University of Melbourne, Fitzroy, Australia
| | - Claire E Clarkin
- School of Biological Sciences, University of Southampton, Southampton, UK
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Alcorta-Sevillano N, Infante A, Macías I, Rodríguez CI. Murine Animal Models in Osteogenesis Imperfecta: The Quest for Improving the Quality of Life. Int J Mol Sci 2022; 24:ijms24010184. [PMID: 36613624 PMCID: PMC9820162 DOI: 10.3390/ijms24010184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/25/2022] Open
Abstract
Osteogenesis imperfecta is a rare genetic disorder characterized by bone fragility, due to alterations in the type I collagen molecule. It is a very heterogeneous disease, both genetically and phenotypically, with a high variability of clinical phenotypes, ranging from mild to severe forms, the most extreme cases being perinatal lethal. There is no curative treatment for OI, and so great efforts are being made in order to develop effective therapies. In these attempts, the in vivo preclinical studies are of paramount importance; therefore, serious analysis is required to choose the right murine OI model able to emulate as closely as possible the disease of the target OI population. In this review, we summarize the features of OI murine models that have been used for preclinical studies until today, together with recently developed new murine models. The bone parameters that are usually evaluated in order to determine the relevance of new developing therapies are exposed, and finally, current and innovative therapeutic strategies attempts considered in murine OI models, along with their mechanism of action, are reviewed. This review aims to summarize the in vivo studies developed in murine models available in the field of OI to date, in order to help the scientific community choose the most accurate OI murine model when developing new therapeutic strategies capable of improving the quality of life.
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Affiliation(s)
- Natividad Alcorta-Sevillano
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
- Department of Cell Biology and Histology, University of Basque Country UPV/EHU, 48940 Leioa, Spain
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
| | - Iratxe Macías
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
| | - Clara I. Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
- Correspondence:
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Lee KJ, Rambault L, Bou-Gharios G, Clegg PD, Akhtar R, Czanner G, van ‘t Hof R, Canty-Laird EG. Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice. Dis Model Mech 2022; 15:dmm049428. [PMID: 36106514 PMCID: PMC9555767 DOI: 10.1242/dmm.049428] [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: 01/06/2022] [Accepted: 08/23/2022] [Indexed: 11/20/2022] Open
Abstract
The osteogenesis imperfecta murine (oim) model with solely homotrimeric (α1)3 type I collagen, owing to a dysfunctional α2(I) collagen chain, has a brittle bone phenotype, implying that the (α1)2(α2)1 heterotrimer is required for physiological bone function. Here, we comprehensively show, for the first time, that mice lacking the α2(I) chain do not have impaired bone biomechanical or structural properties, unlike oim homozygous mice. However, Mendelian inheritance was affected in male mice of both lines, and male mice null for the α2(I) chain exhibited age-related loss of condition. Compound heterozygotes were generated to test whether gene dosage was responsible for the less-severe phenotype of oim heterozygotes, after allelic discrimination showed that the oim mutant allele was not downregulated in heterozygotes. Compound heterozygotes had impaired bone structural properties compared to those of oim heterozygotes, albeit to a lesser extent than those of oim homozygotes. Hence, the presence of heterotrimeric type I collagen in oim heterozygotes alleviates the effect of the oim mutant allele, but a genetic interaction between homotrimeric type I collagen and the oim mutant allele leads to bone fragility.
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Affiliation(s)
- Katie J. Lee
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
| | - Lisa Rambault
- Département d'Informatique, Université de Poitiers, 86073 Poitiers Cedex 9, France
| | - George Bou-Gharios
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
| | - Peter D. Clegg
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
- The Medical Research Council Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
| | - Riaz Akhtar
- Department of Mechanical, Materials and Aerospace Engineering, School of Engineering, University of Liverpool, Liverpool L69 3GH, UK
| | - Gabriela Czanner
- School of Computer Science and Mathematics, Faculty of Engineering and Technology, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK
| | - Rob van ‘t Hof
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
| | - Elizabeth G. Canty-Laird
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
- The Medical Research Council Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
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11
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Deng Z, Gao X, Utsunomiya H, Arner JW, Ruzbarsky JJ, Huard M, Ravuri S, Philippon MJ, Huard J. Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model. Bone Rep 2022; 16:101526. [PMID: 35372645 PMCID: PMC8971351 DOI: 10.1016/j.bonr.2022.101526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 11/26/2022] Open
Abstract
Background and aims Previous work has shown that oral losartan can enhance microfracture-mediated cartilage repair in a rabbit osteochondral defect injury model. In this study, we aimed to determine whether oral losartan would have a detrimental effect on articular cartilage and bone homeostasis in the uninjured sides. Methods New Zealand rabbits were divided into 4 groups including normal uninjured (Normal), contralateral uninjured side of osteochondral defect (Defect), osteochondral defect plus microfracture (Microfracture) and osteochondral defect plus microfracture and losartan oral administration (10 mg/kg/day) (Losartan). Rabbits underwent different surgeries and treatment and were sacrificed at 12 weeks. Both side of the normal group and uninjured side of treatment groups tibias were harvested for Micro-CT and histological analysis for cartilage and bone including H&E staining, Herovici's staining (bone and cartilage) Alcian blue and Safranin O staining (cartilage) as well as immunohistochemistry of losartan related signaling pathways molecules for both cartilage and bone. Results Our results showed losartan oral treatment at 10 mg/kg/day slightly increase Alcian blue positive matrix as well as decrease collagen type 3 in articular cartilage while having no significant effect on articular cartilage structure, cellularity, and other matrix. Losartan treatment also did not affect angiotensin receptor type 1 (AGTR1), angiotensin receptor type 2 (AGTR2) and phosphorylated transforming factor β1 activated kinase 1 (pTAK1) expression level and pattern in the articular cartilage. Furthermore, losartan treatment did not affect microarchitecture of normal cancellous bone and cortical bone of tibias compared to normal and other groups. Losartan treatment slightly increased osteocalcin positive osteoblasts on the surface of cancellous bone and did not affect bone matrix collagen type 1 content and did not change AGTR1, AGTR2 and pTAK1 signal molecule expression. Conclusion Oral losartan used as a microfracture augmentation therapeutic does not have significant effect on uninjured articular cartilage and bone based on our preclinical rabbit model. These results provided further evidence that the current regimen of using losartan as a microfracture augmentation therapeutic is safe with respect to bone and cartilage homeostasis and support clinical trials for its application in human cartilage repair.
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12
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Shanas N, Querido W, Oswald J, Jepsen K, Carter E, Raggio C, Pleshko N. Infrared Spectroscopy-Determined Bone Compositional Changes Associated with Anti-Resorptive Treatment of the oim/oim Mouse Model of Osteogenesis Imperfecta. APPLIED SPECTROSCOPY 2022; 76:416-427. [PMID: 34643134 DOI: 10.1177/00037028211055477] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Applications of vibrational spectroscopy to assess bone disease and therapeutic interventions are continually advancing, with tissue mineral and protein composition frequently investigated. Here, we used two spectroscopic approaches for determining bone composition in a mouse model (oim) of the brittle bone disease osteogenesis imperfecta (OI) with and without antiresorptive agent treatment (alendronate, or ALN, and RANK-Fc). Near-infrared (NIR) spectral analysis using a fiber optic probe and attenuated total reflection Fourier transform infrared spectroscopy (ATR FTIR) mode were applied to investigate bone composition, including water, mineral, and protein content. Spectral parameters revealed differences among the control wildtype (WT) and OIM groups. NIR spectral analysis of protein and water showed that OIM mouse humerii had ∼50% lower protein and ∼50% higher overall water content compared to WT bone. Moreover, some OIM-treated groups showed a reduction in bone water compared to OIM controls, approximating values observed in WT bone. Differences in bone quality based on increased mineral content and reduced carbonate content were also found between some groups of treated OIM and WT bone, but crystallinity did not differ among all groups. The spectroscopically determined parameters were evaluated for correlations with gold-standard mechanical testing values to gain insight into how composition influenced bone strength. As expected, bone mechanical strength parameters were consistently up to threefold greater in WT mice compared to OIM groups, except for stiffness in the ALN-treated OIM groups. Furthermore, bone stiffness, maximum load, and post-yield displacement showed the strongest correlations with NIR-determined protein content (positive correlations) and bound-water content (negative correlations). These results demonstrate that in this study, NIR spectral parameters were more sensitive to bone composition differences than ATR parameters, highlighting the potential of this nondestructive approach for screening of bone diseases and therapeutic efficacy in pre-clinical models.
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Affiliation(s)
- No'ad Shanas
- Department of Bioengineering, Temple University, Philadelphia, PA, USA
| | - William Querido
- Department of Bioengineering, Temple University, Philadelphia, PA, USA
| | - Jack Oswald
- Department of Bioengineering, Temple University, Philadelphia, PA, USA
| | - Karl Jepsen
- Department of Orthopaedic Surgery and Bioengineering. University of Michigan, Ann Arbor, MI, USA
| | - Erin Carter
- Kathryn O. and Alan C. Greenberg Center for Skeletal Dysplasias, 25062Hospital for Special Surgery, New York City, NY, USA
| | - Cathleen Raggio
- Kathryn O. and Alan C. Greenberg Center for Skeletal Dysplasias, 25062Hospital for Special Surgery, New York City, NY, USA
| | - Nancy Pleshko
- Department of Bioengineering, Temple University, Philadelphia, PA, USA
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13
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Scheiber AL, Wilkinson KJ, Suzuki A, Enomoto-Iwamoto M, Kaito T, Cheah KS, Iwamoto M, Leikin S, Otsuru S. 4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts. JCI Insight 2022; 7:149636. [PMID: 34990412 PMCID: PMC8855815 DOI: 10.1172/jci.insight.149636] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 12/21/2021] [Indexed: 11/17/2022] Open
Abstract
Short stature is a major skeletal phenotype in osteogenesis imperfecta (OI), a genetic disorder mainly caused by mutations in genes encoding type I collagen. However, the underlying mechanism is poorly understood, and no effective treatment is available. In OI mice that carry a G610C mutation in COL1A2, we previously found that mature hypertrophic chondrocytes (HCs) are exposed to cell stress due to accumulation of misfolded mutant type I procollagen in the endoplasmic reticulum (ER). By fate mapping analysis of HCs in G610C OI mice, we found that HCs stagnate in the growth plate, inhibiting translocation of HC descendants to the trabecular area and their differentiation to osteoblasts. Treatment with 4-phenylbutyric acid (4PBA), a chemical chaperone, restored HC ER structure and rescued this inhibition, resulting in enhanced longitudinal bone growth in G610C OI mice. Interestingly, the effects of 4PBA on ER dilation were limited in osteoblasts, and the bone fragility was not ameliorated. These results highlight the importance of targeting HCs to treat growth deficiency in OI. Our findings demonstrate that HC dysfunction induced by ER disruption plays a critical role in the pathogenesis of OI growth deficiency, which lays the foundation for developing new therapies for OI.
