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Goddard JF, Mehrotra S, Mehrotra M. Osteogenesis imperfecta: exploring an autoimmune and immunotherapy perspective. JBMR Plus 2025; 9:ziaf053. [PMID: 40353205 PMCID: PMC12063996 DOI: 10.1093/jbmrpl/ziaf053] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/07/2025] [Accepted: 03/23/2025] [Indexed: 05/14/2025] Open
Abstract
Osteogenesis imperfecta (OI), also called brittle bone disease, is a genetic osteodysplasia characterized by a defect in type 1 collagen. Often diagnosed in infancy or early childhood, young patients are affected by frequent fractures. Osteogenesis imperfecta was first named almost 200 yr ago, yet there are still no FDA-approved treatments for OI, and existing treatments target only the skeletal defects of the disease. In this review, we briefly examine current treatments and ongoing clinical trials. Then, by analyzing OI with an osteoimmunological perspective, we have compiled evidence that OI has an autoimmune component. This autoimmune component of OI remains unconsidered, even though an immunology-based therapy has shown promise in treating OI. Acknowledging an autoimmune component of OI is critical to understanding its mechanisms and allowing for the development of more efficacious treatments and novel immunotherapies. Considering the existing literature and the growing impact of immunotherapeutic therapies in cancer and other autoimmune diseases, we believe it may be time to rethink the immune aspects of this genetic disorder and develop novel immunomodulating strategies to improve the quality of life for OI patients.
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Affiliation(s)
- Jackson F Goddard
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Shikhar Mehrotra
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Meenal Mehrotra
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, United States
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Valeeva D, Akhiiarova K, Minniakhmetov I, Mokrysheva N, Khusainova R, Tyurin A. Complex Analysis of Micronutrient Levels and Bone Mineral Density in Patients with Different Types of Osteogenesis Imperfecta. Diagnostics (Basel) 2025; 15:250. [PMID: 39941180 PMCID: PMC11817190 DOI: 10.3390/diagnostics15030250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/16/2025] [Accepted: 01/18/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Osteogenesis imperfecta (OI) is a rare monogenic connective tissue disorder characterized by fragility of bones and recurrent fractures. In addition to the hereditary component, there are a number of factors that influence the course of the disease, the contribution of which is poorly understood, in particular the levels of micronutrients. Methods: A cross-sectional study was conducted involving 45 with OI and 45 healthy individuals. The concentrations of micronutrients (calcium, copper, inorganic phosphorus, zinc, and magnesium) and bone mineral density (BMD) were evaluated in all the participants. Results: The concentrations of micronutrients in all the groups were within the reference values. In the OI overall, magnesium and copper were elevated, and phosphorus and zinc were lower. Type I exhibited higher concentrations of magnesium and copper and the lowest phosphorus; type III was associated with lower zinc, type IV with lower calcium and higher copper, and type V with the lowest phosphorus. OI overall was associated with lower BMD values. A correlational analysis in the OI group showed that the number of fractures correlated with BMD in absolute values but not with the Z-score. Conclusions: The obtained data emphasize the importance of the levels of micronutrients in the pathogenesis of connective tissue diseases, in particular OI. As in the results of previous studies, the levels of micronutrients were within the population norm, which probably requires the development of individual criteria for the content of substances in this category of patients.
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Affiliation(s)
- Diana Valeeva
- Internal Medicine and Clinical Psychology Department, Bashkir State Medical University, 450008 Ufa, Russia; (D.V.); (K.A.); (R.K.)
| | - Karina Akhiiarova
- Internal Medicine and Clinical Psychology Department, Bashkir State Medical University, 450008 Ufa, Russia; (D.V.); (K.A.); (R.K.)
| | - Ildar Minniakhmetov
- Endocrinology Research Centre, Dmitriya Ulianova Street, 11, 117036 Moscow, Russia; (I.M.); (N.M.)
| | - Natalia Mokrysheva
- Endocrinology Research Centre, Dmitriya Ulianova Street, 11, 117036 Moscow, Russia; (I.M.); (N.M.)
| | - Rita Khusainova
- Internal Medicine and Clinical Psychology Department, Bashkir State Medical University, 450008 Ufa, Russia; (D.V.); (K.A.); (R.K.)
- Endocrinology Research Centre, Dmitriya Ulianova Street, 11, 117036 Moscow, Russia; (I.M.); (N.M.)
| | - Anton Tyurin
- Internal Medicine and Clinical Psychology Department, Bashkir State Medical University, 450008 Ufa, Russia; (D.V.); (K.A.); (R.K.)
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Garibaldi N, Besio R, Pirota V, Albini B, Colombo G, Galinetto P, Doria F, Carriero A, Forlino A. A novel chemical chaperone ameliorates osteoblast homeostasis and extracellular matrix in osteogenesis imperfecta. Life Sci 2025; 361:123320. [PMID: 39706289 DOI: 10.1016/j.lfs.2024.123320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/13/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
AIMS Osteogenesis imperfecta (OI) is a collagen I-related heritable family of skeletal diseases associated to extreme bone fragility and deformity. Its classical forms are caused by dominant mutations in COL1A1 and COL1A2, which encode for the protein α chains, and are characterized by impairment in collagen I structure, folding, and secretion. Mutant collagen I assembles in an altered extracellular matrix affecting mineralization and bone properties and partially accumulating inside the cells, leading to impaired trafficking and cellular stress. Recently, the chemical chaperone 4-phenylbutyrate (4-PBA) has been proposed as an innovative drug for OI based on its ability to restore intracellular homeostasis, stimulate secretion, and ameliorate collagen-producing cell functions, positively affecting bone properties. However, the limited half-life of the molecule represents a serious hurdle for its use. MATERIALS AND METHODS To efficiently target cellular stress as OI treatment, two new compounds were designed by molecular modelling based on the 4-PBA structure to increase its stability and its ability to implement protein secretion. The short butyryl fatty acid chain of 4-PBA was substituted with a nitro functional group or with a glycine, respectively. The latter, N-benzyl glycine (N-BG), showed the best docking score, less toxicity, and higher stability than 4-PBA. KEY FINDINGS N-BG improved extracellular matrix quality and mineral content together with ameliorating OI cells' homeostasis by increasing ER-associated degradation pathway, reducing apoptosis, and stimulating protein secretion, thus facilitating intracellular clearance from accumulated misfolded proteins. SIGNIFICANCE In conclusion, N-BG represents a novel potential available compound to target altered homeostasis in OI with the aim to ameliorate the disease phenotype.
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Affiliation(s)
- Nadia Garibaldi
- Department of Biomedical Engineering, The City College of New York, New York, USA; Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
| | - Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
| | | | | | | | | | - Filippo Doria
- Department of Chemistry, University of Pavia, Pavia, Italy.
| | - Alessandra Carriero
- Department of Biomedical Engineering, The City College of New York, New York, USA.
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
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Saitou H, Ohata Y, Takeyari S, Nishizawa C, Nakayama H, Fujiwara M, Kitabatake Y, Kubota T, Ozono K. Characterization of a Novel Col1a1 G643S/+ Osteogenesis Imperfecta Mouse Model with Insights into Skeletal Phenotype, Fragility, and Therapeutic Evaluations. Calcif Tissue Int 2025; 116:13. [PMID: 39751826 PMCID: PMC11698804 DOI: 10.1007/s00223-024-01320-2] [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: 02/05/2024] [Accepted: 10/30/2024] [Indexed: 01/04/2025]
Abstract
Osteogenesis imperfecta (OI) is an inheritable skeletal disorder characterized by bone fragility often caused by pathogenic variants in the COL1A1 gene. Current OI mouse models with a glycine substitution in Col1a1 exhibit excessive severity, thereby limiting long-term pathophysiological analysis and drug effect assessments. To address this limitation, we constructed a novel OI mouse model mimicking a patient with OI type III. This was achieved by introducing a G-to-A transversion at nucleotide position 2428 in the Col1a1 gene via CRISPR-Cas9 technology in C57BL/6 J mice. The resulting heterozygous variant mice (Col1a1G643S/+) displayed reduced body weight and pronounced skeletal abnormalities. Micro-CT analysis at 12 weeks revealed decreased vertebral bone parameters and altered cortical bone characteristics, indicative of bone fragility. Additionally, the abnormalities of the anisotropy, complexity, connectivity, and structure of trabecular bone were revealed. A three-point bending test confirmed the fragility, with reduced displacement and fracture energy in both sexes. Furthermore, we evaluated the effect of 4-phenylbutyric acid on the bone in Col1a1G643S/+ mice at 12 weeks, observing no significant effects, likely due to the absence of collagen retention in the ER in this model. Despite being a moderate OI model, Col1a1G643S/+ mice manifest a distinct and fragile bone phenotype, making them suitable for extended studies. This model offers a valuable platform for investigating long-term pathophysiological aspects of OI and assessing the efficacy of potential therapeutic interventions.
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Affiliation(s)
- Hiroyuki Saitou
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
- Department of Pediatrics, ISEIKAI International General Hospital, 4-14, Minamiogi-machi, Kita-ku, Osaka, 530-0052, Japan
| | - Yasuhisa Ohata
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shinji Takeyari
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Chiaki Nishizawa
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
- Surgery for Oral and Maxillofacial Disease, Osaka University School of Dentistry, Suita, Japan
| | - Hirofumi Nakayama
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
- Surgery for Oral and Maxillofacial Disease, Osaka University School of Dentistry, Suita, Japan
| | - Makoto Fujiwara
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yasuji Kitabatake
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takuo Kubota
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Keiichi Ozono
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.
- Department of Pediatrics, ISEIKAI International General Hospital, 4-14, Minamiogi-machi, Kita-ku, Osaka, 530-0052, Japan.
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Misof BM, Fratzl-Zelman N. Bone Quality and Mineralization and Effects of Treatment in Osteogenesis Imperfecta. Calcif Tissue Int 2024; 115:777-804. [PMID: 39231826 DOI: 10.1007/s00223-024-01263-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 07/10/2024] [Indexed: 09/06/2024]
Abstract
Osteogenesis imperfecta (OI) is a rare congenital bone dysplasia characterized by high fracture rates and broad variations in clinical manifestations ranging from mild to increasingly severe and perinatal lethal forms. The underlying mutations affect either the synthesis or processing of the type I procollagen molecule itself or proteins that are involved in the formation and mineralization of the collagen matrix. Consequently, the collagen forming cells, the osteoblasts, become broadly dysfunctional in OI. Strikingly, hypermineralized bone matrix seems to be a frequent feature in OI, despite the variability in clinical severity and mutations in the so far studied different forms of human OI. While the causes of the increased mineral content of the bone matrix are not fully understood yet, there is evidence that the descendants of the osteoblasts, the osteocytes, which play a critical role not only in bone remodeling, but also in mineralization and sensing of mechanical loads, are also highly dysregulated and might be of major importance in the pathogenesis of OI. In this review article, we firstly summarize findings of cellular abnormalities in osteoblasts and osteocytes, alterations of the organic matrix, as well as of the microstructural organization of bone. Secondly, we focus on the hypermineralization of the bone matrix in OI as observed in several different forms of human OI as well as in animal models, its measurement and potential mechanical implications and its effect on the bone mineral density measured by dual X-ray absorptiometry. Thirdly, we give an overview of established medication treatments of OI and new approaches with a focus of their known or possible effects on the bone material, particularly on bone matrix mineralization.
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Affiliation(s)
- Barbara M Misof
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
- Vienna Bone and Growth Center, Vienna, Austria
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria.
- Vienna Bone and Growth Center, Vienna, Austria.
