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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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Crawford TK, Lafaver BN, Phillips CL. Extra-Skeletal Manifestations in Osteogenesis Imperfecta Mouse Models. Calcif Tissue Int 2024; 115:847-862. [PMID: 38641703 DOI: 10.1007/s00223-024-01213-4] [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: 02/26/2024] [Accepted: 03/25/2024] [Indexed: 04/21/2024]
Abstract
Osteogenesis imperfecta (OI) is a rare heritable connective tissue disorder of skeletal fragility with an incidence of roughly 1:15,000. Approximately 85% of the pathogenic variants responsible for OI are in the type I collagen genes, COL1A1 and COL1A2, with the remaining pathogenic OI variants spanning at least 20 additional genetic loci that often involve type I collagen post-translational modification, folding, and intracellular transport as well as matrix incorporation and mineralization. In addition to being the most abundant collagen in the body, type I collagen is an important structural and extracellular matrix signaling molecule in multiple organ systems and tissues. Thus, OI disease-causing variants result not only in skeletal fragility, decreased bone mineral density (BMD), kyphoscoliosis, and short stature, but can also result in hearing loss, dentinogenesis imperfecta, blue gray sclera, cardiopulmonary abnormalities, and muscle weakness. The extensive genetic and clinical heterogeneity in OI has necessitated the generation of multiple mouse models, the growing awareness of non-skeletal organ and tissue involvement, and OI being more broadly recognized as a type I collagenopathy.This has driven the investigation of mutation-specific skeletal and extra-skeletal manifestations and broadened the search of potential mechanistic therapeutic strategies. The purpose of this review is to outline several of the extra-skeletal manifestations that have recently been characterized through the use of genetically and phenotypically heterogeneous mouse models of osteogenesis imperfecta, demonstrating the significant potential impact of OI disease-causing variants as a collagenopathy (affecting multiple organ systems and tissues), and its implications to overall health.
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Affiliation(s)
- Tara K Crawford
- Department of Biochemistry, University of Missouri-Columbia, Columbia, MO, USA
| | - Brittany N Lafaver
- Department of Biochemistry, University of Missouri-Columbia, Columbia, MO, USA
| | - Charlotte L Phillips
- Departments of Biochemistry and Child Health, University of Missouri-Columbia, 117 Schweitzer Hall, Columbia, MO, 65211, USA.
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Che Z, Sun Q, Zhao Z, Wu Y, Xing H, Song K, Chen A, Wang B, Cai M. Growth factor-functionalized titanium implants for enhanced bone regeneration: A review. Int J Biol Macromol 2024; 274:133153. [PMID: 38897500 DOI: 10.1016/j.ijbiomac.2024.133153] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 06/02/2024] [Accepted: 06/12/2024] [Indexed: 06/21/2024]
Abstract
Titanium and titanium alloys are widely favored materials for orthopedic implants due to their exceptional mechanical properties and biological inertness. The additional benefit of sustained local release of bioactive substances further promotes bone tissue formation, thereby augmenting the osseointegration capacity of titanium implants and attracting increasing attention in bone tissue engineering. Among these bioactive substances, growth factors have shown remarkable osteogenic and angiogenic induction capabilities. Consequently, researchers have developed various physical, chemical, and biological loading techniques to incorporate growth factors into titanium implants, ensuring controlled release kinetics. In contrast to conventional treatment modalities, the localized release of growth factors from functionalized titanium implants not only enhances osseointegration but also reduces the risk of complications. This review provides a comprehensive examination of the types and mechanisms of growth factors, along with a detailed exploration of the methodologies used to load growth factors onto the surface of titanium implants. Moreover, it highlights recent advancements in the application of growth factors to the surface of titanium implants (Scheme 1). Finally, the review discusses current limitations and future prospects for growth factor-functionalized titanium implants. In summary, this paper presents cutting-edge design strategies aimed at enhancing the bone regenerative capacity of growth factor-functionalized titanium implants-a significant advancement in the field of enhanced bone regeneration.
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Affiliation(s)
- Zhenjia Che
- Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai 200072, People's Republic of China.
| | - Qi Sun
- Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai 200072, People's Republic of China
| | - Zhenyu Zhao
- Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai 200072, People's Republic of China
| | - Yanglin Wu
- Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai 200072, People's Republic of China
| | - Hu Xing
- Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai 200072, People's Republic of China
| | - Kaihang Song
- Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai 200072, People's Republic of China
| | - Aopan Chen
- Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai 200072, People's Republic of China
| | - Bo Wang
- Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai 200072, People's Republic of China.
| | - Ming Cai
- Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai 200072, People's Republic of China.
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Creecy A, Segvich D, Metzger C, Kohler R, Wallace JM. Combining anabolic loading and raloxifene improves bone quantity and some quality measures in a mouse model of osteogenesis imperfecta. Bone 2024; 184:117106. [PMID: 38641232 PMCID: PMC11130993 DOI: 10.1016/j.bone.2024.117106] [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: 01/25/2024] [Revised: 03/20/2024] [Accepted: 04/15/2024] [Indexed: 04/21/2024]
Abstract
Osteogenesis imperfecta (OI) increases fracture risk due to changes in bone quantity and quality caused by mutations in collagen and its processing proteins. Current therapeutics improve bone quantity, but do not treat the underlying quality deficiencies. Male and female G610C+/- mice, a murine model of OI, were treated with a combination of raloxifene and in vivo axial tibial compressive loading starting at 10 weeks of age and continuing for 6 weeks to improve bone quantity and quality. Bone geometry and mechanical properties were measured to determine whole bone and tissue-level material properties. A colocalized Raman/nanoindentation system was used to measure chemical composition and nanomechanical properties in newly formed bone compared to old bone to determine if bone formed during the treatment regimen differed in quality compared to bone formed prior to treatment. Lastly, lacunar geometry and osteocyte apoptosis were assessed. OI mice were able to build bone in response to the loading, but this response was less robust than in control mice. Raloxifene improved some bone material properties in female but not male OI mice. Raloxifene did not alter nanomechanical properties, but loading did. Lacunar geometry was largely unchanged with raloxifene and loading. However, osteocyte apoptosis was increased with loading in raloxifene treated female mice. Overall, combination treatment with raloxifene and loading resulted in positive but subtle changes to bone quality.
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Affiliation(s)
- Amy Creecy
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, United States of America.
| | - Dyann Segvich
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, United States of America
| | - Corinne Metzger
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Rachel Kohler
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, United States of America
| | - Joseph M Wallace
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, United States of America
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Li S, Mei L, He C, Cai X, Wu H, Wu X, Liu Y, Feng Y, Song J. Identification of a family with van der Hoeve's syndrome harboring a novel COL1A1 mutation and generation of patient-derived iPSC lines and CRISPR/Cas9-corrected isogenic iPSCs. Hum Cell 2024; 37:817-831. [PMID: 38379122 DOI: 10.1007/s13577-024-01028-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 01/11/2024] [Indexed: 02/22/2024]
Abstract
Van der Hoeve's syndrome, also known as osteogenesis imperfecta (OI), is a genetic connective tissue disorder characterized by fragile, fracture-prone bone and hearing loss. The disease is caused by a gene mutation in one of the two type I collagen genes COL1A1 or COL1A2. In this study, we identified a novel frameshift mutation of the COL1A1 gene (c.1607delG) in a family with OI using whole-exome sequencing, bioinformatics analysis and Sanger sequencing. This mutation may lead to the deletion of a portion of exon 23 and the generation of a premature stop codon in the COL1A1 gene. To further investigate the impact of this mutation, we established two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells of OI patients carrying a novel mutation in the COL1A1 gene. Osteoblasts (OB) derived from OI-iPSCs exhibited reduced production of type I collagen and diminished ability to differentiate into osteoblasts. Using a CRISPR-based homology-directed repair strategy, we corrected the OI disease-causing COL1A1 novel mutations in iPSCs generated from an affected individual. Our results demonstrated that the diminished expression of type I collagen and osteogenic potential were enhanced in OB induced from corrected OI-iPSCs compared to those from OI-iPSCs. Overall, our results provide new insights into the genetic basis of Van der Hoeve's syndrome and highlight the potential of iPSC technology for disease modeling and therapeutic development.
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Affiliation(s)
- SiJun Li
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
- Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, Hunan, China
| | - Lingyun Mei
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
- Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, Hunan, China
| | - Chufeng He
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
- Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, Hunan, China
| | - Xinzhang Cai
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
- Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, Hunan, China
| | - Hong Wu
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
- Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, Hunan, China
| | - XueWen Wu
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
- Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, Hunan, China
| | - Yalan Liu
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
- Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, Hunan, China
| | - Yong Feng
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Department of Otorhinolaryngology, The Affiliated Maternal and Child Health Hospital of Hunan Province, Hengyang Medical School, University of South China, Changsha, Hunan, China.
- MOE Key Lab of Rare Pediatric Diseases and Institute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, Hunan, China.
| | - Jian Song
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Gençer EB, Lor YK, Abomaray F, El Andaloussi S, Pernemalm M, Sharma N, Hagey DW, Görgens A, Gustafsson MO, Le Blanc K, Asad Toonsi M, Walther-Jallow L, Götherström C. Transcriptomic and proteomic profiles of fetal versus adult mesenchymal stromal cells and mesenchymal stromal cell-derived extracellular vesicles. Stem Cell Res Ther 2024; 15:77. [PMID: 38475970 DOI: 10.1186/s13287-024-03683-7] [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: 11/08/2023] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Mesenchymal stem/stromal cells (MSCs) can regenerate tissues through engraftment and differentiation but also via paracrine signalling via extracellular vesicles (EVs). Fetal-derived MSCs (fMSCs) have been shown, both in vitro and in animal studies, to be more efficient than adult MSC (aMSCs) in generating bone and muscle but the underlying reason for this difference has not yet been clearly elucidated. In this study, we aimed to systematically investigate the differences between fetal and adult MSCs and MSC-derived EVs at the phenotypic, RNA, and protein levels. METHODS We carried out a detailed and comparative characterization of culture-expanded fetal liver derived MSCs (fMSCs) and adult bone marrow derived MSCs (aMSCs) phenotypically, and the MSCs and MSC-derived EVs were analysed using transcriptomics and proteomics approaches with RNA Sequencing and Mass Spectrometry. RESULTS Fetal MSCs were smaller, exhibited increased proliferation and colony-forming capacity, delayed onset of senescence, and demonstrated superior osteoblast differentiation capability compared to their adult counterparts. Gene Ontology analysis revealed that fMSCs displayed upregulated gene sets such as "Positive regulation of stem cell populations", "Maintenance of stemness" and "Muscle cell development/contraction/Myogenesis" in comparison to aMSCs. Conversely, aMSCs displayed upregulated gene sets such as "Complement cascade", "Adipogenesis", "Extracellular matrix glycoproteins" and "Cellular metabolism", and on the protein level, "Epithelial cell differentiation" pathways. Signalling entropy analysis suggested that fMSCs exhibit higher signalling promiscuity and hence, higher potency than aMSCs. Gene ontology comparisons revealed that fetal MSC-derived EVs (fEVs) were enriched for "Collagen fibril organization", "Protein folding", and "Response to transforming growth factor beta" compared to adult MSC-derived EVs (aEVs), whereas no significant difference in protein expression in aEVs compared to fEVs could be detected. CONCLUSIONS This study provides detailed and systematic insight into the differences between fMSCs and aMSCs, and MSC-derived EVs. The key finding across phenotypic, transcriptomic and proteomic levels is that fMSCs exhibit higher potency than aMSCs, meaning they are in a more undifferentiated state. Additionally, fMSCs and fMSC-derived EVs may possess greater bone forming capacity compared to aMSCs. Therefore, using fMSCs may lead to better treatment efficacy, especially in musculoskeletal diseases.