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Affiliation(s)
- Amanda L Scheiber
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
| | - Kevin J Wilkinson
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
| | - Akiko Suzuki
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
| | - Motomi Enomoto-Iwamoto
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
| | - Takashi Kaito
- Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Kathryn Se Cheah
- School of Biomedical Sciences, University of Hong Kong, Hong Kong, China
| | - Masahiro Iwamoto
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
| | - Sergey Leikin
- Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health & Human Developme, Bethesda, United States of America
| | - Satoru Otsuru
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States of America
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14
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Cardinal M, Chretien A, Roels T, Lafont S, Ominsky MS, Devogelaer JP, Manicourt DH, Behets C. Gender-Related Impact of Sclerostin Antibody on Bone in the Osteogenesis Imperfecta Mouse. Front Genet 2021; 12:705505. [PMID: 34447412 PMCID: PMC8383339 DOI: 10.3389/fgene.2021.705505] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 06/29/2021] [Indexed: 11/13/2022] Open
Abstract
Osteogenesis imperfecta (OI), which is most often due to a collagen type 1 gene mutation, is characterized by low bone density and bone fragility. In OI patients, gender-related differences were reported, but data in the literature are not convergent. We previously observed that sclerostin antibody (Scl-Ab), which stimulates osteoblast Wnt pathway via sclerostin inactivation, improved spine and long-bone parameters and biomechanical strength in female oim/oim mice, a validated model of human type 3 OI. Here, we wanted to highlight the effect of Scl-Ab on male oim/oim bones in order to identify a possible distinct therapeutic effect from that observed in females. According to the same protocol as our previous study with female mice, male wild-type (Wt) and oim/oim mice received vehicle or Scl-Ab from 5 to 14 weeks of age. Clinimetric and quantitative bone parameters were studied using X-rays, peripheral quantitative computed tomography, microradiography, and dynamic histomorphometry and compared to those of females. Contrary to Wt mice, male oim/oim had significantly lower weight, snout-sacrum length, and bone mineral content than females at 5 weeks. No significant difference in these clinimetric parameters was observed at 14 weeks, whereas male oim showed significantly more long-bone fractures than females. Scl-Ab improved bone mineral density and bone volume/total volume ratio (BV/TV) of vertebral body in Wt and oim/oim, without significant difference between male and female at 14 weeks. Male vehicle oim/oim had a significantly lower cortical thickness (Ct.Th) and BV/TV of tibial diaphysis than female and showed a higher number of fractures at 14 weeks. Scl-Ab increased midshaft periosteal apposition rate in such a way that tibial Ct.Th of male oim/oim was not significantly different from the female one at 14 weeks. The number of fractures was lower in male than female oim/oim after 14 weeks of Scl-Ab treatment, but this difference was not significant. Nevertheless, Scl-Ab-treated oim/oim male and female mice remained smaller than the Wt ones. In conclusion, our results highlighted differences between male and female oim/oim at 4 and 14 weeks of age, as well as some male-specific response of cortical bone to Scl-Ab. These gender-related particularities of oim/oim should be considered when testing experimental treatments.
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Affiliation(s)
- Mickaël Cardinal
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Antoine Chretien
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Thomas Roels
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Sébastien Lafont
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Michael S Ominsky
- Radius Inc., Waltham, MA, United States.,Amgen Inc., Thousand Oaks, CA, United States
| | - Jean-Pierre Devogelaer
- Pole of Rheumatic Pathologies, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Daniel H Manicourt
- Pole of Rheumatic Pathologies, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Catherine Behets
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
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15
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Kohler R, Tastad CA, Creecy A, Wallace JM. Morphological and mechanical characterization of bone phenotypes in the Amish G610C murine model of osteogenesis imperfecta. PLoS One 2021; 16:e0255315. [PMID: 34449800 PMCID: PMC8396767 DOI: 10.1371/journal.pone.0255315] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/13/2021] [Indexed: 11/27/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a hereditary bone disease where gene mutations affect Type I collagen formation resulting in osteopenia and increased fracture risk. There are several established mouse models of OI, but some are severe and result in spontaneous fractures or early animal death. The Amish Col1a2G610C/+ (G610C) mouse model is a newer, moderate OI model that is currently being used in a variety of intervention studies, with differing background strains, sexes, ages, and bone endpoints. This study is a comprehensive mechanical and architectural characterization of bone in G610C mice bred on a C57BL/6 inbred strain and will provide a baseline for future treatment studies. Male and female wild-type (WT) and G610C mice were euthanized at 10 and 16 weeks (n = 13-16). Harvested tibiae, femora, and L4 vertebrae were scanned via micro-computed tomography and analyzed for cortical and trabecular architectural properties. Femora and tibiae were then mechanically tested to failure. G610C mice had less bone but more highly mineralized cortical and trabecular tissue than their sex- and age-matched WT counterparts, with cortical cross-sectional area, thickness, and mineral density, and trabecular bone volume, mineral density, spacing, and number all differing significantly as a function of genotype (2 Way ANOVA with main effects of sex and genotype at each age). In addition, mechanical yield force, ultimate force, displacement, strain, and toughness were all significantly lower in G610C vs. WT, highlighting a brittle phenotype. This characterization demonstrates that despite being a moderate OI model, the Amish G610C mouse model maintains a distinctly brittle phenotype and is well-suited for use in future intervention studies.
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Affiliation(s)
- Rachel Kohler
- Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States of America
| | - Carli A. Tastad
- Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States of America
| | - Amy Creecy
- Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States of America
| | - Joseph M. Wallace
- Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States of America
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16
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Sharma A, Goring A, Johnson PB, Emery RJH, Hesse E, Boyde A, Olsen BR, Pitsillides AA, Oreffo ROC, Mahajan S, Clarkin CE. Multiscale molecular profiling of pathological bone resolves sexually dimorphic control of extracellular matrix composition. Dis Model Mech 2021; 14:dmm048116. [PMID: 33563616 PMCID: PMC7988766 DOI: 10.1242/dmm.048116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/21/2021] [Indexed: 11/28/2022] Open
Abstract
Collagen assembly during development is essential for successful matrix mineralisation, which determines bone quality and mechanocompetence. However, the biochemical and structural perturbations that drive pathological skeletal collagen configuration remain unclear. Deletion of vascular endothelial growth factor (VEGF; also known as VEGFA) in bone-forming osteoblasts (OBs) induces sex-specific alterations in extracellular matrix (ECM) conformation and mineralisation coupled to vascular changes, which are augmented in males. Whether this phenotypic dimorphism arises as a result of the divergent control of ECM composition and its subsequent arrangement is unknown and is the focus of this study. Herein, we used murine osteocalcin-specific Vegf knockout (OcnVEGFKO) and performed ex vivo multiscale analysis at the tibiofibular junction of both sexes. Label-free and non-destructive polarisation-resolved second-harmonic generation (p-SHG) microscopy revealed a reduction in collagen fibre number in males following the loss of VEGF, complemented by observable defects in matrix organisation by backscattered electron scanning electron microscopy. This was accompanied by localised divergence in collagen orientation, determined by p-SHG anisotropy measurements, as a result of OcnVEGFKO. Raman spectroscopy confirmed that the effect on collagen was linked to molecular dimorphic VEGF effects on collagen-specific proline and hydroxyproline, and collagen intra-strand stability, in addition to matrix carbonation and mineralisation. Vegf deletion in male and female murine OB cultures in vitro further highlighted divergence in genes regulating local ECM structure, including Adamts2, Spp1, Mmp9 and Lama1. Our results demonstrate the utility of macromolecular imaging and spectroscopic modalities for the detection of collagen arrangement and ECM composition in pathological bone. Linking the sex-specific genetic regulators to matrix signatures could be important for treatment of dimorphic bone disorders that clinically manifest in pathological nano- and macro-level disorganisation. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Aikta Sharma
- School of Biological Sciences, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK
| | - Alice Goring
- School of Biological Sciences, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK
| | - Peter B. Johnson
- School of Chemistry and Institute for Life Sciences, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK
| | - Roger J. H. Emery
- Department of Surgery and Cancer, Faculty of Medicine, St Mary's Campus, Imperial College London, London W2 1PG, UK
| | - Eric Hesse
- Institute of Molecular Musculoskeletal Research, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Munich 80336, Germany
| | - Alan Boyde
- Dental Physical Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK
| | - Bjorn R. Olsen
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA
| | - Andrew A. Pitsillides
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK
| | - Richard O. C. Oreffo
- Centre for Human Development, Stem Cell and Regeneration, Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Sumeet Mahajan
- School of Chemistry and Institute for Life Sciences, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK
| | - Claire E. Clarkin
- School of Biological Sciences, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK
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17
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Maghsoudi-Ganjeh M, Samuel J, Ahsan AS, Wang X, Zeng X. Intrafibrillar mineralization deficiency and osteogenesis imperfecta mouse bone fragility. J Mech Behav Biomed Mater 2021; 117:104377. [PMID: 33636677 DOI: 10.1016/j.jmbbm.2021.104377] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/27/2021] [Accepted: 01/30/2021] [Indexed: 01/25/2023]
Abstract
Osteogenesis imperfecta (OI), a brittle bone disease, is known to result in severe bone fragility. However, its ultrastructural origins are still poorly understood. In this study, we hypothesized that deficient intrafibrillar mineralization is a key contributor to the OI induced bone brittleness. To test this hypothesis, we explored the mechanical and ultrastructural changes in OI bone using the osteogenesis imperfecta murine (oim) model. Synchrotron X-ray scattering experiments indicated that oim bone had much less intrafibrillar mineralization than wild type bone, thus verifying that the loss of mineral crystals indeed primarily occurred in the intrafibrillar space of oim bone. It was also found that the mineral crystals were organized from preferentially in longitudinal axis in wild type bone to more randomly in oim bone. Moreover, it revealed that the deformation of mineral crystals was more coordinated with collagen fibrils in wild type than in oim bone, suggesting that the load transfer deteriorated between the two phases in oim bone. The micropillar test revealed that the compression work to fracture of oim bone (8.2 ± 0.9 MJ/m3) was significantly smaller (p < 0.05) than that of wild type bone (13.9 ± 2.7 MJ/m3), while the bone strength was not statistically different (p > 0.05) between the two genotype groups. In contrast, the uniaxial tensile test showed that the ultimate strength of wild type bone (50 ± 4.5 MPa) was significantly greater (p < 0.05) than that of oim bone (38 ± 5.3 MPa). Furthermore, the nanoscratch test showed that the toughness of oim bone was much less than that of wild type bone (6.6 ± 2.2 GJ/m3 vs. 12.6 ± 1.4 GJ/m3). Finally, in silico simulations using a finite element model of sub-lamellar bone confirmed the links between the reduced intrafibrillar mineralization and the observed changes in the mechanical behavior of OI bone. Taken together, these results provide important mechanistic insights into the underlying cause of poor mechanical quality of OI bone, thus pave the way toward future treatments of this brittle bone disease.
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Affiliation(s)
| | - Jitin Samuel
- Department of Mechanical Engineering, University of Texas at San Antonio, San Antonio, TX, USA
| | - Abu Saleh Ahsan
- Department of Mechanical Engineering, University of Texas at San Antonio, San Antonio, TX, USA
| | - Xiaodu Wang
- Department of Mechanical Engineering, University of Texas at San Antonio, San Antonio, TX, USA.
| | - Xiaowei Zeng
- Department of Mechanical Engineering, University of Texas at San Antonio, San Antonio, TX, USA.
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18
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Taylor EA, Donnelly E. Raman and Fourier transform infrared imaging for characterization of bone material properties. Bone 2020; 139:115490. [PMID: 32569874 DOI: 10.1016/j.bone.2020.115490] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/08/2020] [Accepted: 06/11/2020] [Indexed: 12/12/2022]
Abstract
As the application of Raman spectroscopy to study bone has grown over the past decade, making it a peer technology to FTIR spectroscopy, it has become critical to understand their complimentary roles. Recent technological advancements have allowed these techniques to collect grids of spectra in a spatially resolved fashion to generate compositional images. The advantage of imaging with these techniques is that it allows the heterogenous bone tissue composition to be resolved and quantified. In this review we compare, for non-experts in the field of vibrational spectroscopy, the instrumentation and underlying physical principles of FTIR imaging (FTIRI) and Raman imaging. Additionally, we discuss the strengths and limitations of FTIR and Raman spectroscopy, address sample preparation, and discuss outcomes to provide researchers insight into which techniques are best suited for a given research question. We then briefly discuss previous applications of FTIRI and Raman imaging to characterize bone tissue composition and relationships of compositional outcomes with mechanical performance. Finally, we discuss emerging technical developments in FTIRI and Raman imaging which provide new opportunities to identify changes in bone tissue composition with disease, age, and drug treatment.