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6
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Jovanovic M, Marini JC. Update on the Genetics of Osteogenesis Imperfecta. Calcif Tissue Int 2024; 115:891-914. [PMID: 39127989 PMCID: PMC11607015 DOI: 10.1007/s00223-024-01266-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024]
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal dysplasia characterized by bone fragility and deformity, growth deficiency, and other secondary connective tissue defects. OI is now understood as a collagen-related disorder caused by defects of genes whose protein products interact with collagen for folding, post-translational modification, processing and trafficking, affecting bone mineralization and osteoblast differentiation. This review provides the latest updates on genetics of OI, including new developments in both dominant and rare OI forms, as well as the signaling pathways involved in OI pathophysiology. There is a special emphasis on discoveries of recessive mutations in TENT5A, MESD, KDELR2 and CCDC134 whose causality of OI types XIX, XX, XXI and XXI, respectively, is now established and expends the complexity of mechanisms underlying OI to overlap LRP5/6 and MAPK/ERK pathways. We also review in detail new discoveries connecting the known OI types to each other, which may underlie an eventual understanding of a final common pathway in OI cellular and bone biology.
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Affiliation(s)
- Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
- Section on Adolescent Bone and Body Composition, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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7
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Aksornthong S, Patel P, Komarova SV. Osteoclast indices in osteogenesis imperfecta: systematic review and meta-analysis. JBMR Plus 2024; 8:ziae112. [PMID: 39372603 PMCID: PMC11450326 DOI: 10.1093/jbmrpl/ziae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 07/25/2024] [Accepted: 08/16/2024] [Indexed: 10/08/2024] Open
Abstract
Osteogenesis imperfecta (OI) is a rare bone fragility disorder caused by mutations in genes encoding collagen type I or that affect its processing. Alterations in osteoclasts were suggested to contribute to OI pathophysiology. We aimed to systematically identify studies reporting measures of osteoclast formation and function in patients and mouse models of OI, to quantify OI-induced changes. The systematic search of Medline, Ovid, and Web of Science identified 798 unique studies. After screening, we included 23 studies for meta-analysis, reporting osteoclast parameters in 310 patients with OI of 9 different types and 16 studies reporting osteoclast parameters in 406 animals of 11 different OI mouse models. The standardized mean difference with 95% confidence interval (CI) was used as the effect size, and random-effects meta-analysis was performed. In patients with OI, collagen degradation markers were significantly higher compared with age-matched controls, with an effect size of 1.23 (CI: 0.36, 2.10]. Collagen degradation markers were the most elevated in the 3- to 7-year-old age group and in patients with more severe forms of OI. Bone histomorphometry demonstrated the trends for higher osteoclast numbers (1.16; CI: -0.22, 2.55) and osteoclast surface (0.43; CI: -0.63, 1.49), and significantly higher eroded surface (3.24; CI: 0.51, 5.96) compared with age-matched controls. In OI mice, meta-analysis demonstrated significant increases in collagen degradation markers (1.59; CI: 1.07, 2.11), in osteoclast numbers (0.94; CI: 0.50, 1.39), osteoclast surface (0.73; CI: 0.22, 1.23), and eroded surface (1.31; CI: 0.54, 2.08). The largest differences were in OI mice with the mutations in Col1a1 and Col1a2 genes. There were no differences between males and females in clinical or animal studies. Quantitative estimates of changes in osteoclast indices and their variance for patients with OI are important for planning future studies. We confirmed that similar changes are observed in mice with OI, supporting their translational utility.
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Affiliation(s)
- Sirion Aksornthong
- Department of Experimental Surgery, McGill University, Montreal, Quebec H3G 1A4, Canada
- Shriners Hospital for Children—Canada, Montreal, Quebec H4A 0A9, Canada
| | - Priyesh Patel
- Shriners Hospital for Children—Canada, Montreal, Quebec H4A 0A9, Canada
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Quebec H3A 1G1, Canada
| | - Svetlana V Komarova
- Department of Experimental Surgery, McGill University, Montreal, Quebec H3G 1A4, Canada
- Shriners Hospital for Children—Canada, Montreal, Quebec H4A 0A9, Canada
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Quebec H3A 1G1, Canada
- Department of Biomedical Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta T6G 1H9, Canada
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Khan MP, Sabini E, Beigel K, Lanzolla G, Laslow B, Wang D, Merceron C, Giaccia A, Long F, Taylor D, Schipani E. HIF1 activation safeguards cortical bone formation against impaired oxidative phosphorylation. JCI Insight 2024; 9:e182330. [PMID: 39088272 PMCID: PMC11457864 DOI: 10.1172/jci.insight.182330] [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: 04/30/2024] [Accepted: 07/25/2024] [Indexed: 08/03/2024] Open
Abstract
Energy metabolism, through pathways such as oxidative phosphorylation (OxPhos) and glycolysis, plays a pivotal role in cellular differentiation and function. Our study investigates the impact of OxPhos disruption in cortical bone development by deleting mitochondrial transcription factor A (TFAM). TFAM controls OxPhos by regulating the transcription of mitochondrial genes. The cortical bone, constituting the long bones' rigid shell, is sheathed by the periosteum, a connective tissue layer populated with skeletal progenitors that spawn osteoblasts, the bone-forming cells. TFAM-deficient mice presented with thinner cortical bone, spontaneous midshaft fractures, and compromised periosteal cell bioenergetics, characterized by reduced ATP levels. Additionally, they exhibited an enlarged periosteal progenitor cell pool with impaired osteoblast differentiation. Increasing hypoxia-inducible factor 1a (HIF1) activity within periosteal cells substantially mitigated the detrimental effects induced by TFAM deletion. HIF1 is known to promote glycolysis in all cell types. Our findings underscore the indispensability of OxPhos for the proper accrual of cortical bone mass and indicate a compensatory mechanism between OxPhos and glycolysis in periosteal cells. The study opens new avenues for understanding the relationship between energy metabolism and skeletal health and suggests that modulating bioenergetic pathways may provide a therapeutic avenue for conditions characterized by bone fragility.
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Affiliation(s)
- Mohd P. Khan
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Orthopaedic Surgery, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Elena Sabini
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Katherine Beigel
- Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Giulia Lanzolla
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Brittany Laslow
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Dian Wang
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Christophe Merceron
- Department of Orthopaedic Surgery, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Amato Giaccia
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Fanxin Long
- Department of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Deanne Taylor
- Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Ernestina Schipani
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Orthopaedic Surgery, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Daponte V, Tonelli F, Masiero C, Syx D, Exbrayat-Héritier C, Biggiogera M, Willaert A, Rossi A, Coucke PJ, Ruggiero F, Forlino A. Cell differentiation and matrix organization are differentially affected during bone formation in osteogenesis imperfecta zebrafish models with different genetic defects impacting collagen type I structure. Matrix Biol 2023; 121:105-126. [PMID: 37336269 DOI: 10.1016/j.matbio.2023.06.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/25/2023] [Accepted: 06/16/2023] [Indexed: 06/21/2023]
Abstract
Osteogenesis imperfecta (OI) is a family of rare heritable skeletal disorders associated with dominant mutations in the collagen type I encoding genes and recessive defects in proteins involved in collagen type I synthesis and processing and in osteoblast differentiation and activity. Historically, it was believed that the OI bone phenotype was only caused by abnormal collagen type I fibrils in the extracellular matrix, but more recently it became clear that the altered bone cell homeostasis, due to mutant collagen retention, plays a relevant role in modulating disease severity in most of the OI forms and it is correlated to impaired bone cell differentiation. Despite in vitro evidence, in vivo data are missing. To better understand the physiopathology of OI, we used two zebrafish models: Chihuahua (Chi/+), carrying a dominant p.G736D substitution in the α1 chain of collagen type I, and the recessive p3h1-/-, lacking prolyl 3-hydroxylase (P3h1) enzyme. Both models share the delay of collagen type I folding, resulting in its overmodification and partial intracellular retention. The regeneration of the bony caudal fin of Chi/+ and p3h1-/- was employed to investigate the impact of abnormal collagen synthesis on bone cell differentiation. Reduced regenerative ability was evident in both models, but it was associated to impaired osteoblast differentiation and osteoblastogenesis/adipogenesis switch only in Chi/+. On the contrary, reduced osteoclast number and activity were found in both models during regeneration. The dominant OI model showed a more detrimental effect in the extracellular matrix organization. Interestingly, the chemical chaperone 4-phenylbutyrate (4-PBA), known to reduce cellular stress and increase collagen secretion, improved bone formation only in p3h1-/- by favoring caudal fin growth without affecting bone cell markers expression. Taken together, our in vivo data proved the negative impact of structurally abnormal collagen type I on bone formation but revealed a gene mutation-specific effect on bone cell differentiation and matrix organization in OI. These, together with the distinct ability to respond to the chaperone treatment, underline the need for precision medicine approaches to properly treat the disease.
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Affiliation(s)
- Valentina Daponte
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Francesca Tonelli
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Cecilia Masiero
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Delfien Syx
- Department of Biomolecular Medicine, Center of Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium
| | - Chloé Exbrayat-Héritier
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Marco Biggiogera
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | - Andy Willaert
- Department of Biomolecular Medicine, Center of Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium
| | - Antonio Rossi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Paul J Coucke
- Department of Biomolecular Medicine, Center of Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium
| | - Florence Ruggiero
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
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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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11
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Brain-Type Creatine Kinase Release from Cultured Osteoclasts Exposed to Neridronate in Children Affected by Osteogenesis Imperfecta Type 1. Biomedicines 2023; 11:biomedicines11020458. [PMID: 36830994 PMCID: PMC9953364 DOI: 10.3390/biomedicines11020458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/28/2023] [Accepted: 02/02/2023] [Indexed: 02/09/2023] Open
Abstract
Brain-type creatine kinase (CK-BB) increases during osteoclastogenesis, with high circulating amounts in type I osteogenesis imperfecta (OI) following treatment with neridronate, a bisphosphonate able to inhibit osteoclast activity and survival. The aim of this study was to demonstrate the correlation between osteoclastogenesis and CK-BB release from OI patients' osteoclasts treated with different concentrations of neridronate. Our patients showed reduced bone quality, increased levels of CTX I, a marker of bone resorption, and decreased levels of OPG, an inhibitor of osteoclastogenesis. In OI patients, the presence of MCSF and RANKL determined an increased secretion of CK-BB from osteoclasts (p = 0.04) compared with control conditions without these cytokines; interestingly, in the absence of these factors, the secretion of CK-BB is significantly elevated at 3 µmol/L compared with 0.03 and 1 µmol/L (p = 0.007). In healthy donors' cultures, the higher concentration of CK-BB can be detected following stimulation with 3 µmol/L neridronate compared with the untreated condition both with and without MCSF and RANKL (p = 0.03 and p = 0.006, respectively). Consistently, in osteoclast cultures, neridronate treatment is associated with a decrease in multinucleated TRAP+ cells, together with morphology changes typical of apoptosis. Consistently, in the media of the same osteoclast cultures, we demonstrated a significant increase in caspase-3 levels. In conclusion, our findings support the idea that CK-BB levels increase in the serum of OI-treated patients.