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Affiliation(s)
- Emine Begüm Gençer
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Yuk Kit Lor
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Fawaz Abomaray
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Samir El Andaloussi
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
| | - Maria Pernemalm
- Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology- Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Nidhi Sharma
- Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology- Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Daniel W Hagey
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
| | - André Görgens
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Manuela O Gustafsson
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
| | - Katarina Le Blanc
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Mawaddah Asad Toonsi
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Lilian Walther-Jallow
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Götherström
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
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Fu T, Liu Y, Wang Z, Jing Y, Zhao Y, Shao C, Lv Z, Li G. The recombinant BMP-2 loaded silk fibroin microspheres improved the bone phenotype of mild osteogenesis imperfecta mice. PeerJ 2023; 11:e16191. [PMID: 37927786 PMCID: PMC10621593 DOI: 10.7717/peerj.16191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 09/06/2023] [Indexed: 11/07/2023] Open
Abstract
Osteogenesis imperfecta (OI) is an inherited congenital disorder, characterized primarily by decreased bone mass and increased bone fragility. Bone morphogenetic protein-2 (BMP-2) is a potent cytokine capable of stimulating bone formation, however, its rapid degradation and unanticipated in vivo effects restrict its application. The sustained release characteristic of silk fibroin (SF) microspheres may potentially address the aforementioned challenges, nevertheless they have not previously been tested in OI treatment. In the current investigation, recombinant BMP-2 (rBMP-2) loaded SF (rBMP-2/SF) microspheres-based release carriers were prepared by physical adsorption. The SF microparticles were characterized by scanning electron microscopy (SEM) and were investigated for their cytotoxicity behavior as well as the release profile of rBMP-2. The rBMP-2/SF microspheres were administered via femoral intramedullary injection to two genotypes of OI-modeled mice daily for two weeks. The femoral microstructure and histological performance of OI mice were evaluated 2 weeks later. The findings suggested that rBMP-2/SF spheres with a rough surface and excellent cytocompatibility demonstrated an initial rapid release within the first three days (22.15 ± 2.88% of the loaded factor), followed by a transition to a slower and more consistent release rate, that persisted until the 15th day in an in vitro setting. The factor released from rBMP-2/SF particles exhibited favorable osteoinductive activity. Infusion of rBMP-2/SF microspheres, as opposed to blank SF spheres or rBMP-2 monotherapy, resulted in a noteworthy enhancement of femoral microstructure and promoted bone formation in OI-modeled mice. This research may offer a new therapeutic approach and insight into the management of OI. However, further investigation is required to determine the systematic safety and efficacy of rBMP-2/SF microspheres therapy for OI.
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Affiliation(s)
- Ting Fu
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yi Liu
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Zihan Wang
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yaqing Jing
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yuxia Zhao
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Chenyi Shao
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Zhe Lv
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Guang Li
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
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Robinson ME, Rauch D, Glorieux FH, Rauch F. Standardized growth charts for children with osteogenesis imperfecta. Pediatr Res 2023; 94:1075-1082. [PMID: 36922619 DOI: 10.1038/s41390-023-02550-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 01/06/2023] [Accepted: 02/17/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND Osteogenesis imperfecta (OI) is associated with short stature, which is mild, severe and moderate in OI types I, III and IV, respectively. Standardized OI type- and sex-specific growth charts across all pediatric ages do not exist. METHODS We assessed 573 individuals with OI (type I, III or IV), each with at least one height measurement between ages 3 months and 20 years (total 6523 observations). Analogous to the Centers for Disease Control pediatric growth charts, we generated OI type- and sex-specific growth charts for infants (ages 3-36 months) as well as children and adolescents (ages 2-20 years). Growth curves were fitted to the data using the LMS method and percentiles were smoothed. RESULTS Age was associated with a decline in height z-scores (p < 0.001 for all OI types), which was more pronounced in females. Height multiplier curves were produced to predict adult height in children with OI. Among individuals with OI type I, those with COL1A1 pathogenic variants leading to haploinsufficiency were taller than those with COL1A1 or COL1A2 pathogenic variants not leading to haploinsufficiency. CONCLUSION Our standardized OI type- and sex-specific growth charts can be used to assess the growth of individuals with OI from infancy to adulthood. IMPACT Standardized osteogenesis imperfecta (OI) type- and sex-specific growth charts across all pediatric ages do not exist. Our study is the first to generate OI type- and sex-specific growth charts across all pediatric ages. Our height multiplier curves can be utilized to predict adult height in children with OI.
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Affiliation(s)
- Marie-Eve Robinson
- Shriners Hospital for Children - Canada, McGill University, Montreal, QC, Canada.
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
| | - Damian Rauch
- Shriners Hospital for Children - Canada, McGill University, Montreal, QC, Canada
| | - Francis H Glorieux
- Shriners Hospital for Children - Canada, McGill University, Montreal, QC, Canada
| | - Frank Rauch
- Shriners Hospital for Children - Canada, McGill University, Montreal, QC, Canada
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9
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Omosule CL, Joseph D, Weiler B, Gremminger VL, Silvey S, Lafaver BN, Jeong Y, Kleiner S, Phillips CL. Whole-Body Metabolism and the Musculoskeletal Impacts of Targeting Activin A and Myostatin in Severe Osteogenesis Imperfecta. JBMR Plus 2023; 7:e10753. [PMID: 37457877 PMCID: PMC10339096 DOI: 10.1002/jbm4.10753] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 04/12/2023] [Indexed: 07/18/2023] Open
Abstract
Mutations in the COL1A1 and COL1A2 genes, which encode type I collagen, are present in around 85%-90% of osteogenesis imperfecta (OI) patients. Because type I collagen is the principal protein composition of bones, any changes in its gene sequences or synthesis can severely affect bone structure. As a result, skeletal deformity and bone frailty are defining characteristics of OI. Homozygous oim/oim mice are utilized as models of severe progressive type III OI. Bone adapts to external forces by altering its mass and architecture. Previous attempts to leverage the relationship between muscle and bone involved using a soluble activin receptor type IIB-mFc (sActRIIB-mFc) fusion protein to lower circulating concentrations of activin A and myostatin. These two proteins are part of the TGF-β superfamily that regulate muscle and bone function. While this approach resulted in increased muscle masses and enhanced bone properties, adverse effects emerged due to ligand promiscuity, limiting clinical efficacy and obscuring the precise contributions of myostatin and activin A. In this study, we investigated the musculoskeletal and whole-body metabolism effect of treating 5-week-old wildtype (Wt) and oim/oim mice for 11 weeks with either control antibody (Ctrl-Ab) or monoclonal anti-activin A antibody (ActA-Ab), anti-myostatin antibody (Mstn-Ab), or a combination of ActA-Ab and Mstn-Ab (Combo). We demonstrated that ActA-Ab treatment minimally impacts muscle mass in oim/oim mice, whereas Mstn-Ab and Combo treatments substantially increased muscle mass and overall lean mass regardless of genotype and sex. Further, while no improvements in cortical bone microarchitecture were observed with all treatments, minimal improvements in trabecular bone microarchitecture were observed with the Combo treatment in oim/oim mice. Our findings suggest that individual or combinatorial inhibition of myostatin and activin A alone is insufficient to robustly improve femoral biomechanical and microarchitectural properties in severely affected OI mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
| | - Dominique Joseph
- Department of BiochemistryUniversity of MissouriColumbiaMissouriUSA
| | - Brooke Weiler
- Department of BiochemistryUniversity of MissouriColumbiaMissouriUSA
| | | | - Spencer Silvey
- Department of BiochemistryUniversity of MissouriColumbiaMissouriUSA
| | | | - Youngjae Jeong
- Department of BiochemistryUniversity of MissouriColumbiaMissouriUSA
| | | | - Charlotte L. Phillips
- Department of BiochemistryUniversity of MissouriColumbiaMissouriUSA
- Department of Child HealthUniversity of MissouriColumbiaMissouriUSA
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10
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Landscape of Well-Coordinated Fracture Healing in a Mouse Model Using Molecular and Cellular Analysis. Int J Mol Sci 2023; 24:ijms24043569. [PMID: 36834981 PMCID: PMC9964763 DOI: 10.3390/ijms24043569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
The success of fracture healing relies on overlapping but coordinated cellular and molecular events. Characterizing an outline of differential gene regulation throughout successful healing is essential for identifying crucial phase-specific markers and may serve as the basis for engineering these in challenging healing situations. This study analyzed the healing progression of a standard closed femoral fracture model in C57BL/6N (age = 8 weeks) wild-type male mice. The fracture callus was assessed across various days post fracture (D = days 0, 3, 7, 10, 14, 21, and 28) by microarray, with D0 serving as a control. Histological analyses were carried out on samples from D7 until D28 to support the molecular findings. Microarray analysis revealed a differential regulation of immune response, angiogenesis, ossification, extracellular matrix regulation, mitochondrial and ribosomal genes during healing. In-depth analysis showed differential regulation of mitochondrial and ribosomal genes during the initial phase of healing. Furthermore, the differential gene expression showed an essential role of Serpin Family F Member 1 over the well-known Vascular Endothelial Growth Factor in angiogenesis, especially during the inflammatory phase. The significant upregulation of matrix metalloproteinase 13 and bone sialoprotein from D3 until D21 asserts their importance in bone mineralization. The study also shows type I collagen around osteocytes located in the ossified region at the periosteal surface during the first week of healing. Histological analysis of matrix extracellular phosphoglycoprotein and extracellular signal-regulated kinase stressed their roles in bone homeostasis and the physiological bone-healing process. This study reveals previously unknown and novel candidates, that could serve as a target for specific time points in healing and to remedy cases of impaired healing.