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Affiliation(s)
- Erik A Taylor
- Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, United States of America
| | - Eve Donnelly
- Department of Materials Science and Engineering, Cornell University, Ithaca, NY, United States of America; Research division, Hospital for Special Surgery, New York, NY, United States of America.
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19
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Oestreich AK, DeCata JA, Akers JD, Phillips CL, Schulz LC. Fecundity is impaired in a mouse model of osteogenesis imperfecta. Mol Reprod Dev 2020; 87:927-929. [PMID: 32869432 DOI: 10.1002/mrd.23416] [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: 05/08/2020] [Revised: 07/27/2020] [Accepted: 08/15/2020] [Indexed: 11/11/2022]
Abstract
Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by mutations in genes encoding type I collagen or proteins that process it. Women with OI have a small, but significant increase in risk of serious pregnancy complications including uterine rupture. Here, the OI mouse, Col1a2oim/oim , was used to examine the effects of collagen mutation on establishment and maintenance of pregnancy. Picrosirius birefringence was faint in Col1a2oim/oim uteri, indicating diminished collagen in the myometrium and endometrium. There was some evidence of increased uterine gland number (p = .055) and size (p = .12) in (p = .055) virgin uteri, though the they were not significantly different than controls. There were no differences in the number of corpora lutea, or the time from pairing to delivery of pups between Col1a2oim/oim and control dams, suggesting that ovulation and conception occur normally. However, when examined at Gestation Day 6.5 (postimplantation), gestation Day 10.5 (midpregnancy), and Postnatal Days 1-2, Col1a2oim/oim dams had significantly fewer viable pups than controls overall. In pairwise comparisons, the loss was only significant in the postnatal group, suggesting the gradual loss of pups over time. Overall, the Col1a2oim/oim mouse data suggest that OI impairs uterine function in pregnancy in a way that affects a small but significant number of fetuses.
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Affiliation(s)
- Arin K Oestreich
- Department of Obstetrics, Gynecology, and Women's Health, University of Missouri, Columbia, Missouri
| | - Jenna A DeCata
- Department of Obstetrics, Gynecology, and Women's Health, University of Missouri, Columbia, Missouri
| | - Janae D Akers
- Department of Obstetrics, Gynecology, and Women's Health, University of Missouri, Columbia, Missouri
| | - Charlotte L Phillips
- Departments of Biochemistry and Child Health, University of Missouri, Columbia, Missouri
| | - Laura C Schulz
- Department of Obstetrics, Gynecology, and Women's Health, University of Missouri, Columbia, Missouri
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20
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Oestreich AK, Onuzuriuke A, Yao X, Talton O, Wang Y, Pfeiffer FM, Schulz LC, Phillips CL. Leprdb/+ Dams Protect Wild-type Male Offspring Bone Strength from the Detrimental Effects of a High-Fat Diet. Endocrinology 2020; 161:5850509. [PMID: 32484851 PMCID: PMC7417874 DOI: 10.1210/endocr/bqaa087] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 05/27/2020] [Indexed: 01/03/2023]
Abstract
The prevalence of maternal obesity is increasing at an alarming rate and increases the life-long risk of developing cardiometabolic disease in adult offspring. Leptin, an adipokine, is systemically elevated in the obese milieu. We recently showed that maternal hyperleptinemia without obesity improves offspring insulin sensitivity and glucose tolerance while protecting against weight gain on a high-fat, high-sugar (HFD). Here, we investigate the effect of maternal hyperleptinemia on offspring bone by using 2 independent maternal models. First, we compared wild-type (WT) offspring from severely hyperleptinemic Leprdb/+ (DB/+) dams with those from WT dams. In the second model, WT females were implanted with miniosmotic pumps that released either saline (group SAL) or leptin (group LEP; 650ng/hour) and the WT offspring were compared. At 23 weeks of age, a subset of offspring were challenged with a HFD for 8 weeks. When the offspring were 31 weeks of age, bone geometry, strength, and material properties were investigated. The HFD increased trabecular bone volume but decreased both total breaking strength and material strength of femora from the offspring of WT dams. However, male offspring of DB/+ dams were protected from the detrimental effects of a HFD, while offspring of LEP dams were not. Further material analysis revealed a modest decrease in advanced glycation end product accumulation coupled with increased collagen crosslinking in male offspring from DB/+ dams on a HFD. These data suggest that while maternal leptin may protect bone quality from the effects of a HFD, additional factors of the maternal environment controlled by leptin receptor signaling are likely also involved.
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Affiliation(s)
- Arin K Oestreich
- Division of Biological Sciences, University of Missouri, Columbia, Missouri
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri, Columbia, Missouri
- Correspondence: Arin Oestreich, Washington University School of Medicine, 3rd Floor, Scott McKinley Building, 4523 Clayton Avenue, St Louis, MO, 63110. E-mail:
| | | | - Xiaomei Yao
- School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri
| | | | - Yong Wang
- School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri
| | - Ferris M Pfeiffer
- Department of Biomedical, Biological & Chemical Engineering, University of Missouri, Columbia, Missouri
| | - Laura C Schulz
- Division of Biological Sciences, University of Missouri, Columbia, Missouri
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri, Columbia, Missouri
| | - Charlotte L Phillips
- Department of Biochemistry, University of Missouri, Columbia, Missouri
- Department of Child Health, University of Missouri, Columbia, Missouri
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21
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Dole NS, Yee CS, Mazur CM, Acevedo C, Alliston T. TGFβ Regulation of Perilacunar/Canalicular Remodeling Is Sexually Dimorphic. J Bone Miner Res 2020; 35:1549-1561. [PMID: 32282961 PMCID: PMC9126317 DOI: 10.1002/jbmr.4023] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 03/14/2020] [Accepted: 03/21/2020] [Indexed: 12/12/2022]
Abstract
Bone fragility is the product of defects in bone mass and bone quality, both of which show sex-specific differences. Despite this, the cellular and molecular mechanisms underpinning the sexually dimorphic control of bone quality remain unclear, limiting our ability to effectively prevent fractures, especially in postmenopausal osteoporosis. Recently, using male mice, we found that systemic or osteocyte-intrinsic inhibition of TGFβ signaling, achieved using the 9.6-kb DMP1 promoter-driven Cre recombinase (TβRIIocy-/- mice), suppresses osteocyte perilacunar/canalicular remodeling (PLR) and compromises bone quality. Because systemic TGFβ inhibition more robustly increases bone mass in female than male mice, we postulated that sex-specific differences in bone quality could likewise result, in part, from dimorphic regulation of PLR by TGFβ. Moreover, because lactation induces PLR, we examined the effect of TGFβ inhibition on the female skeleton during lactation. In contrast to males, female mice that possess an osteocyte-intrinsic defect in TGFβ signaling were protected from TGFβ-dependent defects in PLR and bone quality. The expression of requisite PLR enzymes, the lacunocanalicular network (LCN), and the flexural strength of female TβRIIocy-/- bone was intact. With lactation, however, bone loss and induction in PLR and osteocytic parathyroid hormone type I receptor (PTHR1) expression, were suppressed in TβRIIocy-/- bone, relative to the control littermates. Indeed, differential control of PTHR1 expression, by TGFβ and other factors, may contribute to dimorphism in PLR regulation in male and female TβRIIocy-/- mice. These findings provide key insights into the sex-based differences in osteocyte PLR that underlie bone quality and highlight TGFβ signaling as a crucial regulator of lactation-induced PLR. © 2020 American Society for Bone and Mineral Research.
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Affiliation(s)
- Neha S Dole
- Department of Orthopaedic Surgery, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Cristal S Yee
- Department of Orthopaedic Surgery, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Courtney M Mazur
- Department of Orthopaedic Surgery, University of California, San Francisco (UCSF), San Francisco, CA, USA.,University of California (UC) Berkeley-UCSF Graduate Program in Bioengineering, San Francisco, CA, USA
| | - Claire Acevedo
- Department of Mechanical Engineering, University of Utah, Salt Lake City, UT, USA
| | - Tamara Alliston
- Department of Orthopaedic Surgery, University of California, San Francisco (UCSF), San Francisco, CA, USA
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22
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Cardinal M, Dessain A, Roels T, Lafont S, Ominsky MS, Devogelaer JP, Chappard D, Mabilleau G, Ammann P, Nyssen-Behets C, Manicourt DH. Sclerostin-Antibody Treatment Decreases Fracture Rates in Axial Skeleton and Improves the Skeletal Phenotype in Growing oim/oim Mice. Calcif Tissue Int 2020; 106:494-508. [PMID: 32025752 DOI: 10.1007/s00223-019-00655-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 12/28/2019] [Indexed: 12/11/2022]
Abstract
In osteogenesis imperfecta (OI), vertebrae brittleness causes thorax deformations and leads to cardiopulmonary failure. As sclerostin-neutralizing antibodies increase bone mass and strength in animal models of osteoporosis, their administration in two murine models of severe OI enhanced the strength of vertebrae in growing female Crtap-/- mice but not in growing male Col1a1Jrt/+ mice. However, these two studies ignored the impact of antibodies on spine growth, fracture rates, and compressive mechanical properties. Here, we conducted a randomized controlled trial in oim/oim mice, an established model of human severe OI type III due to a mutation in Col1a2. Five-week-old female WT and oim/oim mice received either PBS or sclerostin antibody (Scl-Ab) for 9 weeks. Analyses included radiography, histomorphometry, pQCT, microcomputed tomography, and biomechanical testing. Though it did not modify vertebral axial growth, Scl-Ab treatment markedly reduced the fracture prevalence in the pelvis and caudal vertebrae, enhanced osteoblast activity (L4), increased cervico-sacral spine BMD, and improved the lumbosacral spine bone cross-sectional area. Scl-Ab did not impact vertebral height and body size but enhanced the cortical thickness and trabecular bone volume significantly in the two Scl-Ab groups. At lumbar vertebrae and tibial metaphysis, the absolute increase in cortical and trabecular bone mass was higher in Scl-Ab WT than in Scl-Ab oim/oim. The effects on trabecular bone mass were mainly due to changes in trabecular number at vertebrae and in trabecular thickness at metaphyses. Additionally, Scl-Ab did not restore a standard trabecular network, but improved bone compressive ultimate load with more robust effects at vertebrae than at metaphysis. Overall, Scl-Ab treatment may be beneficial for reducing vertebral fractures and spine deformities in patients with severe OI.