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12
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Tonelli F, Leoni L, Daponte V, Gioia R, Cotti S, Fiedler IAK, Larianova D, Willaert A, Coucke PJ, Villani S, Busse B, Besio R, Rossi A, Witten PE, Forlino A. Zebrafish Tric-b is required for skeletal development and bone cells differentiation. Front Endocrinol (Lausanne) 2023; 14:1002914. [PMID: 36755921 PMCID: PMC9899828 DOI: 10.3389/fendo.2023.1002914] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/03/2023] [Indexed: 01/24/2023] Open
Abstract
INTRODUCTION Trimeric intracellular potassium channels TRIC-A and -B are endoplasmic reticulum (ER) integral membrane proteins, involved in the regulation of calcium release mediated by ryanodine (RyRs) and inositol 1,4,5-trisphosphate (IP3Rs) receptors, respectively. While TRIC-A is mainly expressed in excitable cells, TRIC-B is ubiquitously distributed at moderate level. TRIC-B deficiency causes a dysregulation of calcium flux from the ER, which impacts on multiple collagen specific chaperones and modifying enzymatic activity, leading to a rare form of osteogenesis imperfecta (OI Type XIV). The relevance of TRIC-B on cell homeostasis and the molecular mechanism behind the disease are still unknown. RESULTS In this study, we exploited zebrafish to elucidate the role of TRIC-B in skeletal tissue. We demonstrated, for the first time, that tmem38a and tmem38b genes encoding Tric-a and -b, respectively are expressed at early developmental stages in zebrafish, but only the latter has a maternal expression. Two zebrafish mutants for tmem38b were generated by CRISPR/Cas9, one carrying an out of frame mutation introducing a premature stop codon (tmem38b-/- ) and one with an in frame deletion that removes the highly conserved KEV domain (tmem38bΔ120-7/Δ120-7 ). In both models collagen type I is under-modified and partially intracellularly retained in the endoplasmic reticulum, as described in individuals affected by OI type XIV. Tmem38b-/- showed a mild skeletal phenotype at the late larval and juvenile stages of development whereas tmem38bΔ120-7/Δ120-7 bone outcome was limited to a reduced vertebral length at 21 dpf. A caudal fin regeneration study pointed towards impaired activity of osteoblasts and osteoclasts associated with mineralization impairment. DISCUSSION Our data support the requirement of Tric-b during early development and for bone cell differentiation.
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Affiliation(s)
- Francesca Tonelli
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Laura Leoni
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Valentina Daponte
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Roberta Gioia
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Silvia Cotti
- Department of Biology, Ghent University, Ghent, Belgium
| | - Imke A. K. Fiedler
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Andy Willaert
- Department of Biomolecular Medicine, Center of Medical Genetics, Ghent University-University Hospital, Ghent, Belgium
| | - Paul J. Coucke
- Department of Biomolecular Medicine, Center of Medical Genetics, Ghent University-University Hospital, Ghent, Belgium
| | - Simona Villani
- Department of Public Health and Experimental and Forensic Medicine, Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia, Italy
| | - Björn Busse
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Antonio Rossi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | | | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
- *Correspondence: Antonella Forlino,
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13
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Alcorta-Sevillano N, Infante A, Macías I, Rodríguez CI. Murine Animal Models in Osteogenesis Imperfecta: The Quest for Improving the Quality of Life. Int J Mol Sci 2022; 24:ijms24010184. [PMID: 36613624 PMCID: PMC9820162 DOI: 10.3390/ijms24010184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/25/2022] Open
Abstract
Osteogenesis imperfecta is a rare genetic disorder characterized by bone fragility, due to alterations in the type I collagen molecule. It is a very heterogeneous disease, both genetically and phenotypically, with a high variability of clinical phenotypes, ranging from mild to severe forms, the most extreme cases being perinatal lethal. There is no curative treatment for OI, and so great efforts are being made in order to develop effective therapies. In these attempts, the in vivo preclinical studies are of paramount importance; therefore, serious analysis is required to choose the right murine OI model able to emulate as closely as possible the disease of the target OI population. In this review, we summarize the features of OI murine models that have been used for preclinical studies until today, together with recently developed new murine models. The bone parameters that are usually evaluated in order to determine the relevance of new developing therapies are exposed, and finally, current and innovative therapeutic strategies attempts considered in murine OI models, along with their mechanism of action, are reviewed. This review aims to summarize the in vivo studies developed in murine models available in the field of OI to date, in order to help the scientific community choose the most accurate OI murine model when developing new therapeutic strategies capable of improving the quality of life.
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Affiliation(s)
- Natividad Alcorta-Sevillano
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
- Department of Cell Biology and Histology, University of Basque Country UPV/EHU, 48940 Leioa, Spain
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
| | - Iratxe Macías
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
| | - Clara I. Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain
- Correspondence:
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14
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Gorrell L, Makareeva E, Omari S, Otsuru S, Leikin S. ER, Mitochondria, and ISR Regulation by mt-HSP70 and ATF5 upon Procollagen Misfolding in Osteoblasts. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201273. [PMID: 35988140 PMCID: PMC9561870 DOI: 10.1002/advs.202201273] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 08/02/2022] [Indexed: 06/15/2023]
Abstract
Cellular response to protein misfolding underlies multiple diseases. Collagens are the most abundant vertebrate proteins, yet little is known about cellular response to misfolding of their procollagen precursors. Osteoblasts (OBs)-the cells that make bone-produce so much procollagen that it accounts for up to 40% of mRNAs in the cell, which is why bone bears the brunt of mutations causing procollagen misfolding in osteogenesis imperfecta (OI). The present study of a G610C mouse model of OI by multiple transcriptomic techniques provides first solid clues to how OBs respond to misfolded procollagen accumulation in the endoplasmic reticulum (ER) and how this response affects OB function. Surprisingly, misfolded procollagen escapes the quality control in the ER lumen and indirectly triggers the integrated stress response (ISR) through other cell compartments. In G610C OBs, the ISR is regulated by mitochondrial HSP70 (mt-HSP70) and ATF5 instead of their BIP and ATF4 paralogues, which normally activate and regulate ISR to secretory protein misfolding in the ER. The involvement of mt-HSP70 and ATF5 together with other transcriptomic findings suggest that mitochondria might initiate the ISR upon disruption of ER-mitochondria connections or might respond to the ISR activated by a yet unknown sensor.
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Affiliation(s)
- Laura Gorrell
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)National Institutes of Health (NIH)BethesdaMD20892USA
- Department of Biomedical EngineeringRensselaer Polytechnic InstituteTroyNY12180USA
| | | | - Shakib Omari
- NICHDNIHBethesdaMD20892USA
- Sanford Burnham Prebys Medical Discovery InstituteLa JollaCA92037USA
| | - Satoru Otsuru
- Department of OrthopaedicsUniversity of Maryland School of MedicineBaltimoreMD21201USA
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15
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Hedjazi G, Guterman-Ram G, Blouin S, Schemenz V, Wagermaier W, Fratzl P, Hartmann MA, Zwerina J, Fratzl-Zelman N, Marini JC. Alterations of bone material properties in growing Ifitm5/BRIL p.S42 knock-in mice, a new model for atypical type VI osteogenesis imperfecta. Bone 2022; 162:116451. [PMID: 35654352 PMCID: PMC11162744 DOI: 10.1016/j.bone.2022.116451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 05/17/2022] [Accepted: 05/25/2022] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Osteogenesis imperfecta (OI) is a heterogenous group of heritable connective tissue disorders characterized by high bone fragility due to low bone mass and impaired bone material properties. Atypical type VI OI is an extremely rare and severe form of bone dysplasia resulting from a loss-of-function mutation (p.S40L) in IFITM5/BRIL,the causative gene of OI type V and decreased osteoblast secretion of pigment epithelium-derived factor (PEDF), as in OI type VI. It is not yet known which alterations at the material level might lead to such a severe phenotype. We therefore characterized bone tissue at the micrometer level in a novel heterozygous Ifitm5/BRIL p.S42L knock-in murine model at 4 and 8 weeks of age. METHODS We evaluated in female mice, total body size, femoral and lumbar bone mineral density (BMD) by dual-energy X-ray absorptiometry. In the femoral bone we examined osteoid deposition by light microscopy, assessed bone histomorphometry and mineralization density distribution by quantitative backscattered electron imaging (qBEI). Osteocyte lacunae were examined by qBEI and the osteocyte lacuno-canalicular network by confocal laser scanning microscopy. Vasculature was examined indirectly by qBEI as 2D porosity in cortex, and as 3D porosity by micro-CT in third trochanter. Collagen orientation was examined by second harmonic generation microscopy. Two-way ANOVA was used to discriminate the effect of age and genotype. RESULTS Ifitm5/BRIL p.S42L female mice are viable, do not differ in body size, fat and lean mass from wild type (WT) littermates but have lower whole-body, lumbar and femoral BMD and multiple fractures. The average and most frequent calcium concentration, CaMean and CaPeak, increased with age in metaphyseal and cortical bone in both genotypes and were always higher in Ifitm5/BRIL p.S42L than in WT, except CaMean in metaphysis at 4 weeks of age. The fraction of highly mineralized bone area, CaHigh, was also increased in Ifitm5/BRIL p.S42L metaphyseal bone at 8 weeks of age and at both ages in cortical bone. The fraction of lowly mineralized bone area, CaLow, decreased with age and was not higher in Ifitm5/BRIL p.S42L, consistent with lack of hyperosteoidosis on histological sections by visual exam. Osteocyte lacunae density was higher in Ifitm5/BRIL p.S42L than WT, whereas canalicular density was decreased. Indirect measurements of vascularity revealed a higher pore density at 4 weeks in cortical bone of Ifitm5/BRIL p.S42L than in WT and at both ages in the third trochanter. Importantly, the proportion of bone area with disordered collagen fibrils was highly increased in Ifitm5/BRIL p.S42L at both ages. CONCLUSIONS Despite normal skeletal growth and the lack of a collagen gene mutation, the Ifitm5/BRIL p.S42L mouse shows major OI-related bone tissue alterations such as hypermineralization of the matrix and elevated osteocyte porosity. Together with the disordered lacuno-canalicular network and the disordered collagen fibril orientation, these abnormalities likely contribute to overall bone fragility.
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Affiliation(s)
- Ghazal Hedjazi
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria
| | - Gali Guterman-Ram
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, USA
| | - Stéphane Blouin
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria
| | - Victoria Schemenz
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Am Mühlenberg 1, 14476 Potsdam, Germany
| | - Wolfgang Wagermaier
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Am Mühlenberg 1, 14476 Potsdam, Germany
| | - Peter Fratzl
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Am Mühlenberg 1, 14476 Potsdam, Germany
| | - Markus A Hartmann
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria
| | - Jochen Zwerina
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, USA.
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16
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Garibaldi N, Besio R, Dalgleish R, Villani S, Barnes AM, Marini JC, Forlino A. Dissecting the phenotypic variability of osteogenesis imperfecta. Dis Model Mech 2022; 15:275408. [PMID: 35575034 PMCID: PMC9150118 DOI: 10.1242/dmm.049398] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 03/16/2022] [Indexed: 12/24/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous family of collagen type I-related diseases characterized by bone fragility. OI is most commonly caused by single-nucleotide substitutions that replace glycine residues or exon splicing defects in the COL1A1 and COL1A2 genes that encode the α1(I) and α2(I) collagen chains. Mutant collagen is partially retained intracellularly, impairing cell homeostasis. Upon secretion, it assembles in disorganized fibrils, altering mineralization. OI is characterized by a wide range of clinical outcomes, even in the presence of identical sequence variants. Given the heterotrimeric nature of collagen I, its amino acid composition and the peculiarity of its folding, several causes may underlie the phenotypic variability of OI. A deep analysis of entries regarding glycine and splice site collagen substitution of the largest publicly available patient database reveals a higher risk of lethal phenotype for carriers of variants in α1(I) than in α2(I) chain. However, splice site variants are predominantly associated with lethal phenotype when they occur in COL1A2. In addition, lethality is increased when mutations occur in regions of importance for extracellular matrix interactions. Both extracellular and intracellular determinants of OI clinical severity are discussed in light of the findings from in vitro and in vivo OI models. Combined with meticulous tracking of clinical cases via a publicly available database, the available OI animal models have proven to be a unique tool to shed light on new modulators of phenotype determination for this rare heterogeneous disease.