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11
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Shi C, Sun B, Wu H, Zhang R, Wu L, Guo L, Li C, Xi Y, Yuan W, Zhang Y, Xu G. Dysfunction of Caveolae-Mediated Endocytic TβRI Degradation Results in Hypersensitivity of TGF-β/Smad Signaling in Osteogenesis Imperfecta. J Bone Miner Res 2023; 38:103-118. [PMID: 36321807 DOI: 10.1002/jbmr.4734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 10/22/2022] [Accepted: 10/29/2022] [Indexed: 11/19/2022]
Abstract
Osteogenesis imperfecta (OI) is a genetic disorder caused by mutations of type I collagen-related genes, and excessive transforming growth factor-beta (TGF-β) signaling is a common mechanism. TGF-β/Smad signaling has inhibitory effects on osteoblast differentiation and maturation and is mainly transduced and regulated by the internalization of a tetrameric receptor complex comprising types I and II TGF-β receptors (TβRI and TβRII). During internalization, clathrin-mediated endocytosis enhances TGF-β/Smad signaling via Smad2/3 phosphorylation and receptors recycling, while caveolae-mediated endocytosis turns off TGF-β/Smad signaling by promoting receptor ubiquitination and degradation. In this study, using an animal model of OI (Colla2oim , osteogenesis imperfecta murine [oim]/oim mouse), we found that osteoblastic cells of oim/oim mice were more sensitive to the inhibitory effects of TGF-β on osteoblast differentiation and maturation and had much higher cell membrane protein levels of TGF-β receptors than those of wild-type (wt)/wt mice. Further results showed that clathrin-mediated endocytosis of TβRI was enhanced, whereas caveolae-mediated TβRI endocytic degradation was reduced in oim/oim mice, combined with reduced caveolin-1 (Cav-1) phosphorylation. In addition, type I collagen downregulated TβRI via focal adhesion kinase (FAK) and Src activation-dependent Cav-1 phosphorylation. To further examine this mechanism, 4-week-old oim/oim and wt/wt mice were treated with either TβRI kinase inhibitor (SD-208) or vehicle for 8 weeks. SD-208 treatment significantly reduced the fracture incidence in oim/oim mice. Micro-computed tomography and biomechanical testing showed that femoral bone mass and strength were significantly improved with SD-208 treatment in both genotypes. Additionally, SD-208 significantly promoted osteoblast differentiation and bone formation and inhibited bone resorption. In conclusion, dysfunction of caveolae-mediated endocytic TβRI degradation is a possible mechanism for the enhanced TGF-β/Smad signaling in OI. Targeting this mechanism using a TβRI kinase inhibitor effectively reduced fractures and improved bone mass and strength in OI model and, thus, may offer a new strategy for the treatment of OI. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Changgui Shi
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Bin Sun
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Huiqiao Wu
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Rongcheng Zhang
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Lecheng Wu
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Lei Guo
- Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changwei Li
- Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanhai Xi
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Wen Yuan
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Ying Zhang
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Guohua Xu
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
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12
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Sinkam L, Boraschi-Diaz I, Svensson RB, Kjaer M, Komarova SV, Bergeron R, Rauch F, Veilleux LN. Tendon properties in a mouse model of severe osteogenesis imperfecta. Connect Tissue Res 2022; 64:285-293. [PMID: 36576243 DOI: 10.1080/03008207.2022.2161376] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE/AIM OF THE STUDY Osteogenesis imperfecta is a heritable bone disorder that is usually caused by mutations in collagen type I encoding genes. The impact of such mutations on tendons, a structure with high collagen type I content, remains largely unexplored. We hypothesized that tendon properties are abnormal in the context of a mutation affecting collagen type I. The main purpose of the study was to assess the anatomical, mechanical, and material tendon properties of Col1a1Jrt/+ mice, a model of severe dominant OI. MATERIALS AND METHODS The Flexor Digitorum Longus (FDL) tendon of Col1a1Jrt/+ mice and wild-type littermates (WT) was assessed with in vitro mechanical testing. RESULTS The results showed that width and thickness of FDL tendons were about 40% larger in WT (p < 0.01) than in Col1a1Jrt/+ mice, whereas the cross-sectional area was 138% larger (p < 0.001). The stiffness, peak- and yield-force were between 160% and 194% higher in WT vs. Col1a1Jrt/+ mice. The material properties did not show significant differences between mouse strains with differences <15% between WT and Col1a1Jrt/+ (p > 0.05). Analysis of the Achilles tendon collagen showed no difference between mice strains for the content but collagen solubility in acetic acid was 66% higher in WT than in Col1a1Jrt/+ (p < 0.001). CONCLUSIONS This study shows that the FDL tendon of Col1a1Jrt/+ mice has reduced mechanical properties but apparently normal material properties. It remains unclear whether the tendon phenotype of Col1a1Jrt/+ mice is secondary to muscle weakness or a direct effect of the Col1a1 mutation or a combination of both.
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Affiliation(s)
- Larissa Sinkam
- Motion Analysis Center, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.,Department of Experimental suregery, McGill University, Montreal, Quebec, Canada
| | - Iris Boraschi-Diaz
- Motion Analysis Center, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.,Department of Experimental suregery, McGill University, Montreal, Quebec, Canada
| | - René B Svensson
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Øresund, Denmark.,Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Øresund, Denmark
| | - Michael Kjaer
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Øresund, Denmark.,Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Øresund, Denmark
| | - Svetlana V Komarova
- Motion Analysis Center, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.,Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Raynald Bergeron
- École de kinésiologie et des sciences de l'activité physique. Faculté de médecine, Université de Montréal, Montreal, Quebec, Canada
| | - Frank Rauch
- Motion Analysis Center, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.,Department of Experimental suregery, McGill University, Montreal, Quebec, Canada.,Genetics Unit, Shrines Hospital for Children - Canada, Montreal, Quebec, Canada.,Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Louis-Nicolas Veilleux
- Motion Analysis Center, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.,Department of Experimental suregery, McGill University, Montreal, Quebec, Canada
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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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Lv F, Cai X, Ji L. An Update on Animal Models of Osteogenesis Imperfecta. Calcif Tissue Int 2022; 111:345-366. [PMID: 35767009 DOI: 10.1007/s00223-022-00998-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 06/01/2022] [Indexed: 11/02/2022]
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous disorder characterized by bone fragility, multiple fractures, bone deformity, and short stature. In recent years, the application of next generation sequencing has triggered the discovery of many new genetic causes for OI. Until now, more than 25 genetic causes of OI and closely related disorders have been identified. However, the mechanisms of many genes on skeletal fragility in OI are not entirely clear. Animal models of OI could help to understand the cellular, signaling, and metabolic mechanisms contributing to the disease, and how targeting these pathways can provide therapeutic targets. To date, a lot of animal models, mainly mice and zebrafish, have been described with defects in 19 OI-associated genes. In this review, we summarize the known genetic causes and animal models that recapitulate OI with a main focus on engineered mouse and zebrafish models. Additionally, we briefly discuss domestic animals with naturally occurring OI phenotypes. Knowledge of the specific molecular basis of OI will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches.
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Affiliation(s)
- Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Xizhimen South Street No.11, Beijing, 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Xizhimen South Street No.11, Beijing, 100044, China.
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Xizhimen South Street No.11, Beijing, 100044, China.
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15
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Liu J, Zhang J, Lin X, Boyce BF, Zhang H, Xing L. Age-associated callus senescent cells produce TGF-β1 that inhibits fracture healing in aged mice. J Clin Invest 2022; 132:e148073. [PMID: 35426372 PMCID: PMC9012290 DOI: 10.1172/jci148073] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 02/16/2022] [Indexed: 01/10/2023] Open
Abstract
Cellular senescence plays an important role in human diseases, including osteoporosis and osteoarthritis. Senescent cells (SCs) produce the senescence-associated secretory phenotype to affect the function of neighboring cells and SCs themselves. Delayed fracture healing is common in the elderly and is accompanied by reduced mesenchymal progenitor cells (MPCs). However, the contribution of cellular senescence to fracture healing in the aged has not to our knowledge been studied. Here, we used C57BL/6J 4-month-old young and 20-month-old aged mice and demonstrated a rapid increase in SCs in the fracture callus of aged mice. The senolytic drugs dasatinib plus quercetin enhanced fracture healing in aged mice. Aged callus SCs inhibited the growth and proliferation of callus-derived MPCs (CaMPCs) and expressed high levels of TGF-β1. TGF-β-neutralizing Ab prevented the inhibitory effects of aged callus SCs on CaMPCs and promoted fracture healing in aged mice, which was associated with increased CaMPCs and proliferating cells. Thus, fracture triggered a significant cellular senescence in the callus cells of aged mice, which inhibited MPCs by expressing TGF-β1. Short-term administration of dasatinib plus quercetin depleted callus SCs and accelerated fracture healing in aged mice. Senolytic drugs represent a promising therapy, while TGF-β1 signaling is a molecular mechanism for fractures in the elderly via SCs.