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Affiliation(s)
- Mickaël Cardinal
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium.
| | - Alicia Dessain
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium
| | - Thomas Roels
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium
| | - Sébastien Lafont
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium
| | - Michael S Ominsky
- Radius Health, Inc. (Formerly at Amgen Inc, Thousand Oaks, CA, USA), Waltham, MA, USA
| | - Jean-Pierre Devogelaer
- Pole of Rheumatology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Daniel Chappard
- GEROM, Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux, University of Angers, 49933, Angers, France
| | - Guillaume Mabilleau
- GEROM, Groupe d'Etudes sur le Remodelage Osseux et les bioMatériaux, University of Angers, 49933, Angers, France
| | - Patrick Ammann
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital, Geneva, Switzerland
| | - Catherine Nyssen-Behets
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, 52 Avenue Mounier - B1.52.04, 1200, Brussels, Belgium
| | - Daniel H Manicourt
- Pole of Rheumatology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
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23
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Berman AG, Organ JM, Allen MR, Wallace JM. Muscle contraction induces osteogenic levels of cortical bone strain despite muscle weakness in a mouse model of Osteogenesis Imperfecta. Bone 2020; 132:115061. [PMID: 31805389 PMCID: PMC7720097 DOI: 10.1016/j.bone.2019.115061] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/19/2019] [Accepted: 09/09/2019] [Indexed: 01/05/2023]
Abstract
Mechanical interactions between muscle and bone have long been recognized as integral to bone integrity. However, few studies have directly measured these interactions within the context of musculoskeletal disease. In this study, the osteogenesis imperfecta murine model (oim/oim) was utilized because it has both reduced bone and muscle properties, allowing direct assessment of whether weakened muscle is able to engender strain on weakened bone. To do so, a strain gauge was attached to the tibia of healthy and oim/oim mice, muscles within the posterior quadrant of the lower hind limb were stimulated, and bone strain during muscle contraction was measured. Results indicated that the relationship between maximum muscle torque and maximum engendered strain is altered in oim/oim bone, with less torque required to engender strain compare to wild-type and heterozygous mice. Maximum muscle torque at 150 Hz stimulation frequency was able to engender ~1500 μɛ in oim/oim animals. However, even though the strain engendered in the oim/oim mice was high relative to historical bone formation thresholds, the maximum strain values were still significantly lower than that of the wild-type mice. These results are promising in that they suggest that muscle stimulation may be a viable means of inducing bone formation in oim/oim and potentially other disease models where muscle weakness/atrophy exist.
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Affiliation(s)
- Alycia G Berman
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
| | - Jason M Organ
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Matthew R Allen
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, Indianapolis, IN, USA
| | - Joseph M Wallace
- Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, Indianapolis, IN, USA.
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24
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Mitxitorena I, Infante A, Gener B, Rodríguez CI. Suitability and limitations of mesenchymal stem cells to elucidate human bone illness. World J Stem Cells 2019; 11:578-593. [PMID: 31616536 PMCID: PMC6789184 DOI: 10.4252/wjsc.v11.i9.578] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 07/31/2019] [Accepted: 08/27/2019] [Indexed: 02/06/2023] Open
Abstract
Functional impairment of mesenchymal stem cells (MSCs), osteoblast progenitor cells, has been proposed to be a pathological mechanism contributing to bone disorders, such as osteoporosis (the most common bone disease) and other rare inherited skeletal dysplasias. Pathological bone loss can be caused not only by an enhanced bone resorption activity but also by hampered osteogenic differentiation of MSCs. The majority of the current treatment options counteract bone loss, and therefore bone fragility by blocking bone resorption. These so-called antiresorptive treatments, in spite of being effective at reducing fracture risk, cannot be administered for extended periods due to security concerns. Therefore, there is a real need to develop osteoanabolic therapies to promote bone formation. Human MSCs emerge as a suitable tool to study the etiology of bone disorders at the cellular level as well as to be used for cell therapy purposes for bone diseases. This review will focus on the most relevant findings using human MSCs as an in vitro cell model to unravel pathological bone mechanisms and the application and outcomes of human MSCs in cell therapy clinical trials for bone disease.
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Affiliation(s)
- Izaskun Mitxitorena
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
| | - Blanca Gener
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
- Service of Genetics, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
- Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid 28005, Spain
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
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25
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Gremminger VL, Jeong Y, Cunningham RP, Meers GM, Rector RS, Phillips CL. Compromised Exercise Capacity and Mitochondrial Dysfunction in the Osteogenesis Imperfecta Murine (oim) Mouse Model. J Bone Miner Res 2019; 34:1646-1659. [PMID: 30908713 PMCID: PMC6744299 DOI: 10.1002/jbmr.3732] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 03/13/2019] [Accepted: 03/18/2019] [Indexed: 11/09/2022]
Abstract
Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that most often arises from type I collagen-COL1A1 and COL1A2-gene defects leading to skeletal fragility, short stature, blue-gray sclera, and muscle weakness. Relative to the skeletal fragility, muscle weakness is much less understood. Recent investigations into OI muscle weakness in both patients and mouse models have revealed the presence of an inherent muscle pathology. Understanding the mechanisms responsible for OI muscle weakness is critical, particularly in light of the extensive cross-talk between muscle and bone via mechanotransduction and biochemical signaling. In the following study we initially subjected WT and oim/oim mice, modeling severe human OI type III, to either weight-bearing (voluntary wheel-running) or non-weight-bearing (swimming) exercise regimens as a modality to improve muscle strength and ultimately bone strength. The oim/oim mice ran only 35% to 42% of the distance run by age- and sex-matched WT mice and exhibited little improvement with either exercise regimen. Upon further investigation, we determined that oim/oim gastrocnemius muscle exhibited severe mitochondrial dysfunction as characterized by a 52% to 65% decrease in mitochondrial respiration rates, alterations in markers of mitochondrial biogenesis, mitophagy, and the electron transport chain components, as well as decreased mitochondrial citrate synthase activity, relative to age- and sex-matched WT gastrocnemius muscle. Thus, mitochondrial dysfunction in the oim/oim mouse likely contributes to compromised muscle function and reduced physical activity levels. © 2019 American Society for Bone and Mineral Research.
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Affiliation(s)
| | - Youngjae Jeong
- Department of Biochemistry, University of Missouri, Columbia, Missouri, 65211
| | - Rory P. Cunningham
- Departments of Nutrition and Exercise Physiology and Medicine-GI, University of Missouri; Research Service-Harry S Truman Memorial VA Hospital, Columbia, MO 65201
| | - Grace M. Meers
- Departments of Nutrition and Exercise Physiology and Medicine-GI, University of Missouri; Research Service-Harry S Truman Memorial VA Hospital, Columbia, MO 65201
| | - R. Scott Rector
- Departments of Nutrition and Exercise Physiology and Medicine-GI, University of Missouri; Research Service-Harry S Truman Memorial VA Hospital, Columbia, MO 65201
| | - Charlotte L. Phillips
- Department of Biochemistry, University of Missouri, Columbia, Missouri, 65211
- Department of Child Health, University of Missouri, Columbia, Missouri, 65211
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26
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Cardinal M, Tys J, Roels T, Lafont S, Ominsky MS, Devogelaer JP, Chappard D, Mabilleau G, Ammann P, Nyssen-Behets C, Manicourt DH. Sclerostin antibody reduces long bone fractures in the oim/oim model of osteogenesis imperfecta. Bone 2019; 124:137-147. [PMID: 31051315 DOI: 10.1016/j.bone.2019.04.011] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 03/31/2019] [Accepted: 04/22/2019] [Indexed: 11/24/2022]
Abstract
Osteogenesis imperfecta type III (OI) is a serious genetic condition with poor bone quality and a high fracture rate in children. In a previous study, it was shown that a monoclonal antibody neutralizing sclerostin (Scl-Ab) increases strength and vertebral bone mass while reducing the number of axial fractures in oim/oim, a mouse model of OI type III. Here, we analyze the impact of Scl-Ab on long bones in OI mice. After 9 weeks of treatment, Scl-Ab significantly reduced long bone fractures (3.6 ± 0.3 versus 2.1 ± 0.8 per mouse, p < 0.001). In addition, the cortical thickness of the tibial midshaft was increased (+42%, p < 0.001), as well as BMD (+28%, p < 0.001), ultimate load (+86%, p < 0.05), plastic energy (+184%; p < 0.05) and stiffness (+172%; p < 0.01) in OI Scl-Ab mice compared to OI vehicle controls. Similar effects of Scl-Ab were observed in Wild type (Wt) mice. The plastic energy, which reflects the fragility of the tissue, was lower in the OI than in the Wt and significantly improved with the Scl-Ab treatment. At the tissue level by nanoindentation, Scl-Ab slightly increased the elastic modulus in bones of both OI and Wt, while moderately increasing tissue hardness (+13% compared to the vehicle; p < 0.05) in Wt bones, but not in OI bones. Although it did not change the properties of the OI bone matrix material, Scl-Ab reduced the fracture rate of the long bones by improving its bone mass, density, geometry, and biomechanical strength. These results suggest that Scl-Ab can reduce long-bone fractures in patients with OI.
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Affiliation(s)
- Mickaël Cardinal
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - Janne Tys
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - Thomas Roels
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - Sébastien Lafont
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - Michael S Ominsky
- Radius, Inc., Waltham, MA, USA, formerly at Amgen Inc, Thousand Oaks, CA, USA.
| | - Jean-Pierre Devogelaer
- Pole of Rheumatic Pathologies, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | | | | | - Patrick Ammann
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital, Geneva, Switzerland.
| | - Catherine Nyssen-Behets
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - Daniel H Manicourt
- Pole of Rheumatic Pathologies, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
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27
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Wang N, Wang L, Wang Z, Cheng L, Wang J. Solanum muricatum
Ameliorates the Symptoms of Osteogenesis Imperfecta
In Vivo. J Food Sci 2019; 84:1646-1650. [PMID: 31116433 DOI: 10.1111/1750-3841.14637] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 04/07/2019] [Accepted: 04/08/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Nan Wang
- Dept. of Emergency Surgerythe First Affiliated Hospital of Zhengzhou Univ. No. 1 Jianshe Rd. Zhengzhou 450052 Henan China
| | - Luyao Wang
- The Center of Stomatologythe First Affiliated Hospital of Zhengzhou Univ. No. 1 Jianshe Rd. Zhengzhou 450052 Henan China
| | - Zhihong Wang
- Dept. of Obstetrics and Gynecologythe Second Affiliated Hospital of Zhengzhou Univ. No. 2 Jingba Rd. Zhengzhou 450014 Henan China
| | - Liangxing Cheng
- Editorial Dept. of Journal of Basic and Clinical Oncologythe First Affiliated Hospital of Zhengzhou Univ. No. 40 Daxue Rd. Zhengzhou 450052 Henan China
| | - Jiaxiang Wang
- Dept. of Pediatric Surgerythe First Affiliated Hospital of Zhengzhou Univ. No. 1 Jianshe Rd. Zhengzhou 450052 Henan China
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28
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Blouin S, Fratzl-Zelman N, Roschger A, Cabral WA, Klaushofer K, Marini JC, Fratzl P, Roschger P. Cortical bone properties in the Brtl/+ mouse model of Osteogenesis imperfecta as evidenced by acoustic transmission microscopy. J Mech Behav Biomed Mater 2018; 90:125-132. [PMID: 30366302 DOI: 10.1016/j.jmbbm.2018.10.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/24/2018] [Accepted: 10/03/2018] [Indexed: 10/28/2022]
Abstract
Higher skeletal fragility has been established for the Brtl/+ mouse model of osteogenesis imperfecta at the whole bone level, but previous investigations of mechanical properties at the bone material level were inconclusive. Bone material was analyzed separately at endosteal (ER) and periosteal regions (PR) on transverse femoral midshaft sections for 2-month old mice (wild-type n = 6; Brtl/+ n = 6). Quantitative backscattered electron imaging revealed that the mass density computed from mineral density maps was higher in PR than in ER for both wild-type (+2.1%, p < 0.05) and Brtl/+ mice (+1.8%, p < 0.05). Electron induced X-ray fluorescence analysis indicated significantly lower atomic Ca/P ratios and higher Na/Ca, Mg/Ca and K/Ca ratios in PR bone compared to ER independently of genotype. Second harmonic generation microscopy indicated that the occurrence of periodically alternating collagen orientation in ER of Brtl/+ mice was strongly reduced compared to wild-type mice. Scanning acoustic microscopy in time of flight mode revealed that the sound velocity and Young's modulus (estimated based on sound velocity and mass density maps) were significantly greater in PR (respectively +6% and +15%) compared to ER in wild-type mice but not in Brtl/+ mice. ER sound velocity and Young's modulus were significantly increased in Brtl/+ mice (+9.4% and +22%, respectively) compared to wild-type mice. These data demonstrate that the Col1a1 G349C mutation in Brtl/+ mice affects the mechanical behavior of bone material predominantly in the endosteal region by altering the collagen orientation.