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Affiliation(s)
- Nadia Garibaldi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100 Pavia, Italy
| | - Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100 Pavia, Italy
| | - Raymond Dalgleish
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, United Kingdom
| | - Simona Villani
- Department of Public Health and Experimental and Forensic Medicine, Unit of Biostatistics and Clinical Epidemiology, University of Pavia, 27100 Pavia, Italy
| | - Aileen M Barnes
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, 20892 Bethesda, MD, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, 20892 Bethesda, MD, USA
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100 Pavia, Italy
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17
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Jovanovic M, Guterman-Ram G, Marini JC. Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types. Endocr Rev 2022; 43:61-90. [PMID: 34007986 PMCID: PMC8755987 DOI: 10.1210/endrev/bnab017] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous skeletal dysplasia characterized by bone fragility, growth deficiency, and skeletal deformity. Previously known to be caused by defects in type I collagen, the major protein of extracellular matrix, it is now also understood to be a collagen-related disorder caused by defects in collagen folding, posttranslational modification and processing, bone mineralization, and osteoblast differentiation, with inheritance of OI types spanning autosomal dominant and recessive as well as X-linked recessive. This review provides the latest updates on OI, encompassing both classical OI and rare forms, their mechanism, and the signaling pathways involved in their pathophysiology. There is a special emphasis on mutations in type I procollagen C-propeptide structure and processing, the later causing OI with strikingly high bone mass. Types V and VI OI, while notably different, are shown to be interrelated by the interferon-induced transmembrane protein 5 p.S40L mutation that reveals the connection between the bone-restricted interferon-induced transmembrane protein-like protein and pigment epithelium-derived factor pathways. The function of regulated intramembrane proteolysis has been extended beyond cholesterol metabolism to bone formation by defects in regulated membrane proteolysis components site-2 protease and old astrocyte specifically induced-substance. Several recently proposed candidate genes for new types of OI are also presented. Discoveries of new OI genes add complexity to already-challenging OI management; current and potential approaches are summarized.
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Affiliation(s)
- Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Gali Guterman-Ram
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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18
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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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19
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Cotti S, Huysseune A, Larionova D, Koppe W, Forlino A, Witten PE. Compression Fractures and Partial Phenotype Rescue With a Low Phosphorus Diet in the Chihuahua Zebrafish Osteogenesis Imperfecta Model. Front Endocrinol (Lausanne) 2022; 13:851879. [PMID: 35282456 PMCID: PMC8913339 DOI: 10.3389/fendo.2022.851879] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/01/2022] [Indexed: 12/15/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a group of heritable disorders affecting bone and other connective tissues. Dominant OI forms are mainly caused by mutations in collagen type I. Patients suffer from skeletal deformities, fractures of long bones and vertebral compression fractures from early childhood onward. Altered collagen structure and excess mineralisation are the main causes for the bone phenotype. The Chihuahua (Chi/+) zebrafish has become an important model for OI. Given that reduced dietary phosphorus (P) intake reduces the bone mineral content and promotes bone matrix formation in teleosts, including zebrafish, we tested whether a low dietary P (LP) intake mitigates the OI phenotype in the Chi/+ model. To answer this question, we characterised the Chi/+ vertebral column phenotype at a morphological, cellular and subcellular level. We present the first description of vertebral compression fractures in Chi/+ and assess the effects of LP diet on the Chi/+ phenotype (Chi/+LP). Compared to untreated Chi/+, two months of LP dietary treatment decreases vertebral deformities in the abdominal region and reduces shape variation of caudal vertebral bodies to a condition more similar to wild type (WT). At the histological level, the osteoid layer, covering the bone at the vertebral body endplates in WT zebrafish, is absent in Chi/+, but it is partially restored with the LP diet. Whole mount-stained specimens and histological sections show various stages of vertebral compression fractures in Chi/+ and Chi/+LP animals. Both Chi/+ and Chi/+LP show abundant osteoclast activity compared to WT. Finally, the ultrastructure analysis of WT, Chi/+ and Chi/+LP shows Chi/+ and Chi/+LP osteoblasts with enlarged endoplasmic reticulum cisternae and a high protein content, consistent with intracellular retention of mutated collagen. Nevertheless, the secreted collagen in Chi/+LP appears better organised concerning fibre periodicity compared to Chi/+. Our findings suggest that a reduced mineral content of Chi/+ bone could explain the lower frequency of vertebral column deformities and the restored shape of the vertebral bodies in Chi/+LP animals. This, together with the improved quality of the bone extracellular matrix, suggests that two months of reduced dietary P intake can alleviate the severe bone phenotype in Chi/+ zebrafish.
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Affiliation(s)
- Silvia Cotti
- Evolutionary Developmental Biology Group, Department of Biology, Ghent University, Gent, Belgium
- Biochemistry Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy
- *Correspondence: Silvia Cotti,
| | - Ann Huysseune
- Evolutionary Developmental Biology Group, Department of Biology, Ghent University, Gent, Belgium
| | - Daria Larionova
- Evolutionary Developmental Biology Group, Department of Biology, Ghent University, Gent, Belgium
| | | | - Antonella Forlino
- Biochemistry Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Paul Eckhard Witten
- Evolutionary Developmental Biology Group, Department of Biology, Ghent University, Gent, Belgium
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20
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Duangchan T, Tawonsawatruk T, Angsanuntsukh C, Trachoo O, Hongeng S, Kitiyanant N, Supokawej A. Amelioration of osteogenesis in iPSC-derived mesenchymal stem cells from osteogenesis imperfecta patients by endoplasmic reticulum stress inhibitor. Life Sci 2021; 278:119628. [PMID: 34015290 DOI: 10.1016/j.lfs.2021.119628] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 12/20/2022]
Abstract
AIM Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder primarily caused by mutations in COL1A1 or COL1A2, which encode type I collagen. These mutations affect the quantity and/or quality of collagen composition in bones, leading to bone fragility. Currently, there is still a lack of treatment that addresses disease-causing factors due to an insufficient understanding of the pathological mechanisms involved. MAIN METHODS Induced pluripotent stem cells (iPSCs) were generated from OI patients with glycine substitution mutations in COL1A1 and COL1A2 and developed into mesenchymal stem cells (iPS-MSCs). OI-derived iPS-MSCs underwent in vitro osteogenic induction to study cell growth, osteogenic differentiation capacity, mRNA expression of osteogenic and unfolded protein response (UPR) markers and apoptosis. The effects of 4-phenylbutyric acid (4-PBA) were examined after treatment of OI iPS-MSCs during osteogenesis. KEY FINDINGS OI-derived iPS-MSCs exhibited decreased cell growth and impaired osteogenic differentiation and collagen expression. Expression of UPR genes was increased, which led to an increase in apoptotic cell death. 4-PBA treatment decreased apoptotic cells and reduced expression of UPR genes, including HSPA5, XBP1, ATF4, DDIT3, and ATF6. Osteogenic phenotypes, including RUNX2, SPP1, BGLAP, and IBPS expression, as well as calcium mineralization, were also improved. SIGNIFICANCE MSCs differentiated from disease-specific iPSCs have utility as a disease model for identifying disease-specific treatments. In addition, the ER stress-associated UPR could be a pathogenic mechanism associated with OI. Treatment with 4-PBA alleviated OI pathogenesis by attenuating UPR markers and apoptotic cell death.
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Affiliation(s)
- Thitinat Duangchan
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Phutthamonthon, Nakhon Pathom 73170, Thailand
| | - Tulyapruek Tawonsawatruk
- Department of Orthopedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Chanika Angsanuntsukh
- Department of Orthopedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Objoon Trachoo
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Suradej Hongeng
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Narisorn Kitiyanant
- Stem Cell Research Group, Institute of Molecular Biosciences, Mahidol University, Phutthamonthon, Nakhon Pathom 73170, Thailand
| | - Aungkura Supokawej
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Phutthamonthon, Nakhon Pathom 73170, Thailand.
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21
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Mähr M, Blouin S, Behanova M, Misof BM, Glorieux FH, Zwerina J, Rauch F, Hartmann MA, Fratzl-Zelman N. Increased Osteocyte Lacunae Density in the Hypermineralized Bone Matrix of Children with Osteogenesis Imperfecta Type I. Int J Mol Sci 2021; 22:ijms22094508. [PMID: 33925942 PMCID: PMC8123504 DOI: 10.3390/ijms22094508] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/23/2022] Open
Abstract
Osteocytes are terminally differentiated osteoblasts embedded within the bone matrix and key orchestrators of bone metabolism. However, they are generally not characterized by conventional bone histomorphometry because of their location and the limited resolution of light microscopy. OI is characterized by disturbed bone homeostasis, matrix abnormalities and elevated bone matrix mineralization density. To gain further insights into osteocyte characteristics and bone metabolism in OI, we evaluated 2D osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging in transiliac bone biopsy samples from children with OI type I (n = 19) and age-matched controls (n = 24). The OLS characteristics were related to previously obtained, re-visited histomorphometric parameters. Moreover, we present pediatric bone mineralization density distribution reference data in OI type I (n = 19) and controls (n = 50) obtained with a field emission scanning electron microscope. Compared to controls, OI has highly increased OLS density in cortical and trabecular bone (+50.66%, +61.73%; both p < 0.001), whereas OLS area is slightly decreased in trabecular bone (−10.28%; p = 0.015). Correlation analyses show a low to moderate, positive association of OLS density with surface-based bone formation parameters and negative association with indices of osteoblast function. In conclusion, hyperosteocytosis of the hypermineralized OI bone matrix associates with abnormal bone cell metabolism and might further impact the mechanical competence of the bone tissue.
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Affiliation(s)
- Matthias Mähr
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Stéphane Blouin
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Martina Behanova
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Barbara M. Misof
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Francis H. Glorieux
- Genetics Unit, Shriners Hospital for Children and McGill University, Montreal, ON H4A 0A9, Canada; (F.H.G.); (F.R.)
| | - Jochen Zwerina
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Frank Rauch
- Genetics Unit, Shriners Hospital for Children and McGill University, Montreal, ON H4A 0A9, Canada; (F.H.G.); (F.R.)
| | - Markus A. Hartmann
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Nadja Fratzl-Zelman
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
- Correspondence: ; Tel.: +43-5-9393-55770
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22
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Garibaldi N, Contento BM, Babini G, Morini J, Siciliani S, Biggiogera M, Raspanti M, Marini JC, Rossi A, Forlino A, Besio R. Targeting cellular stress in vitro improves osteoblast homeostasis, matrix collagen content and mineralization in two murine models of osteogenesis imperfecta. Matrix Biol 2021; 98:1-20. [PMID: 33798677 PMCID: PMC11162743 DOI: 10.1016/j.matbio.2021.03.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 03/26/2021] [Accepted: 03/26/2021] [Indexed: 12/14/2022]
Abstract
Most cases of dominantly inherited osteogenesis imperfecta (OI) are caused by glycine substitutions in the triple helical domain of type I collagen α chains, which delay collagen folding, and cause the synthesis of collagen triple helical molecules with abnormal structure and post-translational modification. A variable extent of mutant collagen ER retention and other secondary mutation effects perturb osteoblast homeostasis and impair bone matrix quality. Amelioration of OI osteoblast homeostasis could be beneficial both to osteoblast anabolic activity and to the content of the extracellular matrix they deposit. Therefore, the effect of the chemical chaperone 4-phenylbutyrate (4-PBA) on cell homeostasis, collagen trafficking, matrix production and mineralization was investigated in primary osteoblasts from two murine models of moderate OI, Col1a1+/G349C and Col1a2+/G610C. At the cellular level, 4-PBA prevented intracellular accumulation of collagen and increased protein secretion, reducing aggregates within the mutant cells and normalizing ER morphology. At the extracellular level, increased collagen incorporation into matrix, associated with more mature collagen fibrils, was observed in osteoblasts from both models. 4-PBA also promoted OI osteoblast mineral deposition by increasing alkaline phosphatase expression and activity. Targeting osteoblast stress with 4-PBA improved both cellular and matrix abnormalities in culture, supporting further in vivo studies of its effect on bone tissue composition, strength and mineralization as a potential treatment for classical OI.