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Affiliation(s)
- Jiatong Liu
- Department of Pathology and Laboratory Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Jun Zhang
- Plastic Surgery Center, Department of Orthopedics, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, China
- Suzhou Institute of Systems Medicine, Suzhou, China
| | - Xi Lin
- Department of Pathology and Laboratory Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Brendan F. Boyce
- Department of Pathology and Laboratory Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Hengwei Zhang
- Department of Pathology and Laboratory Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Lianping Xing
- Department of Pathology and Laboratory Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA
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16
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Duran I, Zieba J, Csukasi F, Martin JH, Wachtell D, Barad M, Dawson B, Fafilek B, Jacobsen CM, Ambrose CG, Cohn DH, Krejci P, Lee BH, Krakow D. 4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta. J Bone Miner Res 2022; 37:675-686. [PMID: 34997935 PMCID: PMC9018561 DOI: 10.1002/jbmr.4501] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 12/01/2022]
Abstract
Osteogenesis imperfecta (OI) is a genetically heterogenous disorder most often due to heterozygosity for mutations in the type I procollagen genes, COL1A1 or COL1A2. The disorder is characterized by bone fragility leading to increased fracture incidence and long-bone deformities. Although multiple mechanisms underlie OI, endoplasmic reticulum (ER) stress as a cellular response to defective collagen trafficking is emerging as a contributor to OI pathogenesis. Herein, we used 4-phenylbutiric acid (4-PBA), an established chemical chaperone, to determine if treatment of Aga2+/- mice, a model for moderately severe OI due to a Col1a1 structural mutation, could attenuate the phenotype. In vitro, Aga2+/- osteoblasts show increased protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation protein levels, which improved upon treatment with 4-PBA. The in vivo data demonstrate that a postweaning 5-week 4-PBA treatment increased total body length and weight, decreased fracture incidence, increased femoral bone volume fraction (BV/TV), and increased cortical thickness. These findings were associated with in vivo evidence of decreased bone-derived protein levels of the ER stress markers binding immunoglobulin protein (BiP), CCAAT/-enhancer-binding protein homologous protein (CHOP), and activating transcription factor 4 (ATF4) as well as increased levels of the autophagosome marker light chain 3A/B (LC3A/B). Genetic ablation of CHOP in Aga2+/- mice resulted in increased severity of the Aga2+/- phenotype, suggesting that the reduction in CHOP observed in vitro after treatment is a consequence rather than a cause of reduced ER stress. These findings suggest the potential use of chemical chaperones as an adjunct treatment for forms of OI associated with ER stress. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Ivan Duran
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, University of Málaga, Institute of Biomedical Research in Malaga (IBIMA), Málaga, Spain.,Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain
| | - Jennifer Zieba
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
| | - Fabiana Csukasi
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, University of Málaga, Institute of Biomedical Research in Malaga (IBIMA), Málaga, Spain.,Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain
| | - Jorge H Martin
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
| | - Davis Wachtell
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
| | - Maya Barad
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
| | - Brian Dawson
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Bohumil Fafilek
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Christina M Jacobsen
- Divisions of Endocrinology and Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Catherine G Ambrose
- Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Daniel H Cohn
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Department of Molecular Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, CA, USA
| | - Pavel Krejci
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Brendan H Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Deborah Krakow
- Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Department of Human Genetics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA.,Department of Pediatrics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
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17
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Drug Treatment of Low Bone Mass and Other Bone Conditions in Pediatric Patients. Paediatr Drugs 2022; 24:103-119. [PMID: 35013997 DOI: 10.1007/s40272-021-00487-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/01/2021] [Indexed: 10/19/2022]
Abstract
Osteoporosis may affect young individuals, albeit infrequently. In childhood, bone mass increases, reaching its peak between the second and third decades; then, after a period of stability, it gradually declines. Several conditions, including genetic disorders, chronic diseases, and some medications, can have an impact on bone homeostasis. Diagnosis in young patients is based on the criteria defined by the International Society for Clinical Densitometry (ISCD), published in 2013. High risk factors should be identified and monitored. Often simple interventions aimed to eliminate the underlying cause, to minimize the negative bone effects linked to drugs, or to increase calcium and vitamin D intake can protect bone mass. However, in selected cases, pharmacological treatment should be considered. Bisphosphonates remain the main therapeutic agent for children with significant skeletal fragility and are also useful in a large number of other bone conditions. Denosumab, an anti-RANKL antibody, could become a potential alternative treatment. Clinical trials to evaluate the long-term effects and safety of denosumab in children are ongoing.
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18
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Characterization and functional analysis of the adipose tissue-derived stromal vascular fraction of pediatric patients with osteogenesis imperfecta. Sci Rep 2022; 12:2414. [PMID: 35165317 PMCID: PMC8844034 DOI: 10.1038/s41598-022-06063-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 01/12/2022] [Indexed: 11/08/2022] Open
Abstract
AbstractPediatric patients with Osteogenesis Imperfecta (OI), a heritable connective tissue disorder, frequently suffer from long bone deformations. Surgical correction often results in bone non-unions, necessitating revision surgery with autogenous bone grafting using bone-marrow-derived stem cells (BM-SC) to regenerate bone. BM-SC harvest is generally invasive and limited in supply; thus, adipose tissue's stromal vascular fraction (SVF) has been introduced as an alternative stem cell reservoir. To elucidate if OI patients' surgical site dissected adipose tissue could be used as autologous bone graft in future, we investigated whether the underlying genetic condition alters SVF's cell populations and in vitro differentiation capacity. After optimizing SVF isolation, we demonstrate successful isolation of SVF of pediatric OI patients and non-OI controls. The number of viable cells was comparable between OI and controls, with about 450,000 per gram tissue. Age, sex, type of OI, disease-causing collagen mutation, or anatomical site of harvest did not affect cell outcome. Further, SVF-containing cell populations were similar between OI and controls, and all isolated SVF's demonstrated chondrogenic, adipogenic, and osteogenic differentiation capacity in vitro. These results indicate that SVF from pediatric OI patients could be used as a source of stem cells for autologous stem cell therapy in OI.
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19
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Infante A, Cabodevilla L, Gener B, Rodríguez CI. Circulating TGF-β Pathway in Osteogenesis Imperfecta Pediatric Patients Subjected to MSCs-Based Cell Therapy. Front Cell Dev Biol 2022; 10:830928. [PMID: 35223854 PMCID: PMC8865676 DOI: 10.3389/fcell.2022.830928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
Osteogenesis Imperfecta (OI) is a rare genetic disease characterized by bone fragility, with a wide range in the severity of clinical manifestations. The majority of cases are due to mutations in COL1A1 or COL1A2, which encode type I collagen. There is no cure for OI, and real concerns exist for current therapeutic approaches, mainly antiresorptive drugs, regarding their effectiveness and security. Safer and effective therapeutic approaches are demanded. Cell therapy with mesenchymal stem cells (MSCs), osteoprogenitors capable of secreting type I collagen, has been tested to treat pediatric OI with encouraging outcomes. Another therapeutic approach currently under clinical development focuses on the inhibition of TGF-β pathway, based on the excessive TGF-β signaling found in the skeleton of severe OI mice models, and the fact that TGF-β neutralizing antibody treatment rescued bone phenotypes in those OI murine models. An increased serum expression of TGF-β superfamily members has been described for a number of bone pathologies, but still it has not been addressed in OI patients. To delve into this unexplored question, in the present study we investigated serum TGF-β signalling pathway in two OI pediatric patients who participated in TERCELOI, a phase I clinical trial based on reiterative infusions of MSCs. We examined not only the expression and bioactivity of circulating TGF-β pathway in TERCELOI patients, but also the effects that MSCs therapy could elicit. Strikingly, basal serum from the most severe patient showed an enhanced expression of several TGF-β superfamily members and increased TGF-β bioactivity, which were modulated after MSCs therapy.
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Affiliation(s)
- Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Spain
| | - Leire Cabodevilla
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Spain
| | - Blanca Gener
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Spain
- Service of Genetics, Cruces University Hospital, Barakaldo, Spain
| | - Clara I. Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Spain
- *Correspondence: Clara I. Rodríguez,
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20
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Song IW, Nagamani SC, Nguyen D, Grafe I, Sutton VR, Gannon FH, Munivez E, Jiang MM, Tran A, Wallace M, Esposito P, Musaad S, Strudthoff E, McGuire S, Thornton M, Shenava V, Rosenfeld S, Shypailo R, Orwoll E, Lee B. Targeting transforming growth factor- β (TGF-β) for treatment of osteogenesis imperfecta. J Clin Invest 2022; 132:152571. [PMID: 35113812 PMCID: PMC8970679 DOI: 10.1172/jci152571] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 01/28/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies have shown that excessive TGF-β signaling is a driver of pathogenesis in OI. Here, we evaluated TGF-β signaling in children with OI and translated this discovery by conducting a phase 1 clinical trial of TGF-β inhibition in adults with OI. METHODS Histology and RNASeq were performed on bones obtained from children affected (n=10) and unaffected (n=4) by OI. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify key dysregulated pathways. Reverse-phase protein array (RPPA), Western blot (WB), and Immunohistochemistry (IHC) were performed to evaluate changes at the protein level. A phase 1 study with a single administration of fresolimumab, a pan-anti-TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects of fresolimumab on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed. RESULTS OI bone demonstrated woven structure, increased osteocyte density, high turnover, and reduced bone maturation. SMAD phosphorylation was the most significantly up-regulated GO molecular event. GSEA identified TGF-β pathway as top activated signaling pathway in OI. IPA showed that TGF-β was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increase in LS aBMD in participants with OI type IV, while those with more severe OI type III and VIII had unchanged or decreased LS aBMD. CONCLUSIONS Our data confirm that TGF-β signaling is a driver pathogenic mechanism in OI bone and that anti-TGF-β therapy could be a potential disease-specific therapy with dose-dependent effects on bone mass and turnover. TRIAL REGISTRATION NCT03064074 FUNDING. This work was supported by the Brittle Bone Disorders Consortium (BBDC) (U54AR068069). The BBDC is a part of the National Center for Advancing Translational Science's (NCATS') RDCRN. The BBDC is funded through a collaboration between the Office of Rare Disease Research (ORDR) of NCATS, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Mental Health (NIMH) and National Institute of Child Health and Human Development (NICHD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The BBDC was also supported by the OI Foundation. The work was supported by The Clinical Translational Core of BCM IDDRC (P50HD103555) from the Eunice Kennedy Shriver NICHD. Funding from the USDA/ARS under Cooperative Agreement No. 58-6250-6-001 also facilitated analysis for the study procedures. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The study was supported by a research agreement with Sanofi Genzyme.