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Affiliation(s)
- S Blouin
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria.
| | - N Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria
| | - A Roschger
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Postdam, Germany
| | - W A Cabral
- Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
| | - K Klaushofer
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria
| | - J C Marini
- Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
| | - P Fratzl
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Postdam, Germany
| | - P Roschger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria
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29
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Rosemberg DL, Goiano EO, Akkari M, Santili C. Effects of a telescopic intramedullary rod for treating patients with osteogenesis imperfecta of the femur. J Child Orthop 2018; 12:97-103. [PMID: 29456761 PMCID: PMC5813132 DOI: 10.1302/1863-2548.12.170009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
PURPOSE To introduce a new model of telescopic intramedullary rod (TIR), evaluate its effects on treating patients presenting with moderate and severe osteogenesis imperfecta (OI) and to compare the findings with those of other telescopic rods. METHODS A total of 21 patients (nine girls and 12 boys; mean age at first operation, 6.6 years, 1.52 to 13.18) who underwent 52 femoral operations were monitored during a mean of 9.96 years (3.39 to 14.54). Patient characteristics, telescoping rod capability and its complications were examined. RESULTS According to the Sillence classification, we investigated one patient with type I, nine with type III and 11 with type IV OI. Revision rates at up to five years (36%) were inferior to those found for the Fassier-Duval rod (46%). The main cause of revision was fracture (15 patients), followed by rod migration (nine), and infection (two). The rod exhibited higher telescopic capacity in boys than girls. Type III most commonly required an operation; the age group with the highest number of procedures was five to ten years. Male migration was the main cause of rod migration. CONCLUSION The TIR has a satisfactory cost-benefit ratio with less complication rates and low production costs. The TIR is a feasible alternative to the commonly used Fassier-Duval rod. LEVEL OF EVIDENCE IV.
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Affiliation(s)
- D. L. Rosemberg
- Santa Casa de Sao Paulo School of Medical Sciences, School of Medicine, São Paulo, SP, Brazil,Correspondence should be sent to D. L. Rosemberg, Santa Casa de Sao Paulo School of Medical Sciences, School of Medicine, R. Dr. Gabriel dos Santos, 559, ap 201, São Paulo, SP, Brazil. E-mail:
| | - E. O. Goiano
- Santa Casa de Sao Paulo School of Medical Sciences, Dpto. De Ortopedia, Vila Buarque, São Paulo, SP, Brazil
| | - M. Akkari
- Santa Casa de Sao Paulo School of Medical Sciences, Dpto. De Ortopedia, Vila Buarque, São Paulo, SP, Brazil
| | - C. Santili
- Santa Casa de Sao Paulo School of Medical Sciences, Dpto. De Ortopedia, Vila Buarque, São Paulo, SP, Brazil
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30
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Boskey AL, Imbert L. Bone quality changes associated with aging and disease: a review. Ann N Y Acad Sci 2018; 1410:93-106. [PMID: 29265417 DOI: 10.1111/nyas.13572] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 11/11/2017] [Accepted: 11/13/2017] [Indexed: 12/11/2022]
Abstract
Bone quality encompasses all the characteristics of bone that, in addition to density, contribute to its resistance to fracture. In this review, we consider changes in architecture, porosity, and composition, including collagen structure, mineral composition, and crystal size. These factors all are known to vary with tissue and animal ages, and health status. Bone morphology and presence of microcracks, which also contribute to bone quality, will not be discussed in this review. Correlations with mechanical performance for collagen cross-linking, crystallinity, and carbonate content are contrasted with mineral content. Age-dependent changes in humans and rodents are discussed in relation to rodent models of disease. Examples are osteoporosis, osteomalacia, osteogenesis imperfecta (OI), and osteopetrosis in both humans and animal models. Each of these conditions, along with aging, is associated with increased fracture risk for distinct reasons.
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Affiliation(s)
- Adele L Boskey
- Mineralized Tissue Laboratory, Hospital for Special Surgery, New York, New York.,Department of Biochemistry, Weill Cornell Medical College, New York, New York
| | - Laurianne Imbert
- Mineralized Tissue Laboratory, Hospital for Special Surgery, New York, New York
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31
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Matthews BG, Roeder E, Wang X, Aguila HL, Lee SK, Grcevic D, Kalajzic I. Splenomegaly, myeloid lineage expansion and increased osteoclastogenesis in osteogenesis imperfecta murine. Bone 2017; 103:1-11. [PMID: 28600151 PMCID: PMC5764163 DOI: 10.1016/j.bone.2017.06.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 05/14/2017] [Accepted: 06/04/2017] [Indexed: 01/14/2023]
Abstract
Osteogenesis imperfecta (OI) is a disease caused by defects in type I collagen production that results in brittle bones. While the pathology is mainly caused by defects in the osteoblast lineage, there is also elevated bone resorption by osteoclasts resulting in high bone turnover in severe forms of the disease. Osteoclasts originate from hematopoietic myeloid cells, however changes in hematopoiesis have not been previously documented in OI. In this study, we evaluated hematopoietic lineage distribution and osteoclast progenitor cell frequency in bone marrow, spleen and peripheral blood of osteogenesis imperfecta murine (OIM) mice, a model of severe OI. We found splenomegaly in all ages examined, and expansion of myeloid lineage cells (CD11b+) in bone marrow and spleen of 7-9week old male OIM animals. OIM spleens also showed an increased frequency of purified osteoclast progenitors. This phenotype is suggestive of chronic inflammation. Isolated osteoclast precursors from both spleen and bone marrow formed osteoclasts more rapidly than wild-type controls. We found that serum TNFα levels were increased in OIM, as was IL1α in OIM females. We targeted inflammation therapeutically by treating growing animals with murine TNFR2:Fc, a compound that blocks TNFα activity. Anti-TNFα treatment marginally decreased spleen mass in OIM females, but failed to reduce bone resorption, or improve bone parameters or fracture rate in OIM animals. We have demonstrated that OIM mice have changes in their hematopoietic system, and form osteoclasts more rapidly even in the absence of OI osteoblast signals, however therapy targeting TNFα did not improve disease parameters.
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Affiliation(s)
- Brya G Matthews
- Department of Reconstructive Sciences, University of Connecticut, Farmington, CT 06030, USA.
| | - Emilie Roeder
- Department of Reconstructive Sciences, University of Connecticut, Farmington, CT 06030, USA
| | - Xi Wang
- Department of Reconstructive Sciences, University of Connecticut, Farmington, CT 06030, USA
| | | | - Sun-Kyeong Lee
- Center on Aging, University of Connecticut, Farmington, CT 06030, USA
| | - Danka Grcevic
- Department of Physiology and Immunology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Ivo Kalajzic
- Department of Reconstructive Sciences, University of Connecticut, Farmington, CT 06030, USA.
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Bi X, Grafe I, Ding H, Flores R, Munivez E, Jiang MM, Dawson B, Lee B, Ambrose CG. Correlations Between Bone Mechanical Properties and Bone Composition Parameters in Mouse Models of Dominant and Recessive Osteogenesis Imperfecta and the Response to Anti-TGF-β Treatment. J Bone Miner Res 2017; 32:347-359. [PMID: 27649409 PMCID: PMC7894383 DOI: 10.1002/jbmr.2997] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 08/31/2016] [Accepted: 09/08/2016] [Indexed: 12/12/2022]
Abstract
Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by brittle bones that are prone to fracture. Although previous studies in animal models investigated the mechanical properties and material composition of OI bone, little work has been conducted to statistically correlate these parameters to identify key compositional contributors to the impaired bone mechanical behaviors in OI. Further, although increased TGF-β signaling has been demonstrated as a contributing mechanism to the bone pathology in OI models, the relationship between mechanical properties and bone composition after anti-TGF-β treatment in OI has not been studied. Here, we performed follow-up analyses of femurs collected in an earlier study from OI mice with and without anti-TGF-β treatment from both recessive (Crtap-/- ) and dominant (Col1a2+/P.G610C ) OI mouse models and WT mice. Mechanical properties were determined using three-point bending tests and evaluated for statistical correlation with molecular composition in bone tissue assessed by Raman spectroscopy. Statistical regression analysis was conducted to determine significant compositional determinants of mechanical integrity. Interestingly, we found differences in the relationships between bone composition and mechanical properties and in the response to anti-TGF-β treatment. Femurs of both OI models exhibited increased brittleness, which was associated with reduced collagen content and carbonate substitution. In the Col1a2+/P.G610C femurs, reduced hydroxyapatite crystallinity was also found to be associated with increased brittleness, and increased mineral-to-collagen ratio was correlated with increased ultimate strength, elastic modulus, and bone brittleness. In both models of OI, regression analysis demonstrated that collagen content was an important predictor of the increased brittleness. In summary, this work provides new insights into the relationships between bone composition and material properties in models of OI, identifies key bone compositional parameters that correlate with the impaired mechanical integrity of OI bone, and explores the effects of anti-TGF-β treatment on bone-quality parameters in these models. © 2016 American Society for Bone and Mineral Research.
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Affiliation(s)
- Xiaohong Bi
- Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ingo Grafe
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Hao Ding
- Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Rene Flores
- Academic and Research Affairs, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Elda Munivez
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Ming Ming Jiang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Brian Dawson
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Catherine G Ambrose
- Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA
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Gil JA, DeFroda SF, Sindhu K, Cruz AI, Daniels AH. Challenges of Fracture Management for Adults With Osteogenesis Imperfecta. Orthopedics 2017; 40:e17-e22. [PMID: 27735980 DOI: 10.3928/01477447-20161006-04] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/15/2016] [Indexed: 02/03/2023]
Abstract
Osteogenesis imperfecta is caused by qualitative or quantitative defects in type I collagen. Although often considered a disease with primarily pediatric manifestations, more than 25% of lifetime fractures are reported to occur in adulthood. General care of adults with osteogenesis imperfecta involves measures to preserve bone density, regular monitoring of hearing and dentition, and maintenance of muscle strength through physical therapy. Surgical stabilization of fractures in these patients can be challenging because of low bone mineral density, preexisting skeletal deformities, or obstruction by instrumentation from previous surgeries. Additionally, unique perioperative considerations exist when operatively managing fractures in patients with osteogenesis imperfecta. To date, there is little high-quality literature to help guide the optimal treatment of fractures in adult patients with osteogenesis imperfecta. [Orthopedics. 2017; 40(1):e17-e22.].