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Affiliation(s)
- Nadia Garibaldi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy; Istituto Universitario di Studi Superiori - IUSS, Pavia, Italy.
| | - Barbara M Contento
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
| | | | - Jacopo Morini
- Department of Physics, University of Pavia, Pavia, Italy.
| | - Stella Siciliani
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
| | - Marco Biggiogera
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
| | - Mario Raspanti
- Department of Medicine and Surgery, University of Insubria, Varese, Italy.
| | - Joan C Marini
- Bone and Extracellular Matrix Branch, NICHD, National Institute of Health, Bethesda, MD 20892, USA.
| | - Antonio Rossi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
| | - Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
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23
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Etich J, Rehberg M, Eckes B, Sengle G, Semler O, Zaucke F. Signaling pathways affected by mutations causing osteogenesis imperfecta. Cell Signal 2020; 76:109789. [PMID: 32980496 DOI: 10.1016/j.cellsig.2020.109789] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 12/17/2022]
Abstract
Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility and skeletal deformity. To maintain skeletal strength and integrity, bone undergoes constant remodeling of its extracellular matrix (ECM) tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. There are at least 20 recognized OI-forms caused by mutations in the two collagen type I-encoding genes or genes implicated in collagen folding, posttranslational modifications or secretion of collagen, osteoblast differentiation and function, or bone mineralization. The underlying disease mechanisms of non-classical forms of OI that are not caused by collagen type I mutations are not yet completely understood, but an altered ECM structure as well as disturbed intracellular homeostasis seem to be the main defects. The ECM orchestrates local cell behavior in part by regulating bioavailability of signaling molecules through sequestration, release and activation during the constant bone remodeling process. Here, we provide an overview of signaling pathways that are associated with known OI-causing genes and discuss the impact of these genes on signal transduction. These pathways include WNT-, RANK/RANKL-, TGFβ-, MAPK- and integrin-mediated signaling as well as the unfolded protein response.
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Affiliation(s)
- Julia Etich
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, Frankfurt/Main, 60528, Germany.
| | - Mirko Rehberg
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany
| | - Beate Eckes
- Translational Matrix Biology, Faculty of Medicine, University of Cologne, Cologne 50931, Germany
| | - Gerhard Sengle
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne 50931, Germany; Cologne Center for Musculoskeletal Biomechanics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany
| | - Oliver Semler
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Center for Rare Diseases, University Hospital Cologne, University of Cologne, Cologne 50931, Germany
| | - Frank Zaucke
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, Frankfurt/Main, 60528, Germany
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24
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Scheiber AL, Barton DK, Khoury BM, Marini JC, Swiderski DL, Caird MS, Kozloff KM. Sclerostin Antibody-Induced Changes in Bone Mass Are Site Specific in Developing Crania. J Bone Miner Res 2019; 34:2301-2310. [PMID: 31441963 PMCID: PMC7458133 DOI: 10.1002/jbmr.3858] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 07/24/2019] [Accepted: 08/14/2019] [Indexed: 01/01/2023]
Abstract
Sclerostin antibody (Scl-Ab) is an anabolic bone agent that has been shown to increase bone mass in clinical trials of adult diseases of low bone mass, such as osteoporosis and osteogenesis imperfecta (OI). Its use to decrease bone fragility in pediatric OI has shown efficacy in several growing mouse models, suggesting translational potential to pediatric disorders of low bone mass. However, the effects of pharmacologic inhibition of sclerostin during periods of rapid growth and development have not yet been described with respect to the cranium, where lifelong deficiency of functioning sclerostin leads to patterns of excessive bone growth, cranial compression, and facial palsy. In the present study, we undertook dimensional and volumetric measurements in the skulls of growing Brtl/+ OI mice treated with Scl-Ab to examine whether therapy-induced phenotypic changes were similar to those observed clinically in patients with sclerosteosis or Van Buchem disorder. Mice treated between 3 and 14 weeks of age with high doses of Scl-Ab show significant calvarial thickening capable of rescuing OI-induced deficiencies in skull thickness. Other changes in cranial morphology, such as lengths and distances between anatomic landmarks, intracranial volume, and suture interdigitation, showed minimal effects of Scl-Ab when compared with growth-induced differences over the treatment duration. Treatment-induced narrowing of foramina was limited to sites of vascular but not neural passage, suggesting patterns of local regulation. Together, these findings reveal a site specificity of Scl-Ab action in the calvaria with no measurable cranial nerve impingement or brainstem compression. This differentiation from the observed outcomes of lifelong sclerostin deficiency complements reports of Scl-Ab treatment efficacy at other skeletal sites with the prospect of minimal cranial secondary complications. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.
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Affiliation(s)
- Amanda L Scheiber
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - David K Barton
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Basma M Khoury
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Joan C Marini
- Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Disorders, NIH, Bethesda, MD, USA
| | - Donald L Swiderski
- Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA
| | - Michelle S Caird
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kenneth M Kozloff
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
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25
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Olvera D, Stolzenfeld R, Fisher E, Nolan B, Caird MS, Kozloff KM. Pamidronate Administration During Pregnancy and Lactation Induces Temporal Preservation of Maternal Bone Mass in a Mouse Model of Osteogenesis Imperfecta. J Bone Miner Res 2019; 34:2061-2074. [PMID: 31310351 PMCID: PMC6854294 DOI: 10.1002/jbmr.3831] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 06/25/2019] [Accepted: 07/03/2019] [Indexed: 01/25/2023]
Abstract
During pregnancy and lactation, the maternal skeleton undergoes significant bone loss through increased resorption to provide the necessary calcium supply to the developing fetus and suckling neonate. This period of skeletal vulnerability has not been clearly associated with increased maternal fracture risk, but these physiological conditions can exacerbate an underlying metabolic bone condition like osteogenesis imperfecta. Although bisphosphonates (BPs) are commonly used in postmenopausal women, there are cases where premenopausal women taking BPs become pregnant. Given BPs' long half-life, there is a need to establish how BPs affect the maternal skeleton during periods of demanding metabolic bone changes that are critical for the skeletal development of their offspring. In the present study, pamidronate- (PAM-) amplified pregnancy-induced bone mass gains and lactation-induced bone loss were prevented. This preservation of bone mass was less robust when PAM was administered at late stages of lactation compared with early pregnancy and first day of lactation. Pregnancy-induced osteocyte osteolysis was also observed and was unaffected with PAM treatment. No negative skeletal effects were observed in offspring from PAM-treated dams despite lactation-induced bone loss prevention. These findings provide important insight into (1) a treatment window for when PAM is most effective in preserving maternal bone mass, and (2) the maternal changes in bone metabolism that maintain calcium homeostasis crucial for fetal and neonatal bone development. © 2019 American Society for Bone and Mineral Research.
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Affiliation(s)
- Diana Olvera
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Rachel Stolzenfeld
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Emily Fisher
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Bonnie Nolan
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Michelle S Caird
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kenneth M Kozloff
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
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26
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Liu Y, Wang J, Liu S, Kuang M, Jing Y, Zhao Y, Wang Z, Li G. A novel transgenic murine model with persistently brittle bones simulating osteogenesis imperfecta type I. Bone 2019; 127:646-655. [PMID: 31369917 DOI: 10.1016/j.bone.2019.07.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 06/27/2019] [Accepted: 07/17/2019] [Indexed: 01/10/2023]
Abstract
Osteogenesis imperfecta (OI) type I caused by the null allele of COL1A1 gene is in the majority in clinical OI cases. Currently, heterozygous Mov-13 mice generated by virus insertion in the first intron of col1a1 is the exclusive model to modulate OI type I, in spite of the gradually recovered bone mineral and mechanical properties. A newly designed heterozygous col1a1±365 OI mouse was produced in the present study by partial exons knockout (exon 2-exon 5, 365 nt of mRNA) using CRISPR/Cas9 system. The deletion resulted in generally large decrease in type I collagen synthesis due to frameshift mutation and premature chain termination, closely mimicking the pathogenic mechanism in affected individuals. And the strain possessed significantly sparse mineral scaffolds, bone loss, lowered mechanical strength and broken bone metabolism by 8 and 20 weeks compared to their littermates, suggesting a sustained skeletal weakness. Notably, the remarkable down-regulation of Yes-associated protein (YAP), one of the key coactivator in Hippo signaling pathway, was first found both in the femur and adipose derived mesenchymal stem cells (ADSCs) under osteogenic differentiation of col1a1±365 mice, which might be responsible for the reduced osteogenic potential and brittle bones. Still, further research was needed in order to illuminate the underlying mechanism.
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Affiliation(s)
- Yi Liu
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Jianhai Wang
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Shuo Liu
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Mingjie Kuang
- Department of Orthopedics, Tianjin Medical University General Hospital, 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
| | - Yuxia Zhao
- 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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27
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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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28
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Brunetti G, D'Amato G, Chiarito M, Tullo A, Colaianni G, Colucci S, Grano M, Faienza MF. An update on the role of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways in pediatric diseases. World J Pediatr 2019; 15:4-11. [PMID: 30343446 DOI: 10.1007/s12519-018-0198-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 10/04/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs), the bone-reabsorbing cells, and osteoblasts (OBs), and the bone-forming cells. This equilibrium is regulated by numerous cytokines, but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/β-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis, respectively. The pro-osteoblastogenic activity of the Wnt/β-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1). RANKL, sclerostin and DKKs-1 are often up-regulated in bone diseases, and they are the target of new monoclonal antibodies. DATA SOURCES The authors performed a systematic literature search in PubMed and EMBASE to June 2018, reviewed and selected articles, based on pre-determined selection criteria. RESULTS We re-evaluated the role of RANKL, osteoprotegerin, sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases, such as type 1 diabetes mellitus (T1DM), alkaptonuria (AKU), hemophilia A, osteogenesis imperfecta (OI), 21-hydroxylase deficiency (21OH-D) and Prader-Willi syndrome (PWS). To do so, we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways have been investigated, and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed. CONCLUSIONS The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases. Furthermore, for some of them, bone damage began in childhood but only manifested with age. The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children, although further studies need to be carried out.
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Affiliation(s)
- Giacomina Brunetti
- Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy
| | | | - Mariangela Chiarito
- Pediatric Section, Department of Biomedical Sciences and Human Oncology, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Apollonia Tullo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies-IBIOM, CNR, 70126, Bari, Italy
| | - Graziana Colaianni
- Department of Emergency and Organ Transplantation, University "A. Moro" of Bari, Bari, Italy
| | - Silvia Colucci
- Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Maria Grano
- Department of Emergency and Organ Transplantation, University "A. Moro" of Bari, Bari, Italy
| | - Maria Felicia Faienza
- Pediatric Section, Department of Biomedical Sciences and Human Oncology, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy.