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Affiliation(s)
- I-Wen Song
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
| | - Sandesh Cs Nagamani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
| | - Dianne Nguyen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
| | - Ingo Grafe
- Department of Medicine and Center of Healthy Aging, University Clinic Dresden, Dresden, Germany
| | - Vernon Reid Sutton
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
| | - Francis H Gannon
- Pathology and Immunology and Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
| | - Elda Munivez
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
| | - Ming-Ming Jiang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
| | - Alyssa Tran
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
| | - Maegen Wallace
- Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
| | - Paul Esposito
- Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
| | - Salma Musaad
- Department of Pediatrics-Nutrition, Baylor College of Medicine, Houston, United States of America
| | - Elizabeth Strudthoff
- Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
| | - Sharon McGuire
- Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
| | - Michele Thornton
- Orthopaedic Surgery, University of Nebraska Medical Center, Omaha, United States of America
| | - Vinitha Shenava
- Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
| | - Scott Rosenfeld
- Department of Orthopedic Surgery, Baylor College of Medicine, Houston, United States of America
| | - Roman Shypailo
- Department of Pediatrics, Baylor College of Medicine, Houston, United States of America
| | - Eric Orwoll
- Department of Medicine, Oregon Health & Science University, Portland, United States of America
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America
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21
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Greene B, Russo RJ, Dwyer S, Malley K, Roberts E, Serrielo J, Piepenhagen P, Cummings S, Ryan S, Zarazinski C, Uppuganti S, Bukanov N, Nyman JS, Cox MK, Liu S, Ibraghimov-Beskrovnaya O, Sabbagh Y. Inhibition of TGF-β Increases Bone Volume and Strength in a Mouse Model of Osteogenesis Imperfecta. JBMR Plus 2021; 5:e10530. [PMID: 34532615 PMCID: PMC8441395 DOI: 10.1002/jbm4.10530] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 06/14/2021] [Accepted: 07/02/2021] [Indexed: 12/29/2022] Open
Abstract
Osteogenesis imperfecta (OI), is a genetic disorder of bone fragility caused by mutations in collagen I or proteins involved in collagen processing. Previous studies in mice and human OI bones have shown that excessive activation of TGF-β signaling plays an important role in dominant and recessive OI disease progression. Inhibition of TGF-β signaling with a murine pan-specific TGF-β neutralizing antibody (1D11) was shown to significantly increase trabecular bone volume and long bone strength in mouse models of OI. To investigate the frequency of dosing and dose options of TGF-β neutralizing antibody therapy, we assessed the effect of 1D11 on disease progression in a dominant OI mouse model (col1a2 gene mutation at G610C). In comparison with OI mice treated with a control antibody, we attempted to define mechanistic effects of 1D11 measured via μCT, biomechanical, dynamic histomorphometry, and serum biomarkers of bone turnover. In addition, osteoblast and osteoclast numbers in histological bone sections were assessed to better understand the mechanism of action of the 1D11 antibody in OI. Here we show that 1D11 treatment resulted in both dose and frequency dependency, increases in trabecular bone volume fraction and ultimate force in lumbar bone, and ultimate force, bending strength, yield force, and yield strength in the femur (p ≤ 0.05). Suppression of serum biomarkers of osteoblast differentiation, osteocalcin, resorption, CTx-1, and bone formation were observed after 1D11 treatment of OI mice. Immunohistochemical analysis showed dose and frequency dependent decreases in runt-related transcription factor, and increase in alkaline phosphatase in lumbar bone sections. In addition, a significant decrease in TRACP and the number of osteoclasts to bone surface area was observed with 1D11 treatment. Our results show that inhibition of the TGF-β pathway corrects the high-turnover aspects of bone disease and improves biomechanical properties of OI mice. These results highlight the potential for a novel treatment for osteogenesis imperfecta. © 2021 Sanofi-Genzyme. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Benjamin Greene
- Rare and Neurologic Diseases Research Sanofi Framingham MA USA
| | - Ryan J Russo
- Rare and Neurologic Diseases Research Sanofi Framingham MA USA
| | - Shannon Dwyer
- Rare and Neurologic Diseases Research Sanofi Framingham MA USA
| | - Katie Malley
- Global Discovery Pathology Sanofi Framingham MA USA
| | | | - Joseph Serrielo
- Rare and Neurologic Diseases Research Sanofi Framingham MA USA
| | | | | | - Susan Ryan
- Global Discovery Pathology Sanofi Framingham MA USA
| | | | - Sasidhar Uppuganti
- Department of Orthopaedic Surgery Vanderbilt University Medical Center Nashville TN USA.,Center for Bone Biology Vanderbilt University Medical Center Nashville TN USA
| | - Nikolai Bukanov
- Rare and Neurologic Diseases Research Sanofi Framingham MA USA
| | - Jeffry S Nyman
- Department of Orthopaedic Surgery Vanderbilt University Medical Center Nashville TN USA.,Center for Bone Biology Vanderbilt University Medical Center Nashville TN USA
| | - Megan K Cox
- Rare and Neurologic Diseases Research Sanofi Framingham MA USA
| | - Shiguang Liu
- Rare and Neurologic Diseases Research Sanofi Framingham MA USA
| | | | - Yves Sabbagh
- Rare and Neurologic Diseases Research Sanofi Framingham MA USA.,Inozyme Pharma Boston MA USA
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22
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Marulanda J, Boraschi-Diaz I, Beauparlant P, Crine P, Rauch F. Skeletal Effects of Bone-Targeted TGFbeta Inhibition in a Mouse Model of Duchenne Muscular Dystrophy. Life (Basel) 2021; 11:life11080791. [PMID: 34440535 PMCID: PMC8401157 DOI: 10.3390/life11080791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/31/2021] [Accepted: 08/04/2021] [Indexed: 11/16/2022] Open
Abstract
Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that is frequently associated with secondary osteoporosis. Previous studies have shown that TGFbeta inactivating antibody improves the muscle phenotype in mdx mice, a model of DMD. In the present study, we assessed the skeletal effects of treatment with a bone-targeted TGFbeta antibody (PCT-011) in mdx mice. Micro-computed tomography showed that 8 weeks of intraperitoneal administration of PCT-011 (10 mg per kg body mass, 3 times per week) was associated with more than twofold higher trabecular bone volume at the distal femur, which was explained by a higher trabecular number. At the femoral midshaft, PCT-011 exposure increased cortical thickness but did not significantly affect the results of three-point bending tests. Histomorphometric analyses of the lumbar vertebra 4 showed that PCT-011 treatment led to a lower bone formation rate. In conclusion, treatment with the TGFbeta antibody PCT-011 had a positive effect on bone development in mdx mice. Inhibiting TGFbeta activity thus appears to be a promising approach to treat bone fragility in the context of DMD.
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Affiliation(s)
- Juliana Marulanda
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (J.M.); (I.B.-D.)
- Department of Pediatrics, McGill University, Montreal, QC H3A 0G4, Canada
| | - Iris Boraschi-Diaz
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (J.M.); (I.B.-D.)
- Department of Pediatrics, McGill University, Montreal, QC H3A 0G4, Canada
| | | | - Philippe Crine
- PreciThera Inc., Montreal, QC H3A 2R7, Canada; (P.B.); (P.C.)
| | - Frank Rauch
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (J.M.); (I.B.-D.)
- Department of Pediatrics, McGill University, Montreal, QC H3A 0G4, Canada
- Correspondence:
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23
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Moffatt P, Boraschi-Diaz I, Marulanda J, Bardai G, Rauch F. Calvaria Bone Transcriptome in Mouse Models of Osteogenesis Imperfecta. Int J Mol Sci 2021; 22:ijms22105290. [PMID: 34069814 PMCID: PMC8157281 DOI: 10.3390/ijms22105290] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/05/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a bone fragility disorder that is usually caused by mutations affecting collagen type I. We compared the calvaria bone tissue transcriptome of male 10-week-old heterozygous Jrt (Col1a1 mutation) and homozygous oim mice (Col1a2 mutation) to their respective littermate results. We found that Jrt and oim mice shared 185 differentially expressed genes (upregulated: 106 genes; downregulated: 79 genes). A total of seven genes were upregulated by a factor of two or more in both mouse models (Cyp2e1, Slc13a5, Cgref1, Smpd3, Ifitm5, Cthrc1 and Rerg). One gene (Gypa, coding for a blood group antigen) was downregulated by a factor of two or more in both OI mouse models. Overrepresentation analyses revealed that genes involved in ‘ossification’ were significantly overrepresented among upregulated genes in both Jrt and oim mice, whereas hematopoietic genes were downregulated. Several genes involved in Wnt signaling and transforming growth factor beta signaling were upregulated in oim mice, but less so in Jrt mice. Thus, this study identified a set of genes that are dysregulated across various OI mouse models and are likely to play an important role in the pathophysiology of this disorder.
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Affiliation(s)
- Pierre Moffatt
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (P.M.); (I.B.-D.); (J.M.); (G.B.)
- Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada
| | - Iris Boraschi-Diaz
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (P.M.); (I.B.-D.); (J.M.); (G.B.)
- Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
| | - Juliana Marulanda
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (P.M.); (I.B.-D.); (J.M.); (G.B.)
- Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
| | - Ghalib Bardai
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (P.M.); (I.B.-D.); (J.M.); (G.B.)
| | - Frank Rauch
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (P.M.); (I.B.-D.); (J.M.); (G.B.)
- Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
- Correspondence: ; Tel.: +1-514-282-7193
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24
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Costantini A, Muurinen MH, Mäkitie O. New gene discoveries in skeletal diseases with short stature. Endocr Connect 2021; 10:R160-R174. [PMID: 33830070 PMCID: PMC8183621 DOI: 10.1530/ec-21-0083] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/07/2021] [Indexed: 12/19/2022]
Abstract
In the last decade, the widespread use of massively parallel sequencing has considerably boosted the number of novel gene discoveries in monogenic skeletal diseases with short stature. Defects in genes playing a role in the maintenance and function of the growth plate, the site of longitudinal bone growth, are a well-known cause of skeletal diseases with short stature. However, several genes involved in extracellular matrix composition or maintenance as well as genes partaking in various biological processes have also been characterized. This review aims to describe the latest genetic findings in spondyloepiphyseal dysplasias, spondyloepimetaphyseal dysplasias, and some monogenic forms of isolated short stature. Some examples of novel genetic mechanisms leading to skeletal conditions with short stature will be described. Strategies on how to successfully characterize novel skeletal phenotypes with short stature and genetic approaches to detect and validate novel gene-disease correlations will be discussed in detail. In summary, we review the latest gene discoveries underlying skeletal diseases with short stature and emphasize the importance of characterizing novel molecular mechanisms for genetic counseling, for an optimal management of the disease, and for therapeutic innovations.
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Affiliation(s)
- Alice Costantini
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Mari H Muurinen
- Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland
- Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
| | - Outi Mäkitie
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland
- Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Correspondence should be addressed to O Mäkitie:
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25
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Gremminger VL, Phillips CL. Impact of Intrinsic Muscle Weakness on Muscle-Bone Crosstalk in Osteogenesis Imperfecta. Int J Mol Sci 2021; 22:4963. [PMID: 34066978 PMCID: PMC8125032 DOI: 10.3390/ijms22094963] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/22/2021] [Accepted: 04/30/2021] [Indexed: 01/10/2023] Open
Abstract
Bone and muscle are highly synergistic tissues that communicate extensively via mechanotransduction and biochemical signaling. Osteogenesis imperfecta (OI) is a heritable connective tissue disorder of severe bone fragility and recently recognized skeletal muscle weakness. The presence of impaired bone and muscle in OI leads to a continuous cycle of altered muscle-bone crosstalk with weak muscles further compromising bone and vice versa. Currently, there is no cure for OI and understanding the pathogenesis of the skeletal muscle weakness in relation to the bone pathogenesis of OI in light of the critical role of muscle-bone crosstalk is essential to developing and identifying novel therapeutic targets and strategies for OI. This review will highlight how impaired skeletal muscle function contributes to the pathophysiology of OI and how this phenomenon further perpetuates bone fragility.