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Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta. Proc Natl Acad Sci U S A 2016; 113:13522-13527. [PMID: 27821779 DOI: 10.1073/pnas.1607644113] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
During fetal development, the uterine environment can have effects on offspring bone architecture and integrity that persist into adulthood; however, the biochemical and molecular mechanisms remain unknown. Myostatin is a negative regulator of muscle mass. Parental myostatin deficiency (Mstntm1Sjl/+) increases muscle mass in wild-type offspring, suggesting an intrauterine programming effect. Here, we hypothesized that Mstntm1Sjl/+ dams would also confer increased bone strength. In wild-type offspring, maternal myostatin deficiency altered fetal growth and calvarial collagen content of newborn mice and conferred a lasting impact on bone geometry and biomechanical integrity of offspring at 4 mo of age, the age of peak bone mass. Second, we sought to apply maternal myostatin deficiency to a mouse model with osteogenesis imperfecta (Col1a2oim), a heritable connective tissue disorder caused by abnormalities in the structure and/or synthesis of type I collagen. Femora of male Col1a2oim/+ offspring from natural mating of Mstntm1Sjl/+ dams to Col1a2oim/+sires had a 15% increase in torsional ultimate strength, a 29% increase in tensile strength, and a 24% increase in energy to failure compared with age, sex, and genotype-matched offspring from natural mating of Col1a2oim/+ dams to Col1a2oim/+ sires. Finally, increased bone biomechanical strength of Col1a2oim/+ offspring that had been transferred into Mstntm1Sjl/+ dams as blastocysts demonstrated that the effects of maternal myostatin deficiency were conferred by the postimplantation environment. Thus, targeting the gestational environment, and specifically prenatal myostatin pathways, provides a potential therapeutic window and an approach for treating osteogenesis imperfecta.
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Masci M, Wang M, Imbert L, Barnes AM, Spevak L, Lukashova L, Huang Y, Ma Y, Marini JC, Jacobsen CM, Warman ML, Boskey AL. Bone mineral properties in growing Col1a2(+/G610C) mice, an animal model of osteogenesis imperfecta. Bone 2016; 87:120-9. [PMID: 27083399 PMCID: PMC4862917 DOI: 10.1016/j.bone.2016.04.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Revised: 04/04/2016] [Accepted: 04/10/2016] [Indexed: 10/21/2022]
Abstract
The Col1a2(+/G610C) knock-in mouse, models osteogenesis imperfecta in a large old order Amish family (OOA) with type IV OI, caused by a G-to-T transversion at nucleotide 2098, which alters the gly-610 codon in the triple-helical domain of the α2(I) chain of type I collagen. Mineral and matrix properties of the long bones and vertebrae of male Col1a2(+/G610C) and their wild-type controls (Col1a2(+/+)), were characterized to gain insight into the role of α2-chain collagen mutations in mineralization. Additionally, we examined the rescuability of the composition by sclerostin inhibition initiated by crossing Col1a2(+/G610C) with an LRP(+/A214V) high bone mass allele. At age 10-days, vertebrae and tibia showed few alterations by micro-CT or Fourier transform infrared imaging (FTIRI). At 2-months-of-age, Col1a2(+/G610C) tibias had 13% fewer secondary trabeculae than Col1a2(+/+), these were thinner (11%) and more widely spaced (20%) than those of Col1a2(+/+) mice. Vertebrae of Col1a2(+/G610C) mice at 2-months also had lower bone volume fraction (38%), trabecular number (13%), thickness (13%) and connectivity density (32%) compared to Col1(a2+/+). The cortical bone of Col1a2(+/G610C) tibias at 2-months had 3% higher tissue mineral density compared to Col1a2(+/+); Col1a2(+/G610C) vertebrae had lower cortical thickness (29%), bone area (37%) and polar moment of inertia (38%) relative to Col1a2(+/+). FTIRI analysis, which provides information on bone chemical composition at ~7μm-spatial resolution, showed tibias at 10-days did not differ between genotypes. Comparing identical bone types in Col1a2(+/G610C) to Col1a2(+/+) at 2-months-of-age, tibias showed higher mineral-to-matrix ratio in trabeculae (17%) and cortices (31%). and in vertebral cortices (28%). Collagen maturity was 42% higher at 10-days-of-age in Col1a2(+/G610C) vertebral trabeculae and in 2-month tibial cortices (12%), vertebral trabeculae (42%) and vertebral cortices (12%). Higher acid-phosphate substitution was noted in 10-day-old trabecular bone in vertebrae (31%) and in 2-month old trabecular bone in both tibia (31%) and vertebrae (4%). There was also a 16% lower carbonate-to-phosphate ratio in vertebral trabeculae and a correspondingly higher (22%) carbonate-to-phosphate ratio in 2month-old vertebral cortices. At age 3-months-of-age, male femurs with both a Col1a2(+/G610C) allele and a Lrp5 high bone mass allele (Lrp5+/A214V) showed an improvement in bone composition, presenting higher trabecular carbonate-to-phosphate ratio (18%) and lower trabecular and cortical acid-phosphate substitutions (8% and 18%, respectively). Together, these results indicate that mutant collagen α2(I) chain affects both bone quantity and composition, and the usefulness of this model for studies of potential OI therapies such as anti-sclerostin treatments.
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Affiliation(s)
- Marco Masci
- Weill Cornell Medical College, New York, NY, United States.
| | - Min Wang
- Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States.
| | - Laurianne Imbert
- Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States.
| | - Aileen M Barnes
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
| | - Lyudmila Spevak
- Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States.
| | - Lyudmila Lukashova
- Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States.
| | - Yihe Huang
- Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC, United States.
| | - Yan Ma
- Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC, United States.
| | - Joan C Marini
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
| | - Christina M Jacobsen
- Division of Endocrinology and Genetics, Children's Hospital Boston, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States.
| | - Matthew L Warman
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, United States.
| | - Adele L Boskey
- Weill Cornell Medical College, New York, NY, United States; Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States.
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Paschalis EP, Gamsjaeger S, Fratzl-Zelman N, Roschger P, Masic A, Brozek W, Hassler N, Glorieux FH, Rauch F, Klaushofer K, Fratzl P. Evidence for a Role for Nanoporosity and Pyridinoline Content in Human Mild Osteogenesis Imperfecta. J Bone Miner Res 2016; 31:1050-9. [PMID: 26748579 DOI: 10.1002/jbmr.2780] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 12/21/2015] [Accepted: 01/06/2016] [Indexed: 01/19/2023]
Abstract
Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility that arises from decreased bone mass and abnormalities in bone material quality. OI type I represents the milder form of the disease and according to the original Sillence classification is characterized by minimal skeletal deformities and near-normal stature. Raman microspectroscopy is a vibrational spectroscopic technique that allows the determination of bone material properties in bone biopsy blocks with a spatial resolution of ∼1 µm, as a function of tissue age. In the present study, we used Raman microspectroscopy to evaluate bone material quality in transiliac bone biopsies from children with a mild form of OI, either attributable to collagen haploinsufficiency OI type I (OI-Quant; n = 11) or aberrant collagen structure (OI-Qual; n = 5), as a function of tissue age, and compared it against the previously published values established in a cohort of biopsies from healthy children (n = 54, ages 1 to 23 years). The results indicated significant differences in bone material compositional characteristics between OI-Quant patients and healthy controls, whereas fewer were evident in the OI-Qual patients. Differences in both subgroups of OI compared with healthy children were evident for nanoporosity, mineral maturity/crystallinity as determined by maxima of the v1 PO4 Raman band, and pyridinoline (albeit in different direction) content. These alterations in bone material compositional properties most likely contribute to the bone fragility characterizing this disease. © 2016 American Society for Bone and Mineral Research.
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Affiliation(s)
- Eleftherios P Paschalis
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Sonja Gamsjaeger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Admir Masic
- Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
| | - Wolfgang Brozek
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Norbert Hassler
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Francis H Glorieux
- Genetics Unit, Shriners Hospital for Children, McGill University, Montreal, Canada
| | - Frank Rauch
- Genetics Unit, Shriners Hospital for Children, McGill University, Montreal, Canada
| | - Klaus Klaushofer
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Peter Fratzl
- Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
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Oestreich AK, Carleton SM, Yao X, Gentry BA, Raw CE, Brown M, Pfeiffer FM, Wang Y, Phillips CL. Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice. Osteoporos Int 2016; 27:161-70. [PMID: 26179666 PMCID: PMC8018583 DOI: 10.1007/s00198-015-3226-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 06/30/2015] [Indexed: 01/30/2023]
Abstract
UNLABELLED Mice with osteogenesis imperfecta (+/oim), a disorder of bone fragility, were bred to mice with muscle over growth to test whether increasing muscle mass genetically would improve bone quality and strength. The results demonstrate that femora from mice carrying both mutations have greater mechanical integrity than their +/oim littermates. INTRODUCTION Osteogenesis imperfecta is a heritable connective tissue disorder due primarily to mutations in the type I collagen genes resulting in skeletal deformity and fragility. Currently, there is no cure, and therapeutic strategies encompass the use of antiresorptive pharmaceuticals and surgical bracing, with limited success and significant potential for adverse effects. Bone, a mechanosensing organ, can respond to high mechanical loads by increasing new bone formation and altering bone geometry to withstand increased forces. Skeletal muscle is a major source of physiological loading on bone, and bone strength is proportional to muscle mass. METHODS To test the hypothesis that congenic increases in muscle mass in the osteogenesis imperfecta murine model mouse (oim) will improve their compromised bone quality and strength, heterozygous (+/oim) mice were bred to mice deficient in myostatin (+/mstn), a negative regulator of muscle growth. The resulting adult offspring were evaluated for hindlimb muscle mass, and bone microarchitecture, physiochemistry, and biomechanical integrity. RESULTS +/oim mice deficient in myostatin (+/mstn +/oim) were generated and demonstrated that myostatin deficiency increased body weight, muscle mass, and biomechanical strength in +/mstn +/oim mice as compared to +/oim mice. Additionally, myostatin deficiency altered the physiochemical properties of the +/oim bone but did not alter bone remodeling. CONCLUSIONS Myostatin deficiency partially improved the reduced femoral bone biomechanical strength of adult +/oim mice by increasing muscle mass with concomitant improvements in bone microarchitecture and physiochemical properties.
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Affiliation(s)
- A K Oestreich
- Department of Biological Sciences, University of Missouri, Columbia, MO, 65211, USA
| | - S M Carleton
- Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA
| | - X Yao
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, 64108, USA
| | - B A Gentry
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, 65211, USA
| | - C E Raw
- Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA
| | - M Brown
- Department of Biomedical Sciences and Physical Therapy Program, University of Missouri, Columbia, MO, 65211, USA
| | - F M Pfeiffer
- Department of Orthopaedic Surgery and Bioengineering, University of Missouri, Columbia, MO, 65211, USA
| | - Y Wang
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, 64108, USA
| | - C L Phillips
- Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA.
- Department of Child Health, University of Missouri, 117 Schweitzer Hall, Columbia, MO, 65211, USA.
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Andriotis OG, Chang SW, Vanleene M, Howarth PH, Davies DE, Shefelbine SJ, Buehler MJ, Thurner PJ. Structure-mechanics relationships of collagen fibrils in the osteogenesis imperfecta mouse model. J R Soc Interface 2015; 12:20150701. [PMID: 26468064 PMCID: PMC4614505 DOI: 10.1098/rsif.2015.0701] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 09/24/2015] [Indexed: 12/13/2022] Open
Abstract
The collagen molecule, which is the building block of collagen fibrils, is a triple helix of two α1(I) chains and one α2(I) chain. However, in the severe mouse model of osteogenesis imperfecta (OIM), deletion of the COL1A2 gene results in the substitution of the α2(I) chain by one α1(I) chain. As this substitution severely impairs the structure and mechanics of collagen-rich tissues at the tissue and organ level, the main aim of this study was to investigate how the structure and mechanics are altered in OIM collagen fibrils. Comparing results from atomic force microscopy imaging and cantilever-based nanoindentation on collagen fibrils from OIM and wild-type (WT) animals, we found a 33% lower indentation modulus in OIM when air-dried (bound water present) and an almost fivefold higher indentation modulus in OIM collagen fibrils when fully hydrated (bound and unbound water present) in phosphate-buffered saline solution (PBS) compared with WT collagen fibrils. These mechanical changes were accompanied by an impaired swelling upon hydration within PBS. Our experimental and atomistic simulation results show how the structure and mechanics are altered at the individual collagen fibril level as a result of collagen gene mutation in OIM. We envisage that the combination of experimental and modelling approaches could allow mechanical phenotyping at the collagen fibril level of virtually any alteration of collagen structure or chemistry.