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Besio R, Maruelli S, Battaglia S, Leoni L, Villani S, Layrolle P, Rossi A, Trichet V, Forlino A. Early Fracture Healing is Delayed in the Col1a2 +/G610C Osteogenesis Imperfecta Murine Model. Calcif Tissue Int 2018; 103:653-662. [PMID: 30076439 DOI: 10.1007/s00223-018-0461-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 07/30/2018] [Indexed: 01/08/2023]
Abstract
Osteogenesis imperfecta (OI) is a rare heritable skeletal dysplasia mainly caused by type I collagen abnormalities and characterized by bone fragility and susceptibility to fracture. Over 85% of the patients carry dominant mutations in the genes encoding for the collagen type I α1 and α2 chains. Failure of bone union and/or presence of hyperplastic callus formation after fracture were described in OI patients. Here we used the Col1a2+/G610C mouse, carrying in heterozygosis the α2(I)-G610C substitution, to investigate the healing process of an OI bone. Tibiae of 2-month-old Col1a2+/G610C and wild-type littermates were fractured and the healing process was followed at 2, 3, and 5 weeks after injury from fibrous cartilaginous tissue formation to its bone replacement by radiography, micro-computed tomography (µCT), histological and biochemical approaches. In presence of similar fracture types, in Col1a2+/G610C mice an impairment in the early phase of bone repair was detected compared to wild-type littermates. Smaller callus area, callus bone surface, and bone volume associated to higher percentage of cartilage and lower percentage of bone were evident in Col1a2+/G610C at 2 weeks post fracture (wpf) and no change by 3 wpf. Furthermore, the biochemical analysis of collagen extracted from callus 2 wpf revealed in mutants an increased amount of type II collagen, typical of cartilage, with respect to type I, characteristic of bone. This is the first report of a delay in OI bone fracture repair at the modeling phase.
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Affiliation(s)
- Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Via Taramelli 3B, 27100, Pavia, Italy
| | - Silvia Maruelli
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Via Taramelli 3B, 27100, Pavia, Italy
| | - Severine Battaglia
- INSERM, UMR 1238, PHY-OS, Bone sarcomas and remodeling of calcified tissues, Faculty of Medicine, University of Nantes, Nantes, France
| | - Laura Leoni
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Via Taramelli 3B, 27100, Pavia, Italy
| | - Simona Villani
- Department of Public Health and Experimental and Forensic Medicine, Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia, Italy
| | - Pierre Layrolle
- INSERM, UMR 1238, PHY-OS, Bone sarcomas and remodeling of calcified tissues, Faculty of Medicine, University of Nantes, Nantes, France
| | - Antonio Rossi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Via Taramelli 3B, 27100, Pavia, Italy
| | - Valerie Trichet
- INSERM, UMR 1238, PHY-OS, Bone sarcomas and remodeling of calcified tissues, Faculty of Medicine, University of Nantes, Nantes, France
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Via Taramelli 3B, 27100, Pavia, Italy.
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30
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Morello R. Osteogenesis imperfecta and therapeutics. Matrix Biol 2018; 71-72:294-312. [PMID: 29540309 PMCID: PMC6133774 DOI: 10.1016/j.matbio.2018.03.010] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/08/2018] [Accepted: 03/08/2018] [Indexed: 02/08/2023]
Abstract
Osteogenesis imperfecta, or brittle bone disease, is a congenital disease that primarily causes low bone mass and bone fractures but it can negatively affect other organs. It is usually inherited in an autosomal dominant fashion, although rarer recessive and X-chromosome-linked forms of the disease have been identified. In addition to type I collagen, mutations in a number of other genes, often involved in type I collagen synthesis or in the differentiation and function of osteoblasts, have been identified in the last several years. Seldom, the study of a rare disease has delivered such a wealth of new information that have helped our understanding of multiple processes involved in collagen synthesis and bone formation. In this short review I will describe the clinical features and the molecular genetics of the disease, but then focus on how OI dysregulates all aspects of extracellular matrix biology. I will conclude with a discussion about OI therapeutics.
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Affiliation(s)
- Roy Morello
- Department of Physiology & Biophysics, Orthopaedic Surgery, and Division of Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
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31
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el Demellawy D, Davila J, Shaw A, Nasr Y. Brief Review on Metabolic Bone Disease. Acad Forensic Pathol 2018; 8:611-640. [PMID: 31240061 PMCID: PMC6490580 DOI: 10.1177/1925362118797737] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 07/21/2018] [Indexed: 01/17/2023]
Abstract
Metabolic bone disease (MBD) is a broad term that describes a clinically heterogeneous group of diseases that are only united by a common denominator of an aberrant bone chemical milieu leading to a defective skeleton and bone abnormalities. From a forensic pathologist's perspective, MBDs create a challenging diagnostic dilemma in differentiating them from child abuse, particularly when the victim is an infant. Through this brief narrative review on MBD, bone pathophysiology and two relatively challenging pediatric MBDs will be discussed.
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Affiliation(s)
- Dina el Demellawy
- Dina el Demellawy MD PhD FRCPC, 401 Smyth Rd, Pathology Department, Ottawa ON K1H 8L1,
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Abstract
PURPOSE OF REVIEW Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder of skeletal fragility and more recently muscle weakness. This review highlights our current knowledge of the impact of compromised OI muscle function on muscle-bone interactions and skeletal strength in OI. RECENT FINDINGS The ramifications of inherent muscle weakness in OI muscle-bone interactions are just beginning to be elucidated. Studies in patients and in OI mouse models implicate altered mechanosensing, energy metabolism, mitochondrial dysfunction, and paracrine/endocrine crosstalk in the pathogenesis of OI. Compromised muscle-bone unit impacts mechanosensing and the ability of OI muscle and bone to respond to physiotherapeutic and pharmacologic treatment strategies. Muscle and bone are both compromised in OI, making it essential to understand the mechanisms responsible for both impaired muscle and bone functions and their interdependence, as this will expand and drive new physiotherapeutic and pharmacological approaches to treat OI and other musculoskeletal disorders.
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Affiliation(s)
- Charlotte L Phillips
- Department of Biochemistry, University of Missouri, 117 Schweitzer Hall, Columbia, MO, 65211, USA.
- Department of Child Health, University of Missouri, Columbia, MO, 65211, USA.
| | - Youngjae Jeong
- Department of Biochemistry, University of Missouri, 117 Schweitzer Hall, Columbia, MO, 65211, USA
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33
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Zimmerman SM, Heard-Lipsmeyer ME, Dimori M, Thostenson JD, Mannen EM, O'Brien CA, Morello R. Loss of RANKL in osteocytes dramatically increases cancellous bone mass in the osteogenesis imperfecta mouse (oim). Bone Rep 2018; 9:61-73. [PMID: 30105276 PMCID: PMC6077550 DOI: 10.1016/j.bonr.2018.06.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 05/30/2018] [Accepted: 06/29/2018] [Indexed: 12/24/2022] Open
Abstract
Osteogenesis imperfecta (OI) is characterized by osteopenia and bone fragility, and OI patients during growth often exhibit high bone turnover with the net result of low bone mass. Recent evidence shows that osteocytes significantly affect bone remodeling under physiological and pathological conditions through production of osteoclastogenic cytokines. The receptor activator of nuclear factor kappa-B ligand (RANKL) produced by osteocytes for example, is a critical mediator of bone loss caused by ovariectomy, low-calcium diet, unloading and glucocorticoid treatment. Because OI bone has increased density of osteocytes and these cells are embedded in matrix with abnormal type I collagen, we hypothesized that osteocyte-derived RANKL contributes to the OI bone phenotype. In this study, the conditional loss of RANKL in osteocytes in oim/oim mice (oim-RANKL-cKO) resulted in dramatically increased cancellous bone mass in both the femur and lumbar spine compared to oim/oim mice. Bone cortical thickness increased significantly only in spine but ultimate bone strength in the long bone and spine was minimally improved in oim-RANKL-cKO mice compared to oim/oim mice. Furthermore, unlike previous findings, we report that oim/oim mice do not exhibit high bone turnover suggesting that their low bone mass is likely due to defective bone formation and not increased bone resorption. The loss of osteocyte-derived RANKL further diminished parameters of formation in oim-RANKL-cKO. Our results indicate that osteocytes contribute significantly to the low bone mass observed in OI and the effect of loss of RANKL from these cells is similar to its systemic inhibition.
Osteocyte-specific deletion of RANKL in oim mice greatly increases cancellous bone. Skeletal effects of osteocyte RANKL deletion on OI mimic its systemic inhibition. Oim mice do not have high bone turnover. Low bone mass in oim mice is primarily caused by decreased bone formation. This study supports a potentially important role for osteocytes in OI.
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Affiliation(s)
- Sarah M. Zimmerman
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Melissa E. Heard-Lipsmeyer
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Milena Dimori
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Jeff D. Thostenson
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Erin M. Mannen
- Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Charles A. O'Brien
- Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
- Central Arkansas Veterans Healthcare System, Little Rock, AR, United States of America
- Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Roy Morello
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
- Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
- Division of Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
- Corresponding author at: Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, 4301 W. Markham St., #505, Little Rock, AR 72205-7199, United States of America.
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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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35
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Boraschi-Diaz I, Tauer JT, El-Rifai O, Guillemette D, Lefebvre G, Rauch F, Ferron M, Komarova SV. Metabolic phenotype in the mouse model of osteogenesis imperfecta. J Endocrinol 2017; 234:279-289. [PMID: 28716975 DOI: 10.1530/joe-17-0335] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 07/17/2017] [Indexed: 01/02/2023]
Abstract
Osteogenesis imperfecta (OI) is the most common heritable bone fragility disorder, usually caused by dominant mutations in genes coding for collagen type I alpha chains, COL1A1 or COL1A2 Osteocalcin (OCN) is now recognized as a bone-derived regulator of insulin secretion and sensitivity and glucose homeostasis. Since OI is associated with increased rates of bone formation and resorption, we hypothesized that the levels of undercarboxylated OCN are increased in OI. The objective of this study was to determine changes in OCN and to elucidate the metabolic phenotype in the Col1a1Jrt/+ mouse, a model of dominant OI caused by a Col1a1 mutation. Circulating levels of undercarboxylated OCN were higher in 4-week-old OI mice and normal by 8 weeks of age. Young OI animals exhibited a sex-dependent metabolic phenotype, including increased insulin levels in males, improved glucose tolerance in females, lower levels of random glucose and low adiposity in both sexes. The rates of O2 consumption and CO2 production, as well as energy expenditure assessed using indirect calorimetry were significantly increased in OI animals of both sexes, whereas respiratory exchange ratio was significantly higher in OI males only. Although OI mice have significant physical impairment that may contribute to metabolic differences, we specifically accounted for movement and compared OI and WT animals during the periods of similar activity levels. Taken together, our data strongly suggest that OI animals have alterations in whole body energy metabolism that are consistent with the action of undercarboxylated osteocalcin.
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Affiliation(s)
- Iris Boraschi-Diaz
- Shriners Hospital for Children-CanadaMontreal, Quebec, Canada
- Faculty of DentistryMcGill University, Montreal, Quebec, Canada
| | | | - Omar El-Rifai
- Unité de Recherche en Physiologie Intégrative et MoléculaireInstitut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
| | - Delphine Guillemette
- Shriners Hospital for Children-CanadaMontreal, Quebec, Canada
- Département de MathématiquesUniversité du Québec à Montréal, Montréal, Québec, Canada
| | - Geneviève Lefebvre
- Département de MathématiquesUniversité du Québec à Montréal, Montréal, Québec, Canada
| | - Frank Rauch
- Shriners Hospital for Children-CanadaMontreal, Quebec, Canada
| | - Mathieu Ferron
- Unité de Recherche en Physiologie Intégrative et MoléculaireInstitut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
- Départements de Médecine et de Biochimie et Médecine MoléculaireUniversité de Montréal, Montréal, Québec, Canada
| | - Svetlana V Komarova
- Shriners Hospital for Children-CanadaMontreal, Quebec, Canada
- Faculty of DentistryMcGill University, Montreal, Quebec, Canada
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36
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Lim J, Grafe I, Alexander S, Lee B. Genetic causes and mechanisms of Osteogenesis Imperfecta. Bone 2017; 102:40-49. [PMID: 28232077 PMCID: PMC5607741 DOI: 10.1016/j.bone.2017.02.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 01/07/2017] [Accepted: 02/11/2017] [Indexed: 12/25/2022]
Abstract
Osteogenesis Imperfecta (OI) is a genetic disorder characterized by various clinical features including bone deformities, low bone mass, brittle bones, and connective tissue manifestations. The predominant cause of OI is due to mutations in the two genes that encode type I collagen. However, recent advances in sequencing technology has led to the discovery of novel genes that are implicated in recessive and dominant OI. These include genes that regulate the post-translational modification, secretion and processing of type I collagen as well as those required for osteoblast differentiation and bone mineralization. As such, OI has become a spectrum of genetic disorders informing about the determinants of both bone quantity and quality. Here we summarize the known genetic causes of OI, animal models that recapitulate the human disease and mechanisms that underlie disease pathogenesis. Additionally, we discuss the effects of disrupted collagen networks on extracellular matrix signaling and its impact on disease progression.