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Affiliation(s)
| | - Charlotte L. Phillips
- Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA;
- Department of Child Health, University of Missouri, Columbia, MO 65212, USA
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26
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Boraschi-Diaz I, Chen G, Polak-Nachumow J, Young RN, Rauch F. Effects of treatment with a bone-targeted prostaglandin E2 receptor 4 agonist C3 (Mes-1007) in a mouse model of severe osteogenesis imperfecta. Bone 2021; 145:115867. [PMID: 33524637 DOI: 10.1016/j.bone.2021.115867] [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: 12/27/2020] [Revised: 01/24/2021] [Accepted: 01/26/2021] [Indexed: 10/22/2022]
Abstract
OBJECTIVE Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I synthesis in osteoblasts. Bisphosphonates are widely used to decrease fracture rate but are only partially effective. Bone anabolic compounds, such as prostaglandin E2 receptor 4 (EP4) agonists may be an alternative treatment approach. Here we assessed the effect of Mes-1007, a novel bone-targeted EP4 agonist in Jrt mice, a model of severe OI. STUDY DESIGN Experimental study. RESULTS Male 8-week old wild type (WT) and OI mice were randomly assigned to 4 weeks of three intraperitoneal injections per week with Mes-1007 (25 mg per kg body mass), phosphate-buffered saline, zoledronate (5 μg per kg), or a combination treatment of zoledronate and Mes-1007. Treatment with Mes-1007 alone did not lead to higher trabecular bone volume per tissue volume (BV/TV) in the distal femur or lumbar vertebra 4 in either WT or OI mice. Treatment with zoledronate alone was associated with a significant increase in distal femur and vertebra BV/TV in both genotypes. In zoledronate-treated WT and OI mice, Mes-1007 increased bone formation rate in vertebral trabecular bone and had an additive effect on BV/TV. Vertebral BV/TV in OI mice that received zoledronate or Mes-1007/zoledronate combination treatment was similar to untreated WT mice (p = 0.25). At the femoral midshaft, Mes-1007/zoledronate combination treatment increased cortical thickness in both genotypes and led to higher periosteal diameter in OI mice. Three-point bending tests of femurs showed that Mes-1007/zoledronate combination treatment increased the stiffness, load at yield and maximal load in WT but not in OI mice. CONCLUSION Dosing Mes-1007 in combination with zoledronate improved the bone properties in a manner that is consistent with a mechanism of action of EP4 agonists on bone and additive to effects of anti-resorptives typified by zoledronate.
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Affiliation(s)
- Iris Boraschi-Diaz
- Shriners Hospital for Children-Canada, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Gang Chen
- Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada; Mesentech Inc., Vancouver, British Columbia, Canada
| | | | - Robert N Young
- Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada; Mesentech Inc., Vancouver, British Columbia, Canada
| | - Frank Rauch
- Shriners Hospital for Children-Canada, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
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27
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Omosule CL, Gremminger VL, Aguillard AM, Jeong Y, Harrelson EN, Miloscio L, Mastaitis J, Rafique A, Kleiner S, Pfeiffer FM, Zhang A, Schulz LC, Phillips CL. Impact of Genetic and Pharmacologic Inhibition of Myostatin in a Murine Model of Osteogenesis Imperfecta. J Bone Miner Res 2021; 36:739-756. [PMID: 33249643 PMCID: PMC8111798 DOI: 10.1002/jbmr.4223] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 11/13/2020] [Accepted: 11/19/2020] [Indexed: 01/05/2023]
Abstract
Osteogenesis imperfecta (OI) is a genetic connective tissue disorder characterized by compromised skeletal integrity, altered microarchitecture, and bone fragility. Current OI treatment strategies focus on bone antiresorptives and surgical intervention with limited effectiveness, and thus identifying alternative therapeutic options remains critical. Muscle is an important stimulus for bone formation. Myostatin, a TGF-β superfamily myokine, acts through ActRIIB to negatively regulate muscle growth. Recent studies demonstrated the potential benefit of myostatin inhibition with the soluble ActRIIB fusion protein on skeletal properties, although various OI mouse models exhibited variable skeletal responses. The genetic and clinical heterogeneity associated with OI, the lack of specificity of the ActRIIB decoy molecule for myostatin alone, and adverse events in human clinical trials further the need to clarify myostatin's therapeutic potential and role in skeletal integrity. In this study, we determined musculoskeletal outcomes of genetic myostatin deficiency and postnatal pharmacological myostatin inhibition by a monoclonal anti-myostatin antibody (Regn647) in the G610C mouse, a model of mild-moderate type I/IV human OI. In the postnatal study, 5-week-old wild-type and +/G610C male and female littermates were treated with Regn647 or a control antibody for 11 weeks or for 7 weeks followed by a 4-week treatment holiday. Inhibition of myostatin, whether genetically or pharmacologically, increased muscle mass regardless of OI genotype, although to varying degrees. Genetic myostatin deficiency increased hindlimb muscle weights by 6.9% to 34.4%, whereas pharmacological inhibition increased them by 13.5% to 29.6%. Female +/mstn +/G610C (Dbl.Het) mice tended to have similar trabecular and cortical bone parameters as Wt showing reversal of +/G610C characteristics but with minimal effect of +/mstn occurring in male mice. Pharmacologic myostatin inhibition failed to improve skeletal bone properties of male or female +/G610C mice, although skeletal microarchitectural and biomechanical improvements were observed in male wild-type mice. Four-week treatment holiday did not alter skeletal outcomes. © 2020 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
| | | | | | - Youngjae Jeong
- Department of Biochemistry, University of Missouri, Columbia, MO, USA
| | - Emily N Harrelson
- Department of Biochemistry, University of Missouri, Columbia, MO, USA
| | | | | | | | | | - Ferris M Pfeiffer
- Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, MO, USA
| | - Anqing Zhang
- Department of Biostatistics and Research Design, University of Missouri, Columbia, MO, USA
| | - Laura C Schulz
- Department of Obstetrics, Gynecology, and Women's Health, University of Missouri, Columbia, MO, USA
| | - Charlotte L Phillips
- Department of Biochemistry, University of Missouri, Columbia, MO, USA.,Department of Child Health, University of Missouri, Columbia, MO, USA
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28
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Kumari A, Shonibare Z, Monavarian M, Arend RC, Lee NY, Inman GJ, Mythreye K. TGFβ signaling networks in ovarian cancer progression and plasticity. Clin Exp Metastasis 2021; 38:139-161. [PMID: 33590419 PMCID: PMC7987693 DOI: 10.1007/s10585-021-10077-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 02/03/2021] [Indexed: 02/06/2023]
Abstract
Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. Late-stage diagnosis with significant tumor burden, accompanied by recurrence and chemotherapy resistance, contributes to this poor prognosis. These morbidities are known to be tied to events associated with epithelial-mesenchymal transition (EMT) in cancer. During EMT, localized tumor cells alter their polarity, cell-cell junctions, cell-matrix interactions, acquire motility and invasiveness and an exaggerated potential for metastatic spread. Key triggers for EMT include the Transforming Growth Factor-β (TGFβ) family of growth factors which are actively produced by a wide array of cell types within a specific tumor and metastatic environment. Although TGFβ can act as either a tumor suppressor or promoter in cancer, TGFβ exhibits its pro-tumorigenic functions at least in part via EMT. TGFβ regulates EMT both at the transcriptional and post-transcriptional levels as outlined here. Despite recent advances in TGFβ based therapeutics, limited progress has been seen for ovarian cancers that are in much need of new therapeutic strategies. Here, we summarize and discuss several recent insights into the underlying signaling mechanisms of the TGFβ isoforms in EMT in the unique metastatic environment of EOCs and the current therapeutic interventions that may be relevant.
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Affiliation(s)
- Asha Kumari
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, WTI 320B, 1824 Sixth Avenue South, Birmingham, AL, 35294, USA
| | - Zainab Shonibare
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, WTI 320B, 1824 Sixth Avenue South, Birmingham, AL, 35294, USA
| | - Mehri Monavarian
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, WTI 320B, 1824 Sixth Avenue South, Birmingham, AL, 35294, USA
| | - Rebecca C Arend
- Department of Obstetrics and Gynecology-Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Nam Y Lee
- Division of Pharmacology, Chemistry and Biochemistry, College of Medicine, University of Arizona, Tucson, AZ, 85721, USA
| | - Gareth J Inman
- Cancer Research UK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Karthikeyan Mythreye
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, WTI 320B, 1824 Sixth Avenue South, Birmingham, AL, 35294, USA.
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Omosule CL, Phillips CL. Deciphering Myostatin's Regulatory, Metabolic, and Developmental Influence in Skeletal Diseases. Front Genet 2021; 12:662908. [PMID: 33854530 PMCID: PMC8039523 DOI: 10.3389/fgene.2021.662908] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/05/2021] [Indexed: 01/08/2023] Open
Abstract
Current research findings in humans and other mammalian and non-mammalian species support the potent regulatory role of myostatin in the morphology and function of muscle as well as cellular differentiation and metabolism, with real-life implications in agricultural meat production and human disease. Myostatin null mice (mstn−/−) exhibit skeletal muscle fiber hyperplasia and hypertrophy whereas myostatin deficiency in larger mammals like sheep and pigs engender muscle fiber hyperplasia. Myostatin’s impact extends beyond muscles, with alterations in myostatin present in the pathophysiology of myocardial infarctions, inflammation, insulin resistance, diabetes, aging, cancer cachexia, and musculoskeletal disease. In this review, we explore myostatin’s role in skeletal integrity and bone cell biology either due to direct biochemical signaling or indirect mechanisms of mechanotransduction. In vitro, myostatin inhibits osteoblast differentiation and stimulates osteoclast activity in a dose-dependent manner. Mice deficient in myostatin also have decreased osteoclast numbers, increased cortical thickness, cortical tissue mineral density in the tibia, and increased vertebral bone mineral density. Further, we explore the implications of these biochemical and biomechanical influences of myostatin signaling in the pathophysiology of human disorders that involve musculoskeletal degeneration. The pharmacological inhibition of myostatin directly or via decoy receptors has revealed improvements in muscle and bone properties in mouse models of osteogenesis imperfecta, osteoporosis, osteoarthritis, Duchenne muscular dystrophy, and diabetes. However, recent disappointing clinical trial outcomes of induced myostatin inhibition in diseases with significant neuromuscular wasting and atrophy reiterate complexity and further need for exploration of the translational application of myostatin inhibition in humans.