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Affiliation(s)
- O G Andriotis
- Institute for Lightweight Design and Structural Biomechanics, Vienna University of Technology, Getreidemarkt 9, Vienna 1060, Austria Bioengineering Research Group, Faculty of Engineering and the Environment, University of Southampton, Southampton SO17 1BJ, UK
| | - S W Chang
- Department of Civil Engineering, National Taiwan University, Taipei 10617, Taiwan, Republic of China Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - M Vanleene
- Department of Bioengineering, Imperial College London, London, UK
| | - P H Howarth
- The Brooke Laboratories, Division of Infection, Inflammation and Immunity, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - D E Davies
- The Brooke Laboratories, Division of Infection, Inflammation and Immunity, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - S J Shefelbine
- Department of Bioengineering, Imperial College London, London, UK Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA, USA
| | - M J Buehler
- Center for Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA Center for Computational Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - P J Thurner
- Institute for Lightweight Design and Structural Biomechanics, Vienna University of Technology, Getreidemarkt 9, Vienna 1060, Austria Bioengineering Research Group, Faculty of Engineering and the Environment, University of Southampton, Southampton SO17 1BJ, UK
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Jeong Y, Carleton SM, Gentry BA, Yao X, Ferreira JA, Salamango DJ, Weis M, Oestreich AK, Williams AM, McCray MG, Eyre DR, Brown M, Wang Y, Phillips CL. Hindlimb Skeletal Muscle Function and Skeletal Quality and Strength in +/G610C Mice With and Without Weight-Bearing Exercise. J Bone Miner Res 2015; 30:1874-86. [PMID: 25829218 PMCID: PMC8157311 DOI: 10.1002/jbmr.2518] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 03/16/2015] [Accepted: 03/20/2015] [Indexed: 11/08/2022]
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous heritable connective tissue disorder associated with reduced bone mineral density and skeletal fragility. Bone is inherently mechanosensitive, with bone strength being proportional to muscle mass and strength. Physically active healthy children accrue more bone than inactive children. Children with type I OI exhibit decreased exercise capacity and muscle strength compared with healthy peers. It is unknown whether this muscle weakness reflects decreased physical activity or a muscle pathology. In this study, we used heterozygous G610C OI model mice (+/G610C), which model both the genotype and phenotype of a large Amish OI kindred, to evaluate hindlimb muscle function and physical activity levels before evaluating the ability of +/G610C mice to undergo a treadmill exercise regimen. We found +/G610C mice hindlimb muscles do not exhibit compromised muscle function, and their activity levels were not reduced relative to wild-type mice. The +/G610C mice were also able to complete an 8-week treadmill regimen. Biomechanical integrity of control and exercised wild-type and +/G610C femora were analyzed by torsional loading to failure. The greatest skeletal gains in response to exercise were observed in stiffness and the shear modulus of elasticity with alterations in collagen content. Analysis of tibial cortical bone by Raman spectroscopy demonstrated similar crystallinity and mineral/matrix ratios regardless of sex, exercise, and genotype. Together, these findings demonstrate +/G610C OI mice have equivalent muscle function, activity levels, and ability to complete a weight-bearing exercise regimen as wild-type mice. The +/G610C mice exhibited increased femoral stiffness and decreased hydroxyproline with exercise, whereas other biomechanical parameters remain unaffected, suggesting a more rigorous exercise regimen or another exercise modality may be required to improve bone quality of OI mice.
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Affiliation(s)
- Youngjae Jeong
- Department of Biochemistry, University of Missouri, Columbia, MO, USA
| | | | - Bettina A Gentry
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA
| | - Xiaomei Yao
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, USA
| | - J Andries Ferreira
- Department of Biomedical Sciences and Physical Therapy Program, University of Missouri, Columbia, MO, USA
| | | | - MaryAnn Weis
- Department of Orthopedics and Sports Medicine, University of Washington, Seattle, WA, USA
| | - Arin K Oestreich
- Department of Biological Sciences, University of Missouri, Columbia, MO, USA
| | - Ashlee M Williams
- Department of Biochemistry, University of Missouri, Columbia, MO, USA
| | - Marcus G McCray
- Department of Biochemistry, University of Missouri, Columbia, MO, USA
| | - David R Eyre
- Department of Orthopedics and Sports Medicine, University of Washington, Seattle, WA, USA
| | - Marybeth Brown
- Department of Biomedical Sciences and Physical Therapy Program, University of Missouri, Columbia, MO, USA
| | - Yong Wang
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Charlotte L Phillips
- Department of Biochemistry, University of Missouri, Columbia, MO, USA.,Department of Child Health, University of Missouri, Columbia, MO, USA
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Oestreich AK, Garcia MR, Yao X, Pfeiffer FM, Nobakhti S, Shefelbine SJ, Wang Y, Brodeur AC, Phillips CL. Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry. Mol Genet Metab Rep 2015. [PMID: 28649535 PMCID: PMC5471398 DOI: 10.1016/j.ymgmr.2015.08.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Mucopolysaccharidosis type I (MPS I), is an autosomal recessive lysosomal storage disorder caused by a deficiency in the α-L-iduronidase enzyme, resulting in decreased enzymatic activity and accumulation of glycosaminoglycans. The disorder phenotypically manifests with increased urine glycosaminoglycan excretion, facial dysmorphology, neuropathology, cardiac manifestations, and bone deformities. While the development of new treatment strategies have shown promise in attenuating many symptoms associated with the disorder, the bone phenotype remains unresponsive. The aim of this study was to investigate and further characterize the skeletal manifestations of the Idua-W392X knock-in mouse model, which carries a nonsense mutation corresponding to the IDUA-W402X mutation found in Hurler syndrome (MPS I-H) patients. μCT analysis of the microarchitecture demonstrated increased cortical thickness, trabecular number, and trabecular connectivity along with decreased trabecular separation in the tibiae of female homozygous Idua-W392X knock-in (IDUA−/−) mice, and increased cortical thickness in male IDUA−/− tibiae. Cortical density, as determined by μCT, and bone mineral density distribution, as determined by quantitative backscattered microscopy, were equivalent in IDUA−/− and wildtype (Wt) bone. However, tibial porosity was increased in IDUA−/− cortical bone. Raman spectroscopy results indicated that tibiae from female IDUA−/− had decreased phosphate to matrix ratios and increased carbonate to phosphate ratios compared to Wt female tibiae, whereas these ratios remained equivalent in male IDUA−/− and Wt tibiae. Femora demonstrated altered geometry and upon torsional loading to failure analysis, female IDUA−/− mouse femora exhibited increased torsional ultimate strength, with a decrease in material strength relative to Wt littermates. Taken together, these findings suggest that the IDUA−/− mutation results in increased bone torsional strength by altering the overall bone geometry and the microarchitecture which may be a compensatory response to increased porosity, reduced bone tensile strength and altered physiochemical composition.
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Key Words
- BMD, bone mineral density
- BMDD, bone mineral density distribution
- BV/TV, bone volume/total volume
- Bone biomechanics
- FWHM, full width at half maximum
- G, shear modulus of elasticity
- GAGs, glycosaminoglycans
- IDUA, α-L-iduronidase
- Idua-W392X
- Ks, stiffness
- MPS I, mucopolysaccharidosis type I
- Mucopolysaccharidosis type I
- Raman spectroscopy
- SMI, structure model index
- Su, tensile strength
- Tmax, torsional ultimate strength
- U, energy to failure
- α-L-iduronidase
- μCT, microcomputed tomography
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Affiliation(s)
- Arin K Oestreich
- Department of Biological Sciences, University of Missouri, Columbia, MO 65211, United States
| | - Mekka R Garcia
- Department of Biochemistry, University of Missouri, Columbia, MO 65211, United States
| | - Xiaomei Yao
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, United States
| | - Ferris M Pfeiffer
- Department of Orthopaedic Surgery and Bioengineering, University of Missouri, Columbia, MO 65211, United States
| | - Sabah Nobakhti
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, United States
| | - Sandra J Shefelbine
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, United States
| | - Yong Wang
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, United States
| | - Amanda C Brodeur
- Department of Biomedical Sciences, Missouri State University, Springfield, MO 65804, United States
| | - Charlotte L Phillips
- Department of Biochemistry, University of Missouri, Columbia, MO 65211, United States.,Department of Child Health, University of Missouri, Columbia, MO 65211, United States
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Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent? Clin Orthop Relat Res 2015; 473:2587-98. [PMID: 25903941 PMCID: PMC4488219 DOI: 10.1007/s11999-015-4268-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Osteogenesis imperfecta (OI) is a genetic disease characterized by skeletal fragility and deformity. There is extensive debate regarding treatment options in adults with OI. Antiresorptive treatment reduces the number of fractures in growing oim/oim mice, an animal model that reproducibly mimics the moderate-to-severe form of OI in humans. Effects of long-term treatments with antiresorptive agents, considered for treatment of older patients with OI with similar presentation (moderate-to-severe OI) are, to date, unknown. QUESTIONS/PURPOSES Fourier transform infrared (FTIR) imaging, which produces a map of the spatial variation in chemical composition in thin sections of bone, was used to address the following questions: (1) do oim/oim mice show a sex dependence in compositional properties at 6.5 months of age; (2) is there a sex-dependent response to treatment with antiresorptive agents used in the treatment of OI in humans; and (3) are any compositional parameters in oim/oim mice corrected to wild-type (WT) values after treatment? METHODS FTIR imaging data were collected from femurs from four to five mice per sex per genotype per treatment. Treatments were 24 weeks of saline, alendronate, or RANK-Fc; and 12 weeks of saline+12 weeks RANK-Fc and 12 weeks of alendronate+RANK-Fc. FTIR imaging compositional parameters measured in cortical and cancellous bones were mineral-to-matrix ratio, carbonate-to-mineral ratio, crystal size/perfection, acid phosphate substitution, collagen maturity, and their respective distributions (heterogeneities). Because of the small sample size, nonparametric statistics (Mann-Whitney U- and Kruskal-Wallis tests with Bonferroni correction) were used to compare saline-treated male and female mice of different genotypes and treatment effects by sex and genotype, respectively. Statistical significance was defined as p<0.05. RESULTS At 6.5 months, saline-treated male cortical oim/oim bone had increased mineral-to-matrix ratio (p=0.016), increased acid phosphate substitution (p=0.032), and decreased carbonate-to-mineral ratio (p=0.016) relative to WT. Cancellous bone in male oim/oim also had increased mineral-to-matrix ratio (p=0.016) relative to male WT. Female oim/oim mouse bone composition for all cortical and cancellous bone parameters was comparable to WT (p>0.05). Only the female WT mice showed a response of mean compositional properties to treatment, increasing mineral-to-matrix after RANK-Fc treatment in cancellous bone (p=0.036) compared with saline-treated mice. Male oim/oim increased mineral-to-matrix cortical and cancellous bone heterogeneity in response to all long-term treatments except for saline+RANK-Fc (p<0.04); female oim/oim cortical mineral-to-matrix bone heterogeneity increased with ALN+RANK-Fc and all treatments increased cancellous female oim/oim bone acid phosphate substitution heterogeneity (p<0.04). CONCLUSIONS Both oim/oim and WT mice, which demonstrate sex-dependent differences in composition with saline treatment, showed few responses to long-term treatment with antiresorptive agents. Female WT mice appeared to be more responsive; male oim/oim mice showed more changes in compositional heterogeneity. Changes in bone composition caused by these agents may contribute to improved bone quality in oim/oim mice, because the treatments are known to reduce fracture incidence. CLINICAL RELEVANCE The optimal drug therapy for long-term treatment of patients with moderate-to-severe OI is unknown. Based on bone compositional changes in mice, antiresorptive treatments are useful for continued treatment in OI. There is a reported sexual dimorphism in fracture incidence in adults with OI, but to date, no one has reported differences in response to pharmaceutical intervention. This study suggests that such an investigation is warranted.