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Affiliation(s)
- Joohyun Lim
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ingo Grafe
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Stefanie Alexander
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
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37
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Gene expression profiling of bone marrow mesenchymal stem cells from Osteogenesis Imperfecta patients during osteoblast differentiation. Eur J Med Genet 2017; 60:326-334. [DOI: 10.1016/j.ejmg.2017.04.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 03/22/2017] [Accepted: 04/05/2017] [Indexed: 12/26/2022]
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38
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Kang H, Aryal A C S, Marini JC. Osteogenesis imperfecta: new genes reveal novel mechanisms in bone dysplasia. Transl Res 2017; 181:27-48. [PMID: 27914223 DOI: 10.1016/j.trsl.2016.11.005] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 11/04/2016] [Accepted: 11/07/2016] [Indexed: 12/20/2022]
Abstract
Osteogenesis imperfecta (OI) is a skeletal dysplasia characterized by fragile bones and short stature and known for its clinical and genetic heterogeneity which is now understood as a collagen-related disorder. During the last decade, research has made remarkable progress in identifying new OI-causing genes and beginning to understand the intertwined molecular and biochemical mechanisms of their gene products. Most cases of OI have dominant inheritance. Each new gene for recessive OI, and a recently identified gene for X-linked OI, has shed new light on its (often previously unsuspected) function in bone biology. Here, we summarize the literature that has contributed to our current understanding of the pathogenesis of OI.
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Affiliation(s)
- Heeseog Kang
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, Md
| | - Smriti Aryal A C
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, Md
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, Md.
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39
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Perosky JE, Khoury BM, Jenks TN, Ward FS, Cortright K, Meyer B, Barton DK, Sinder BP, Marini JC, Caird MS, Kozloff KM. Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model. Bone 2016; 93:79-85. [PMID: 27641475 PMCID: PMC5077648 DOI: 10.1016/j.bone.2016.09.013] [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: 08/12/2016] [Revised: 09/14/2016] [Accepted: 09/14/2016] [Indexed: 01/19/2023]
Abstract
Sclerostin antibody has demonstrated a bone-forming effect in pre-clinical models of osteogenesis imperfecta, where mutations in collagen or collagen-associated proteins often result in high bone fragility in pediatric patients. Cessation studies in osteoporotic patients have demonstrated that sclerostin antibody, like intermittent PTH treatment, requires sequential anti-resorptive therapy to preserve the anabolic effects in adult populations. However, the persistence of anabolic gains from either drug has not been explored clinically in OI, or in any animal model. To determine whether cessation of sclerostin antibody therapy in a growing OI skeleton requires sequential anti-resorptive treatment to preserve anabolic gains in bone mass, we treated 3week old Brtl/+ and wild type mice for 5weeks with SclAb, and then withdrew treatment for an additional 6weeks. Trabecular bone loss was evident following cessation, but was preserved in a dose-dependent manner with single administration of pamidronate at the time of cessation. In vivo longitudinal near-infrared optical imaging of cathepsin K activation in the proximal tibia suggests an anti-resorptive effect of both SclAb and pamidronate which is reversed after three weeks of cessation. Cortical bone was considerably less susceptible to cessation effects, and showed no structural or functional deficits in the absence of pamidronate during this cessation period. In conclusion, while SclAb induces a considerable anabolic gain in the rapidly growing Brtl/+ murine model of OI, a single sequential dose of antiresorptive drug is required to maintain bone mass at trabecular sites for 6weeks following cessation.
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Affiliation(s)
- Joseph E Perosky
- University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States
| | - Basma M Khoury
- University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States
| | - Terese N Jenks
- University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States
| | - Ferrous S Ward
- University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States
| | - Kai Cortright
- University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States
| | - Bethany Meyer
- University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States
| | - David K Barton
- University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States
| | - Benjamin P Sinder
- University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States
| | - Joan C Marini
- Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Disorders, NIH, Bethesda, MD, United States
| | - Michelle S Caird
- University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States
| | - Kenneth M Kozloff
- University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States.
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40
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Enderli TA, Burtch SR, Templet JN, Carriero A. Animal models of osteogenesis imperfecta: applications in clinical research. Orthop Res Rev 2016; 8:41-55. [PMID: 30774469 PMCID: PMC6209373 DOI: 10.2147/orr.s85198] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Osteogenesis imperfecta (OI), commonly known as brittle bone disease, is a genetic disease characterized by extreme bone fragility and consequent skeletal deformities. This connective tissue disorder is caused by mutations in the quality and quantity of the collagen that in turn affect the overall mechanical integrity of the bone, increasing its vulnerability to fracture. Animal models of the disease have played a critical role in the understanding of the pathology and causes of OI and in the investigation of a broad range of clinical therapies for the disease. Currently, at least 20 animal models have been officially recognized to represent the phenotype and biochemistry of the 17 different types of OI in humans. These include mice, dogs, and fish. Here, we describe each of the animal models and the type of OI they represent, and present their application in clinical research for treatments of OI, such as drug therapies (ie, bisphosphonates and sclerostin) and mechanical (ie, vibrational) loading. In the future, different dosages and lengths of treatment need to be further investigated on different animal models of OI using potentially promising treatments, such as cellular and chaperone therapies. A combination of therapies may also offer a viable treatment regime to improve bone quality and reduce fragility in animals before being introduced into clinical trials for OI patients.
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Affiliation(s)
- Tanya A Enderli
- Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA,
| | - Stephanie R Burtch
- Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA,
| | - Jara N Templet
- Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA,
| | - Alessandra Carriero
- Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA,
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41
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Brunetti G, Papadia F, Tummolo A, Fischetto R, Nicastro F, Piacente L, Ventura A, Mori G, Oranger A, Gigante I, Colucci S, Ciccarelli M, Grano M, Cavallo L, Delvecchio M, Faienza MF. Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-α. Osteoporos Int 2016; 27:2355-2365. [PMID: 26856585 DOI: 10.1007/s00198-016-3501-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 01/20/2016] [Indexed: 12/23/2022]
Abstract
UNLABELLED In this study, we investigated the bone cell activity in patients with osteogenesis imperfecta (OI) treated and untreated with neridronate. We demonstrated the key role of Dickkopf-1 (DKK1), receptor activator of nuclear factor-κB ligand (RANKL), and tumor necrosis factor alpha (TNF-α) in regulating bone cell of untreated and treated OI subjects. These cytokines could represent new pharmacological targets for OI. INTRODUCTION Bisphosphonates are widely used in the treatment of children with osteogenesis imperfecta (OI) with the objective of reducing the risk of fractures. Although bisphosphonates increase bone mineral density in OI subjects, the effects on fracture incidence are conflicting. The aim of this study was to investigate the mechanisms underlying bone cell activity in subjects with mild untreated forms of OI and in a group of subjects with severe OI treated with cycles of intravenous neridronate. METHODS Sclerostin, DKK1, TNF-α, RANKL, osteoprotegerin (OPG), and bone turnover markers were quantified in serum of 18 OI patients (12 females, mean age 8.86 ± 3.90), 8 of which were receiving cyclic intravenous neridronate, and 21 sex- and age-matched controls. The effects on osteoblastogenesis and OPG expression of media conditioned by the serum of OI patients and anti-DKK1 neutralizing antibody were evaluated. Osteoclastogenesis was assessed in cultures from patients and controls. RESULTS DKK1 and RANKL levels were significantly increased both in untreated and in treated OI subjects with respect to controls. The serum from patients with high DKK1 levels inhibited both osteoblast differentiation and OPG expression in vitro. High RANKL and low OPG messenger RNA (mRNA) levels were found in lymphomonocytes from patients. High amounts of TNF-α were expressed by monocytes, and an elevated percentage of circulating CD11b-CD51/CD61+ osteoclast precursors was observed in patients. CONCLUSIONS Our study demonstrated the key role of DKK1, RANKL, and TNF-α in regulating bone cell activity of subjects with OI untreated and treated with bisphosphonates. These cytokines could represent new pharmacological targets for OI patients.
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Affiliation(s)
- G Brunetti
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy.
| | - F Papadia
- Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children's Hospital, Bari, Italy
| | - A Tummolo
- Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children's Hospital, Bari, Italy
| | - R Fischetto
- Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children's Hospital, Bari, Italy
| | - F Nicastro
- Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children's Hospital, Bari, Italy
| | - L Piacente
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - A Ventura
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - G Mori
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - A Oranger
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - I Gigante
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - S Colucci
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - M Ciccarelli
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - M Grano
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - L Cavallo
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - M Delvecchio
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - M F Faienza
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy.
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Shi C, Hu B, Guo L, Cao P, Tian Y, Ma J, Chen Y, Wu H, Hu J, Deng L, Zhang Y, Yuan W. Strontium Ranelate Reduces the Fracture Incidence in a Growing Mouse Model of Osteogenesis Imperfecta. J Bone Miner Res 2016; 31:1003-14. [PMID: 26679066 DOI: 10.1002/jbmr.2770] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 11/08/2015] [Accepted: 12/15/2015] [Indexed: 11/08/2022]
Abstract
Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by brittle bones with increased fracture risk. Although current treatment options to improve bone strength in OI focus on antiresorptive bisphosphonates, controlled clinical trials suggest they have an equivocal effect on reducing fracture risk. Strontium ranelate (SrR) is a promising therapy with a dual mode of action that is capable of simultaneously maintaining bone formation and reducing bone resorption, and may be beneficial for the treatment of OI. In this study, SrR therapy was investigated to assess its effects on fracture frequency and bone mass and strength in an animal model of OI, the oim/oim mouse. Three-week-old oim/oim and wt/wt mice were treated with either SrR or vehicle (Veh) for 11 weeks. After treatment, the average number of fractures sustained by SrR-treated oim/oim mice was significantly reduced compared to Veh-treated oim/oim mice. Micro-computed tomographic (μCT) analyses of femurs showed that both trabecular and cortical bone mass were significantly improved with SrR treatment in both genotypes. SrR significantly inhibited bone resorption, whereas bone formation indices were maintained. Biomechanical testing revealed improved bone structural properties in both oim/oim and wild-type (wt/wt) mice under the treatment, whereas no significant effects on bone brittleness and material quality were observed. In conclusion, SrR was able to effectively reduce fractures in oim/oim mice by improving bone mass and strength and thus represents a potential therapy for the treatment of pediatric OI. © 2015 American Society for Bone and Mineral Research.