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Affiliation(s)
- Catherine L Omosule
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
| | - Charlotte L Phillips
- Department of Biochemistry, University of Missouri, Columbia, MO, United States.,Department of Child Health, University of Missouri, Columbia, MO, United States
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El-Gazzar A, Högler W. Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis. Int J Mol Sci 2021; 22:ijms22020625. [PMID: 33435159 PMCID: PMC7826666 DOI: 10.3390/ijms22020625] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/07/2021] [Accepted: 01/07/2021] [Indexed: 12/13/2022] Open
Abstract
Bone material strength is determined by several factors, such as bone mass, matrix composition, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-ß signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments.
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Affiliation(s)
| | - Wolfgang Högler
- Correspondence: ; Tel.: +43-(0)5-7680-84-22001; Fax: +43-(0)5-7680-84-22004
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Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach. Int J Mol Sci 2021; 22:ijms22010429. [PMID: 33406681 PMCID: PMC7795927 DOI: 10.3390/ijms22010429] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/28/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a heritable disorder that mainly affects the skeleton. The inheritance is mostly autosomal dominant and associated to mutations in one of the two genes, COL1A1 and COL1A2, encoding for the type I collagen α chains. According to more than 1500 described mutation sites and to outcome spanning from very mild cases to perinatal-lethality, OI is characterized by a wide genotype/phenotype heterogeneity. In order to identify common affected molecular-pathways and disease biomarkers in OI probands with different mutations and lethal or surviving phenotypes, primary fibroblasts from dominant OI patients, carrying COL1A1 or COL1A2 defects, were investigated by applying a Tandem Mass Tag labeling-Liquid Chromatography-Tandem Mass Spectrometry (TMT LC-MS/MS) proteomics approach and bioinformatic tools for comparative protein-abundance profiling. While no difference in α1 or α2 abundance was detected among lethal (type II) and not-lethal (type III) OI patients, 17 proteins, with key effects on matrix structure and organization, cell signaling, and cell and tissue development and differentiation, were significantly different between type II and type III OI patients. Among them, some non-collagenous extracellular matrix (ECM) proteins (e.g., decorin and fibrillin-1) and proteins modulating cytoskeleton (e.g., nestin and palladin) directly correlate to the severity of the disease. Their defective presence may define proband-failure in balancing aberrances related to mutant collagen.
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Badri M, Ghaffarifar F, Hassan ZM, Dalimi A, Cortes H. Immunoregulatory Effects of Somatic Extract of Toxocara canis on Airway Inflammations in Murine Model. IRANIAN JOURNAL OF PARASITOLOGY 2020; 15:500-510. [PMID: 33884007 PMCID: PMC8039495 DOI: 10.18502/ijpa.v15i4.4855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Background: The immunomodulatory role of many parasites is well-documented. The current study designed to assess the immunoregulatory effects of the somatic extract (SE) of Toxocara canis on murine model of airway inflammations. Methods: The experiment was performed in department of parasitology of Tarbiat Mo-dares University, Tehran, Iran from November 2018 to May 2019. Totally 30 female BALB/c mice divided into one control group and two experimental groups (10 mice in each group). The ovalbumin (OVA) group was sensitized with OVA in alum, while the SE group was administered with SE and OVA in alum intraperitoneally. The control group was injected with PBS in alum. Then, SE and OVA groups were intranasally challenged with OVA for three consecutive days and the control group encountered with PBS at the same time. One day after the last challenge, real-time PCR and histopathology survey were conducted on isolated lung tissues. Results: The gene expression of IL-25, IL-33, TNF-α and TLR-4 in SE group was significantly lower than OVA group (P<0.05). The level of IL-10, TGF-β and IFN-γ were considerably higher than the OVA group (P<0.05). The inflammation was reduced in SE group, as the total cell number of bronchoalveolar lavage fluid was less than OVA group. Based on the histopathology findings the inflammation was decreased in SE group compared to the OVA group. Conclusion: Although, an inhibitory effect of SE of T. canis on airway inflammations was detected, there is still a long way ahead regarding the indication of the precise mechanisms.
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Affiliation(s)
- Milad Badri
- Department of Parasitology and Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Ghaffarifar
- Department of Parasitology and Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zuhair M Hassan
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Abdolhossein Dalimi
- Department of Parasitology and Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hélder Cortes
- Victor Caeiro Laboratory of Parasitology, MED-Mediterranean Institute for Agriculture, Environment and Development, Department of Veterinary Medicine, IIFA, University of Évora, Pólo da Mitra, Évora, Portugal
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Zhytnik L, Maasalu K, Reimann E, Märtson A, Kõks S. RNA sequencing analysis reveals increased expression of interferon signaling genes and dysregulation of bone metabolism affecting pathways in the whole blood of patients with osteogenesis imperfecta. BMC Med Genomics 2020; 13:177. [PMID: 33228694 PMCID: PMC7684725 DOI: 10.1186/s12920-020-00825-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 11/15/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Osteogenesis imperfecta (OI) is a rare genetic disorder in which the patients suffer from numerous fractures, skeletal deformities and bluish sclera. The disorder ranges from a mild form to severe and lethal cases. The main objective of this pilot study was to compare the blood transcriptional landscape of OI patients with COL1A1 pathogenic variants and their healthy relatives, in order to find out different gene expression and dysregulated molecular pathways in OI. METHODS We performed RNA sequencing analysis of whole blood in seven individuals affected with different OI severity and their five unaffected relatives from the three families. The data was analyzed using edgeR package of R Bioconductor. Functional profiling and pathway analysis of the identified differently expressed genes was performed with g:GOSt and MinePath web-based tools. RESULTS We identified 114 differently expressed genes. The expression of 79 genes was up-regulated, while 35 genes were down-regulated. The functional analysis identified a presence of dysregulated interferon signaling pathways (IFI27, IFITM3, RSAD12, GBP7). Additionally, the expressions of the genes related to extracellular matrix organization, Wnt signaling, vitamin D metabolism and MAPK-ERK 1/2 pathways were also altered. CONCLUSIONS The current pilot study successfully captured the differential expression of inflammation and bone metabolism pathways in OI patients. This work can contribute to future research of transcriptional bloodomics in OI. Transcriptional bloodomics has a strong potential to become a major contributor to the understanding of OI pathological mechanisms, the discovery of phenotype modifying factors, and the identification of new therapeutic targets. However, further studies in bigger cohorts of OI patients are needed to confirm the findings of the current work.
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Affiliation(s)
- Lidiia Zhytnik
- Clinic of Traumatology and Orthopedics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia.
| | - Katre Maasalu
- Clinic of Traumatology and Orthopedics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia
- Department of Traumatology and Orthopedics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
| | - Ene Reimann
- Estonian Genome Centre, University of Tartu, Tartu, Estonia
| | - Aare Märtson
- Clinic of Traumatology and Orthopedics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia
- Department of Traumatology and Orthopedics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
| | - Sulev Kõks
- Perron Institute for Neurological and Translational Science, QEII Medical Centre, Nedlands, WA, Australia
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA, Australia
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Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions. Int J Mol Sci 2020; 21:ijms21207597. [PMID: 33066607 PMCID: PMC7589189 DOI: 10.3390/ijms21207597] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/09/2020] [Accepted: 10/10/2020] [Indexed: 12/19/2022] Open
Abstract
The balance between bone forming cells (osteoblasts/osteocytes) and bone resorbing cells (osteoclasts) plays a crucial role in tissue homeostasis and bone repair. Several hormones, cytokines, and growth factors-in particular the members of the TGF-β superfamily such as the bone morphogenetic proteins-not only regulate the proliferation, differentiation, and functioning of these cells, but also coordinate the communication between them to ensure an appropriate response. Therefore, this review focuses on TGF-β superfamily and its influence on bone formation and repair, through the regulation of osteoclastogenesis, osteogenic differentiation of stem cells, and osteoblasts/osteoclasts balance. After introducing the main types of bone cells, their differentiation and cooperation during bone remodeling and fracture healing processes are discussed. Then, the TGF-β superfamily, its signaling via canonical and non-canonical pathways, as well as its regulation by Wnt/Notch or microRNAs are described and discussed. Its important role in bone homeostasis, repair, or disease is also highlighted. Finally, the clinical therapeutic uses of members of the TGF-β superfamily and their associated complications are debated.
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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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Zieba J, Munivez E, Castellon A, Jiang MM, Dawson B, Ambrose CG, Lee B. Fracture Healing in Collagen-Related Preclinical Models of Osteogenesis Imperfecta. J Bone Miner Res 2020; 35:1132-1148. [PMID: 32053224 DOI: 10.1002/jbmr.3979] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 01/27/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022]
Abstract
Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by bone deformities and fractures caused by low bone mass and impaired bone quality. OI is a genetically heterogeneous disorder that most commonly arises from dominant mutations in genes encoding type I collagen (COL1A1 and COL1A2). In addition, OI is recessively inherited with the majority of cases resulting from mutations in prolyl-3-hydroxylation complex members, which includes cartilage-associated protein (CRTAP). OI patients are at an increased risk of fracture throughout their lifetimes. However, non-union or delayed healing has been reported in 24% of fractures and 52% of osteotomies. Additionally, refractures typically go unreported, making the frequency of refractures in OI patients unknown. Thus, there is an unmet need to better understand the mechanisms by which OI affects fracture healing. Using an open tibial fracture model, our study demonstrates delayed healing in both Col1a2 G610c/+ and Crtap -/- OI mouse models (dominant and recessive OI, respectively) that is associated with reduced callus size and predicted strength. Callus cartilage distribution and chondrocyte maturation were altered in OI, suggesting accelerated cartilage differentiation. Importantly, we determined that healed fractured tibia in female OI mice are biomechanically weaker when compared with the contralateral unfractured bone, suggesting that abnormal OI fracture healing OI may prime future refracture at the same location. We have previously shown upregulated TGF-β signaling in OI and we confirm this in the context of fracture healing. Interestingly, treatment of Crtap -/- mice with the anti-TGF-β antibody 1D11 resulted in further reduced callus size and predicted strength, highlighting the importance of investigating dose response in treatment strategies. These data provide valuable insight into the effect of the extracellular matrix (ECM) on fracture healing, a poorly understood mechanism, and support the need for prevention of primary fractures to decrease incidence of refracture and deformity in OI patients. © 2020 American Society for Bone and Mineral Research.