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Blue ME, Boskey AL, Doty SB, Fedarko NS, Hossain MA, Shapiro JR. Osteoblast function and bone histomorphometry in a murine model of Rett syndrome. Bone 2015; 76:23-30. [PMID: 25769649 PMCID: PMC7455889 DOI: 10.1016/j.bone.2015.01.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Revised: 01/21/2015] [Accepted: 01/25/2015] [Indexed: 02/07/2023]
Abstract
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder due to mutations affecting the neural transcription factor MeCP2. Approximately 50% of affected females have decreased bone mass. We studied osteoblast function using a murine model of RTT. Female heterozygote (HET) and male Mecp2-null mice were compared to wild type (WT) mice. Micro-CT of tibia from 5 week-old Mecp2-null mice showed significant alterations in trabecular bone including reductions in bone volume fraction (-29%), number (-19%), thickness (-9%) and connectivity density (-32%), and increases in trabecular separation (+28%) compared to WT. We also found significant reductions in cortical bone thickness (-18%) and in polar moment of inertia (-45%). In contrast, cortical and trabecular bone from 8 week-old WT and HET female mice were not significantly different. However, mineral apposition rate, mineralizing surface and bone formation rate/bone surface were each decreased in HET and Mecp2-null mice compared to WT mice. Histomorphometric analysis of femurs showed decreased numbers of osteoblasts but similar numbers of osteoclasts compared to WT, altered osteoblast morphology and decreased tissue synthesis of alkaline phosphatase in Mecp2-null and HET mice. Osteoblasts cultured from Mecp2-null mice, which unlike WT osteoblasts did not express MeCP2, had increased growth rates, but reductions in mRNA expression of type I collagen, Runx2 and Osterix compared to WT osteoblasts. These results indicate that MeCP2 deficiency leads to altered bone growth. Osteoblast dysfunction was more marked in Mecp2-null male than in HET female mice, suggesting that expression of MeCP2 plays a critical role in bone development.
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Affiliation(s)
- Mary E Blue
- Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA.
| | - Adele L Boskey
- Hospital for Special Surgery, Mineralized Tissue Laboratory 535 E 70th Street, New York, NY 10021, USA.
| | - Stephen B Doty
- Hospital for Special Surgery, Mineralized Tissue Laboratory 535 E 70th Street, New York, NY 10021, USA.
| | - Neal S Fedarko
- Geriatric Medicine and Gerontology, Johns Hopkins Medical Institutions, Room 1A-12 JHAAC, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.
| | - Mir Ahamed Hossain
- Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA.
| | - Jay R Shapiro
- Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA.
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Rodriguez-Florez N, Garcia-Tunon E, Mukadam Q, Saiz E, Oldknow KJ, Farquharson C, Millán JL, Boyde A, Shefelbine SJ. An investigation of the mineral in ductile and brittle cortical mouse bone. J Bone Miner Res 2015; 30:786-95. [PMID: 25418329 PMCID: PMC4507744 DOI: 10.1002/jbmr.2414] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 11/07/2014] [Accepted: 11/20/2014] [Indexed: 12/28/2022]
Abstract
Bone is a strong and tough material composed of apatite mineral, organic matter, and water. Changes in composition and organization of these building blocks affect bone's mechanical integrity. Skeletal disorders often affect bone's mineral phase, either by variations in the collagen or directly altering mineralization. The aim of the current study was to explore the differences in the mineral of brittle and ductile cortical bone at the mineral (nm) and tissue (µm) levels using two mouse phenotypes. Osteogenesis imperfecta model, oim(-/-) , mice have a defect in the collagen, which leads to brittle bone; PHOSPHO1 mutants, Phospho1(-/-) , have ductile bone resulting from altered mineralization. Oim(-/-) and Phospho1(-/-) were compared with their respective wild-type controls. Femora were defatted and ground to powder to measure average mineral crystal size using X-ray diffraction (XRD) and to monitor the bulk mineral to matrix ratio via thermogravimetric analysis (TGA). XRD scans were run after TGA for phase identification to assess the fractions of hydroxyapatite and β-tricalcium phosphate. Tibiae were embedded to measure elastic properties with nanoindentation and the extent of mineralization with backscattered electron microscopy (BSE SEM). Results revealed that although both pathology models had extremely different whole-bone mechanics, they both had smaller apatite crystals, lower bulk mineral to matrix ratio, and showed more thermal conversion to β-tricalcium phosphate than their wild types, indicating deviations from stoichiometric hydroxyapatite in the original mineral. In contrast, the degree of mineralization of bone matrix was different for each strain: brittle oim(-/-) were hypermineralized, whereas ductile Phospho1(-/-) were hypomineralized. Despite differences in the mineralization, nanoscale alterations in the mineral were associated with reduced tissue elastic moduli in both pathologies. Results indicated that alterations from normal crystal size, composition, and structure are correlated with reduced mechanical integrity of bone.
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Microstructure and compressive mechanical properties of cortical bone in children with osteogenesis imperfecta treated with bisphosphonates compared with healthy children. J Mech Behav Biomed Mater 2015; 46:261-70. [PMID: 25828157 DOI: 10.1016/j.jmbbm.2014.12.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 12/12/2014] [Accepted: 12/18/2014] [Indexed: 01/17/2023]
Abstract
Osteogenesis imperfecta (OI) is a genetic disorder characterized by a change in bone tissue quality, but little data are available to describe the factors involved at the macroscopic scale. To better understand the effect of microstructure alterations on the mechanical properties at the sample scale, we studied the structural and mechanical properties of six cortical bone samples from children with OI treated with bisphosphonates and compared them to the properties of three controls. Scanning electron microscopy, high resolution computed tomography and compression testing were used to assess these properties. More resorption cavities and a higher osteocyte lacunar density were observed in OI bone compared with controls. Moreover, a higher porosity was measured for OI bones along with lower macroscopic Young's modulus, yield stress and ultimate stress. The microstructure was impaired in OI bones; the higher porosity and osteocyte lacunar density negatively impacted the mechanical properties and made the bone more prone to fracture.
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Mandair GS, Morris MD. Contributions of Raman spectroscopy to the understanding of bone strength. BONEKEY REPORTS 2015; 4:620. [PMID: 25628882 DOI: 10.1038/bonekey.2014.115] [Citation(s) in RCA: 220] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 10/24/2014] [Indexed: 02/07/2023]
Abstract
Raman spectroscopy is increasingly commonly used to understand how changes in bone composition and structure influence tissue-level bone mechanical properties. The spectroscopic technique provides information on bone mineral and matrix collagen components and on the effects of various matrix proteins on bone material properties as well. The Raman spectrum of bone not only contains information on bone mineral crystallinity that is related to bone hardness but also provides information on the orientation of mineral crystallites with respect to the collagen fibril axis. Indirect information on collagen cross-links is also available and will be discussed. After a short introduction to bone Raman spectroscopic parameters and collection methodologies, advances in in vivo Raman spectroscopic measurements for animal and human subject studies will be reviewed. A discussion on the effects of aging, osteogenesis imperfecta, osteoporosis and therapeutic agents on bone composition and mechanical properties will be highlighted, including genetic mouse models in which structure-function and exercise effects are explored. Similarly, extracellular matrix proteins, proteases and transcriptional proteins implicated in the regulation of bone material properties will be reviewed.
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Affiliation(s)
- Gurjit S Mandair
- Department of Chemistry, University of Michigan , Ann Arbor, MI, USA
| | - Michael D Morris
- Department of Chemistry, University of Michigan , Ann Arbor, MI, USA
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Bart ZR, Hammond MA, Wallace JM. Multi-scale analysis of bone chemistry, morphology and mechanics in the oim model of osteogenesis imperfecta. Connect Tissue Res 2014; 55 Suppl 1:4-8. [PMID: 25158170 DOI: 10.3109/03008207.2014.923860] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Osteogenesis imperfecta is a congenital disease commonly characterized by brittle bones and caused by mutations in the genes encoding Type I collagen, the single most abundant protein produced by the body. The oim model has a natural collagen mutation, converting its heterotrimeric structure (two α1 and one α2 chains) into α1 homotrimers. This mutation in collagen may impact formation of the mineral, creating a brittle bone phenotype in animals. Femurs from male wild type (WT) and homozygous (oim/oim) mice, all at 12 weeks of age, were assessed using assays at multiple length scales with minimal sample processing to ensure a near-physiological state. Atomic force microscopy (AFM) demonstrated detectable differences in the organization of collagen at the nanoscale that may partially contribute to alterations in material and structural behavior obtained through mechanical testing and reference point indentation (RPI). Changes in geometric and chemical structure obtained from µ-Computed Tomography and Raman spectroscopy indicate a smaller bone with reduced trabecular architecture and altered chemical composition. Decreased tissue material properties in oim/oim mice are likely driven by changes in collagen fibril structure, decreasing space available for mineral nucleation and growth, as supported by a reduction in mineral crystallinity. Multi-scale analyses of this nature offer much in assessing how molecular changes compound to create a degraded, brittle bone phenotype.
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Affiliation(s)
- Zachary R Bart
- Department of Biomedical Engineering, Indiana University-Purdue University , Indianapolis, IN , USA
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Imbert L, Aurégan JC, Pernelle K, Hoc T. Mechanical and mineral properties of osteogenesis imperfecta human bones at the tissue level. Bone 2014; 65:18-24. [PMID: 24803077 DOI: 10.1016/j.bone.2014.04.030] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 03/18/2014] [Accepted: 04/25/2014] [Indexed: 12/12/2022]
Abstract
Osteogenesis imperfecta (OI) is a genetic disorder characterized by an increase in bone fragility on the macroscopic scale, but few data are available to describe the mechanisms involved on the tissue scale and the possible correlations between these scales. To better understand the effects of OI on the properties of human bone, we studied the mechanical and chemical properties of eight bone samples from children suffering from OI and compared them to the properties of three controls. High-resolution computed tomography, nanoindentation and Raman microspectroscopy were used to assess those properties. A higher tissue mineral density was found for OI bone (1.131 gHA/cm3 vs. 1.032 gHA/cm3, p=0.032), along with a lower Young's modulus (17.6 GPa vs. 20.5 GPa, p=0.024). Obviously, the mutation-induced collagen defects alter the collagen matrix, thereby affecting the mineralization. Raman spectroscopy showed that the mineral-to-matrix ratio was higher in the OI samples, while the crystallinity was lower, suggesting that the mineral crystals were smaller but more abundant in the case of OI. This change in crystal size, distribution and composition contributes to the observed decrease in mechanical strength.
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Affiliation(s)
- Laurianne Imbert
- LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France
| | - Jean-Charles Aurégan
- Department of Pediatric Orthopedics, Necker - Enfants Malades Hospital, AP-HP, Paris Descartes University, 145 rue de Sèvres, 75014 Paris, France; B2OA UMR CNRS 7052, University Paris-Diderot, 10 avenue de Verdun, 75010 Paris, France
| | - Kélig Pernelle
- LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France
| | - Thierry Hoc
- LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France.
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