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Affiliation(s)
- Changgui Shi
- Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Bo Hu
- Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Lei Guo
- Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Peng Cao
- Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Ye Tian
- Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Jun Ma
- Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yuanyuan Chen
- Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Huiqiao Wu
- Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Jinquan Hu
- Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Lianfu Deng
- Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Ying Zhang
- Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Wen Yuan
- Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
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Fratzl-Zelman N, Bächinger HP, Vranka JA, Roschger P, Klaushofer K, Rauch F. Bone matrix hypermineralization in prolyl-3 hydroxylase 1 deficient mice. Bone 2016; 85:15-22. [PMID: 26808442 DOI: 10.1016/j.bone.2016.01.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 01/20/2016] [Accepted: 01/21/2016] [Indexed: 01/02/2023]
Abstract
Lack of prolyl 3-hydroxylase 1 (P3H1) due to mutations in P3H1 results in severe forms of recessive osteogenesis imperfecta. In the present study, we investigated the bone tissue characteristics of P3H1 null mice. Histomorphometric analyses of cancellous bone in the proximal tibia and lumbar vertebra in 1-month and 3-month old mice demonstrated that P3H1 deficient mice had low trabecular bone volume and low mineral apposition rate, but normal osteoid maturation time and normal osteoblast and osteoclast surfaces. Quantitative backscattered electron imaging revealed that the bone mineralization density distribution was shifted towards higher values, indicating hypermineralization of bone matrix. It thus appears that P3H1 deficiency leads to decreased deposition of extracellular matrix by osteoblasts and increased incorporation of mineral into the matrix.
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Affiliation(s)
- Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria
| | | | - Janice A Vranka
- Oregon Health and Science University, Department of Ophtalmology, Portland, OR, USA
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria
| | - Klaus Klaushofer
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria
| | - Frank Rauch
- Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada.
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Sinder BP, Lloyd WR, Salemi JD, Marini JC, Caird MS, Morris MD, Kozloff KM. Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age. Bone 2016; 84:222-229. [PMID: 26769006 PMCID: PMC4757447 DOI: 10.1016/j.bone.2016.01.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 12/17/2015] [Accepted: 01/03/2016] [Indexed: 01/17/2023]
Abstract
Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly➔Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2-4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages>3wks) and rapidly growing Brtl/+ (at tissue ages>4wks) mice compared to WT. At identical tissue ages defined by fluorescent labels, adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age and animal age on bone quality.
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Affiliation(s)
- Benjamin P Sinder
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan Ann Arbor, MI, USA
| | - William R Lloyd
- Department of Chemistry, University of Michigan Ann Arbor, MI, USA
| | - Joseph D Salemi
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan Ann Arbor, MI, USA
| | - Joan C Marini
- Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
| | - Michelle S Caird
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Ann Arbor, MI, USA
| | - Michael D Morris
- Department of Chemistry, University of Michigan Ann Arbor, MI, USA
| | - Kenneth M Kozloff
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan Ann Arbor, MI, USA.
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Alsofi L, Daley E, Hornstra I, Morgan EF, Mason ZD, Acevedo JF, Word RA, Gerstenfeld LC, Trackman PC. Sex-Linked Skeletal Phenotype of Lysyl Oxidase Like-1 Mutant Mice. Calcif Tissue Int 2016; 98:172-85. [PMID: 26538021 PMCID: PMC8627178 DOI: 10.1007/s00223-015-0076-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Accepted: 10/25/2015] [Indexed: 01/22/2023]
Abstract
Lysyl oxidases are required for collagen and elastin cross-linking and extracellular matrix maturation including in bone. The lysyl oxidase family consists of lysyl oxidase (LOX) and 4 isoforms (LOXL1-4). Here we investigate whether deletion of LOXL1, which has been linked primarily to elastin maturation, leads to skeletal abnormalities. Left femurs (n = 8), L5 vertebrae (n = 8), and tibiae (n = 8) were analyzed by micro-computed tomography in 13-week-old wild-type (WT) and LOXL1-/- male and female mice. Right femurs (n = 8) were subjected to immunohistochemistry for LOXL1, and histochemical/histology analyses of osteoclasts and growth plates. Sera from all mice were analyzed for bone turnover markers. Results indicate strong expression of LOXL1 in wild-type growth plates in femurs. Significant deterioration of trabecular bone structure in long bones and vertebrae from female was observed but not from male, mutant mice compared with WT. Decreases in BV/TV, Conn.D, trabecular thickness, and number in the femoral distal metaphysis were observed in female, but not in male, mutant mice. Trabecular spacing was increased significantly in femurs of female mutant mice. Findings were similar in trabeculae of L5 vertebrae from female mutant mice. The number of TRAP positive osteoclasts at the trabecular bone surface was increased in female mutant mice compared with WT females, consistent with increased serum RANKL and decreased OPG levels. Analysis of bone turnover markers confirmed increased bone resorption as indicated by significantly elevated CTX-1 in the serum of female LOXL1-/- mice compared to their wild-type counterparts, as well as decreased bone formation as measured by decreased serum levels of PINP. Picrosirius red staining revealed a loss of heterogeneity in collagen organization in female LOXL1-/- mice only, with little to no yellow and orange birefringence. Organization was also impaired in chondrocyte columns in both female and male LOXL1-/- mice, but to a greater extent in females. Data indicate that LOXL1-/- mutant mice develop appendicular and axial skeletal phenotypes characterized by decreased bone volume fraction and compromised trabecular microstructure, predominantly in females.
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Affiliation(s)
- Loai Alsofi
- Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, 700 Albany Street, W-201, Boston, MA, 02118, USA
- Department of Endodontics, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Eileen Daley
- Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, 700 Albany Street, W-201, Boston, MA, 02118, USA
| | - Ian Hornstra
- Division of Dermatology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Elise F Morgan
- Department of Mechanical Engineering, Boston University, 110 Cummington Mall, Boston, MA, 02215, USA
| | - Zachary D Mason
- Department of Mechanical Engineering, Boston University, 110 Cummington Mall, Boston, MA, 02215, USA
| | - Jesus F Acevedo
- Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - R Ann Word
- Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Louis C Gerstenfeld
- Department of Orthopaedic Surgery, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Philip C Trackman
- Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, 700 Albany Street, W-201, Boston, MA, 02118, USA.
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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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Abdelaziz DM, Abdullah S, Magnussen C, Ribeiro-da-Silva A, Komarova SV, Rauch F, Stone LS. Behavioral signs of pain and functional impairment in a mouse model of osteogenesis imperfecta. Bone 2015; 81:400-406. [PMID: 26277094 DOI: 10.1016/j.bone.2015.08.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 07/29/2015] [Accepted: 08/03/2015] [Indexed: 01/19/2023]
Abstract
Osteogenesis imperfecta (OI) is a congenital disorder caused most often by dominant mutations in the COL1A1 or COL1A2 genes that encode the alpha chains of type I collagen. Severe forms of OI are associated with skeletal deformities and frequent fractures. Skeletal pain can occur acutely after fracture, but also arises chronically without preceding fractures. In this study we assessed OI-associated pain in the Col1a1Jrt/+ mouse, a recently developed model of severe dominant OI. Similar to severe OI in humans, this mouse has significant skeletal abnormalities and develops spontaneous fractures, joint dislocations and vertebral deformities. In this model, we investigated behavioral measures of pain and functional impairment. Significant hypersensitivity to mechanical, heat and cold stimuli, assessed by von Frey filaments, radiant heat paw withdrawal and the acetone tests, respectively, were observed in OI compared to control wildtype littermates. OI mice also displayed reduced motor activity in the running wheel and open field assays. Immunocytochemical analysis revealed no changes between OI and WT mice in innervation of the glabrous skin of the hindpaw or in expression of the pain-related neuropeptide calcitonin gene-related protein in sensory neurons. In contrast, increased sensitivity to mechanical and cold stimulation strongly correlated with the extent of skeletal deformities in OI mice. Thus, we demonstrated that the Col1a1Jrt/+ mouse model of severe OI has hypersensitivity to mechanical and thermal stimuli, consistent with a state of chronic pain.
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Affiliation(s)
- Dareen M Abdelaziz
- Faculty of Dentistry, McGill University, Montreal, QC, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada
| | - Sami Abdullah
- Shriners Hospitals for Children-Canada and McGill University, Montreal, QC, Canada
| | - Claire Magnussen
- Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada; Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Alfredo Ribeiro-da-Silva
- Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada; Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada
| | - Svetlana V Komarova
- Faculty of Dentistry, McGill University, Montreal, QC, Canada; Shriners Hospitals for Children-Canada and McGill University, Montreal, QC, Canada
| | - Frank Rauch
- Shriners Hospitals for Children-Canada and McGill University, Montreal, QC, Canada
| | - Laura S Stone
- Faculty of Dentistry, McGill University, Montreal, QC, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada; Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada; Department of Anaesthesiology, Faculty of Medicine, McGill University, Montreal, QC, Canada.
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Bianchi L, Gagliardi A, Maruelli S, Besio R, Landi C, Gioia R, Kozloff KM, Khoury BM, Coucke PJ, Symoens S, Marini JC, Rossi A, Bini L, Forlino A. Altered cytoskeletal organization characterized lethal but not surviving Brtl+/- mice: insight on phenotypic variability in osteogenesis imperfecta. Hum Mol Genet 2015; 24:6118-33. [PMID: 26264579 DOI: 10.1093/hmg/ddv328] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 08/06/2015] [Indexed: 02/02/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl(+/-) to investigate the molecular basis of OI phenotypic variability. Brtl(+/-) resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the α1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl(+/-) mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl(+/-) lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-β signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment.
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Affiliation(s)
- Laura Bianchi
- Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, Siena, Italy
| | - Assunta Gagliardi
- Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, Siena, Italy
| | - Silvia Maruelli
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Claudia Landi
- Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, Siena, Italy
| | - Roberta Gioia
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Kenneth M Kozloff
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Basma M Khoury
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Paul J Coucke
- Center for Medical Genetics, Ghent University, Ghent, Belgium and
| | - Sofie Symoens
- Center for Medical Genetics, Ghent University, Ghent, Belgium and
| | - Joan C Marini
- Bone and Extracellular Matrix Branch, NICHD, National Institute of Health, Bethesda, MD, USA
| | - Antonio Rossi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Luca Bini
- Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, Siena, Italy
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy,
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Sinder BP, Salemi JD, Ominsky MS, Caird MS, Marini JC, Kozloff KM. Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment. Bone 2015; 71:115-23. [PMID: 25445450 PMCID: PMC4274252 DOI: 10.1016/j.bone.2014.10.012] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 09/24/2014] [Accepted: 10/17/2014] [Indexed: 11/15/2022]
Abstract
Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk that presents most severely in children. Anti-resorptive bisphosphonates are frequently used to treat pediatric OI and controlled clinical trials have shown that bisphosphonate therapy improves vertebral outcomes but has little benefit on long bone fracture rate. New treatments which increase bone mass throughout the pediatric OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for pediatric OI and functions by stimulating osteoblastic bone formation via the canonical Wnt signaling pathway. To explore the effect of Scl-Ab on the rapidly growing OI skeleton, we treated rapidly growing 3week old Brtl/+ mice, harboring a typical heterozygous OI-causing Gly→Cys substitution on col1a1, for 5weeks with Scl-Ab. Scl-Ab had anabolic effects in Brtl/+ and led to new cortical bone formation and increased cortical bone mass. This anabolic action resulted in improved mechanical strength to WT Veh levels without altering the underlying brittle nature of the material. While Scl-Ab was anabolic in trabecular bone of the distal femur in both genotypes, the effect was less strong in these rapidly growing Brtl/+ mice compared to WT. In conclusion, Scl-Ab was able to stimulate bone formation in a rapidly growing Brtl/+ murine model of OI, and represents a potential new therapy to improve bone mass and reduce fracture risk in pediatric OI.
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Affiliation(s)
- Benjamin P Sinder
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Joseph D Salemi
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Michael S Ominsky
- Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, United States
| | - Michelle S Caird
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Joan C Marini
- Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, United States
| | - Kenneth M Kozloff
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States.
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Molecular, phenotypic aspects and therapeutic horizons of rare genetic bone disorders. BIOMED RESEARCH INTERNATIONAL 2014; 2014:670842. [PMID: 25530967 PMCID: PMC4230237 DOI: 10.1155/2014/670842] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 08/12/2014] [Accepted: 08/24/2014] [Indexed: 12/21/2022]
Abstract
A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.
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