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Affiliation(s)
- Jennifer Zieba
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Elda Munivez
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Alexis Castellon
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Ming-Ming Jiang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Brian Dawson
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Catherine G Ambrose
- Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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Marzin P, Cormier-Daire V. New perspectives on the treatment of skeletal dysplasia. Ther Adv Endocrinol Metab 2020; 11:2042018820904016. [PMID: 32166011 PMCID: PMC7054735 DOI: 10.1177/2042018820904016] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 01/13/2020] [Indexed: 12/19/2022] Open
Abstract
The last few decades have been marked by the identification of numerous genes implicated in genetic disorders, helping in the elucidation of the underlying pathophysiology of these conditions. This has allowed new therapeutic approaches to emerge such as cellular therapy, gene therapy, or pharmacological therapy for various conditions. Skeletal dysplasias are good models to illustrate these scientific advances. Indeed, several therapeutic strategies are currently being investigated in osteogenesis imperfecta; there are ongoing clinical trials based on pharmacological approaches, targeting signaling pathways in achondroplasia and fibrodysplasia ossificans progressiva or the endoplasmic reticulum stress in metaphyseal dysplasia type Schmid or pseudoachondroplasia. Moreover, the treatment of hypophosphatasia or Morquio A disease illustrates the efficacy of enzyme drug replacement. To provide a highly specialized multidisciplinary approach, these treatments are managed by reference centers. The emergence of treatments in skeletal dysplasia provides new perspectives on the prognosis of these severe conditions and may change prenatal counseling in these diseases over the coming years.
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Affiliation(s)
- Pauline Marzin
- Clinical Genetics, INSERM UMR 1163, Paris
Descartes-Sorbonne Paris Cité University, IMAGINE Institute, Necker Enfants
Malades Hospital, Paris, France
| | - Valérie Cormier-Daire
- Clinical Genetics, INSERM UMR 1163, Paris
Descartes-Sorbonne Paris Cité University, IMAGINE Institute, Necker Enfants
Malades Hospital, 149 rue de sevres, Paris, 75015, France
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Kaupp S, Horan DJ, Lim KE, Feldman HA, Robling AG, Warman ML, Jacobsen CM. Combination therapy in the Col1a2 G610C mouse model of Osteogenesis Imperfecta reveals an additive effect of enhancing LRP5 signaling and inhibiting TGFβ signaling on trabecular bone but not on cortical bone. Bone 2020; 131:115084. [PMID: 31648079 PMCID: PMC7232829 DOI: 10.1016/j.bone.2019.115084] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 09/09/2019] [Accepted: 09/26/2019] [Indexed: 01/05/2023]
Abstract
Enhancing LRP5 signaling and inhibiting TGFβ signaling have each been reported to increase bone mass and improve bone strength in wild-type mice. Monotherapy targeting LRP5 signaling, or TGFβ signaling, also improved bone properties in mouse models of Osteogenesis Imperfecta (OI). We investigated whether additive or synergistic increases in bone properties would be attained if enhanced LRP5 signaling was combined with TGFβ inhibition. We crossed an Lrp5 high bone mass (HBM) allele (Lrp5A214V) into the Col1a2G610C/+ mouse model of OI. At 6-weeks-of-age we began treating mice with an antibody that inhibits TGFβ1, β2, and β3 (mAb 1D11), or with an isotype-matched control antibody (mAb 13C4). At 12-weeks-old, we observed that combining enhanced LRP5 signaling with inhibited TGFβ signaling produced an additive effect on femoral and vertebral trabecular bone volumes, but not on cortical bone volumes. Although enhanced LRP5 signaling increased femur strength in a 3-point bending assay in Col1a2G610C/+ mice, femur strength did not improve further with TGFβ inhibition. Neither enhanced LRP5 signaling nor TGFβ inhibition, alone or in combination, improved femur 3-point-bending post-yield displacement in Col1a2G610C/+ mice. These pre-clinical studies indicate combination therapies that target LRP5 and TGFβ signaling should increase trabecular bone mass in patients with OI more than targeting either signaling pathway alone. Whether additive increases in trabecular bone mass will occur in, and clinically benefit, patients with OI needs to be determined.
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Affiliation(s)
- Shannon Kaupp
- Orthopedic Research Laboratories, Department of Orthopedic Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Dan J Horan
- Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA
| | - Kyung-Eun Lim
- Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA
| | - Henry A Feldman
- Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA
| | - Alexander G Robling
- Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA
| | - Matthew L Warman
- Orthopedic Research Laboratories, Department of Orthopedic Surgery, Boston Children's Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Christina M Jacobsen
- Divisions of Endocrinology and Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
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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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Tauer JT, Robinson ME, Rauch F. Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research. JBMR Plus 2019; 3:e10174. [PMID: 31485550 PMCID: PMC6715783 DOI: 10.1002/jbm4.10174] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/04/2019] [Accepted: 01/16/2019] [Indexed: 12/30/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a monogenic bone fragility disorder that usually is caused by mutations in one of the two genes coding for collagen type I alpha chains, COL1A1 or COL1A2. Mutations in at least 18 other genes can also lead to an OI phenotype. As genetic testing is more widely used, mutations in these genes are also more frequently discovered in individuals who have a propensity for fractures, but who do not have other typical clinical characteristics of OI. Intravenous bisphosphonate therapy is still the most widely used drug treatment approach. Preclinical studies in OI mouse models have shown encouraging effects when the antiresorptive effect of a bisphosphonate was combined with bone anabolic therapy using a sclerostin antibody. Other novel experimental treatment approaches include inhibition of transforming growth factor beta signaling with a neutralizing antibody and the inhibition of myostatin and activin A by a soluble activin receptor 2B. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research
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Affiliation(s)
| | | | - Frank Rauch
- Shriners Hospital for Children Montreal Quebec Canada
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Kozloff KM. Osteogenesis Imperfecta: A Need to Understand Divergent Treatment Outcomes in a Disorder Rich in Heterogeneity. J Bone Miner Res 2019; 34:205-206. [PMID: 30645778 DOI: 10.1002/jbmr.3647] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Ralston SH, Gaston MS. Management of Osteogenesis Imperfecta. Front Endocrinol (Lausanne) 2019; 10:924. [PMID: 32117044 PMCID: PMC7026366 DOI: 10.3389/fendo.2019.00924] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 12/18/2019] [Indexed: 12/24/2022] Open
Abstract
Osteogenesis imperfecta (OI) is the term used to describe a group of rare inherited skeletal disorders characterized by a greatly increased risk of fragility fractures (1). Mutations in several genes can cause OI but the condition is most commonly caused by mutations of COLIA1 or COL1A2 resulting in the production of collagen which is abnormal or present in reduced amounts. Fractures in OI are particularly common during childhood but the elevated fracture risk continues throughout life. Bone mineral density (BMD) can be reduced in OI but the magnitude of increase in fracture risk is far greater than can be accounted for by low BMD, highlighting that a key mechanism of bone fragility is reduced bone quality due to defects of bone matrix and mineralization. A multidisciplinary approach is needed to optimize management of OI, with input from physicians, orthopedic surgeons, physiotherapists, occupational therapists, and other allied health professionals. Orthopedic surgery plays a key role both in the fixation of fractures and in the correction of limb deformities. Bisphosphonates have been widely used in the treatment of children and adults with OI. Although there is good evidence that they increase BMD, it is uncertain to what extent they reduce fracture risk. Clinical trials of bone anabolic drugs such as teriparatide and inhibitors of sclerostin have also been studied; although they increase BMD, studies of these agents have not been powered to look at fracture endpoints. Various other treatment modalities including denosumab, and cell therapy have been explored but haven't gained acceptance in routine clinical practice. There have been huge advances in understanding the pathogenesis of OI but these have not been accompanied by advances in treatment. This signals need for well-designed clinical trials with fracture endpoints in OI, both with existing agents and with the newer therapeutic agents that are now starting to emerge.
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Affiliation(s)
- Stuart H. Ralston
- Centre for Genetics and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom
- *Correspondence: Stuart H. Ralston
| | - Mark S. Gaston
- Royal Hospital for Sick Children, Edinburgh, United Kingdom
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Mäkitie RE, Costantini A, Kämpe A, Alm JJ, Mäkitie O. New Insights Into Monogenic Causes of Osteoporosis. Front Endocrinol (Lausanne) 2019; 10:70. [PMID: 30858824 PMCID: PMC6397842 DOI: 10.3389/fendo.2019.00070] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 01/24/2019] [Indexed: 12/17/2022] Open
Abstract
Osteoporosis, characterized by deteriorated bone microarchitecture and low bone mineral density, is a chronic skeletal disease with high worldwide prevalence. Osteoporosis related to aging is the most common form and causes significant morbidity and mortality. Rare, monogenic forms of osteoporosis have their onset usually in childhood or young adulthood and have specific phenotypic features and clinical course depending on the underlying cause. The most common form is osteogenesis imperfecta linked to mutations in COL1A1 and COL1A2, the two genes encoding type I collagen. However, in the past years, remarkable advancements in bone research have expanded our understanding of the intricacies behind bone metabolism and identified novel molecular mechanisms contributing to skeletal health and disease. Especially high-throughput sequencing techniques have made family-based studies an efficient way to identify single genes causative of rare monogenic forms of osteoporosis and these have yielded several novel genes that encode proteins partaking in type I collagen modification or regulating bone cell function directly. New forms of monogenic osteoporosis, such as autosomal dominant osteoporosis caused by WNT1 mutations or X-linked osteoporosis due to PLS3 mutations, have revealed previously unidentified bone-regulating proteins and clarified specific roles of bone cells, expanded our understanding of possible inheritance mechanisms and paces of disease progression, and highlighted the potential of monogenic bone diseases to extend beyond the skeletal tissue. The novel gene discoveries have introduced new challenges to the classification and diagnosis of monogenic osteoporosis, but also provided promising new molecular targets for development of pharmacotherapies. In this article we give an overview of the recent discoveries in the area of monogenic forms of osteoporosis, describing the key cellular mechanisms leading to skeletal fragility, the major recent research findings and the essential challenges and avenues in future diagnostics and treatments.
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Affiliation(s)
- Riikka E. Mäkitie
- Folkhälsan Institute of Genetics and University of Helsinki, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Alice Costantini
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anders Kämpe
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jessica J. Alm
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Outi Mäkitie
- Folkhälsan Institute of Genetics and University of Helsinki, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Children's Hospital, Pediatric Research Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
- Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- *Correspondence: Outi Mäkitie
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