Early Fracture Healing is Delayed in the Col1a2+/G610C Osteogenesis Imperfecta Murine Model

Besio, Roberta; Maruelli, Silvia; Battaglia, Séverine; Leoni, Laura; Villani, Simona; Layrolle, Pierre; Rossi, Antonio; Trichet, Valérie; Forlino, Antonella

doi:10.1007/s00223-018-0461-x

Cited by 10 publications

(8 citation statements)

References 40 publications

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“…Even when OI patient fractures do successfully heal, refractures typically go unreported and fracture databases do not distinguish between contralateral limbs, resulting in little to no information concerning the strength of OI bone after healing . Two recent studies showed delayed fracture healing in OI mouse models . These studies, however, did not explore the biomechanical consequences of abnormal fracture healing in OI murine models.…”

Section: Introductionmentioning

confidence: 99%

“…(13) Two recent studies showed delayed fracture healing in OI mouse models. (28,29) These studies, however, did not explore the biomechanical consequences of abnormal fracture healing in OI murine models. Thus, there is an unmet need to better understand the mechanisms by which OI affects fracture healing and its relation to healed bone quality and strength in the context of abnormal matrix and signaling.…”

Section: Introductionmentioning

confidence: 99%

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Fracture Healing in Collagen-Related Preclinical Models of Osteogenesis Imperfecta

Zieba

Munivez

Castellon

et al. 2020

Journal of Bone and Mineral Research

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fracture Healing in Collagen-Related Preclinical Models of Osteogenesis Imperfecta

Zieba

Munivez

Castellon

et al. 2020

Journal of Bone and Mineral Research

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“…While these patients are more prone to fracture than the general population, fracture healing is also affected by the inherent poor bone quality and can be complicated by non-union and refracture (66,67). Studies in dominant and recessive mouse models of OI show delayed fracture healing and reduced strength of the healed bone (68,69). While fractures, particularly in young children, may be treated nonoperatively with immobilization, this can result in muscle weakness, joint stiffness and disuse osteopenia.…”

Section: Fracturesmentioning

confidence: 99%

Management of Endocrine Disease: Osteogenesis imperfecta: an update on clinical features and therapies

Marom

Rabenhorst

Morello

2020

European Journal of Endocrinology

161

138

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Osteogenesis imperfecta (OI) is an inherited skeletal dysplasia characterized by bone fragility and skeletal deformities. While the majority of cases are associated with pathogenic variants in COL1A1 and COL1A2, the genes encoding type I collagen, up to 25% of cases are associated with other genes that function within the collagen biosynthesis pathway or are involved in osteoblast differentiation and bone mineralization. Clinically, OI is heterogeneous in features and variable in severity. In addition to the skeletal findings, it can affect multiple systems including dental and craniofacial abnormalities, muscle weakness, hearing loss, respiratory and cardiovascular complications. A multi-disciplinary approach to care is recommended to address not only the fractures, reduced mobility, growth and bone pain but also other extra-skeletal manifestations. While bisphosphonates remain the mainstay of treatment in OI, new strategies are being explored, such as sclerostin inhibitory antibodies and TGF beta inhibition, to address not only the low bone mineral density but also the inherent bone fragility. Studies in animal models have expanded the understanding of pathomechanisms of OI and, along with ongoing clinical trials, will allow to develop better therapeutic approaches for these patients.

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“…These characteristics make the Col1a2 G610C/+ (G610C) model attractive for intervention studies and biomechanical analysis. Accordingly, the model has been used to investigate the role of mutant collagen in causing OI symptoms such as growth deficiencies [11], defective mineralization of developing bone [12], disrupted osteoblast differentiation [13], and impaired fracture healing [14]. It has also been used in preclinical trials of OI treatments such as upregulating the LRP5 pathway [15,16], diet-based attempts to degrade mutant procollagen and thereby increase bone strength [17,18], sclerostin antibody and zoledronate combination therapy [19], bone marrow transplant [20], TGF-beta inhibition [16,21], activin receptor inhibitor treatment to improve muscle contractility [22], myostatin inhibition [23], and BMP-2 injections for fracture healing [24].…”

Section: Introductionmentioning

confidence: 99%

Morphological and mechanical characterization of bone phenotypes in the Amish G610C murine model of osteogenesis imperfecta

et al. 2021

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Osteogenesis imperfecta (OI) is a hereditary bone disease where gene mutations affect Type I collagen formation resulting in osteopenia and increased fracture risk. There are several established mouse models of OI, but some are severe and result in spontaneous fractures or early animal death. The Amish Col1a2G610C/+ (G610C) mouse model is a newer, moderate OI model that is currently being used in a variety of intervention studies, with differing background strains, sexes, ages, and bone endpoints. This study is a comprehensive mechanical and architectural characterization of bone in G610C mice bred on a C57BL/6 inbred strain and will provide a baseline for future treatment studies. Male and female wild-type (WT) and G610C mice were euthanized at 10 and 16 weeks (n = 13–16). Harvested tibiae, femora, and L4 vertebrae were scanned via micro-computed tomography and analyzed for cortical and trabecular architectural properties. Femora and tibiae were then mechanically tested to failure. G610C mice had less bone but more highly mineralized cortical and trabecular tissue than their sex- and age-matched WT counterparts, with cortical cross-sectional area, thickness, and mineral density, and trabecular bone volume, mineral density, spacing, and number all differing significantly as a function of genotype (2 Way ANOVA with main effects of sex and genotype at each age). In addition, mechanical yield force, ultimate force, displacement, strain, and toughness were all significantly lower in G610C vs. WT, highlighting a brittle phenotype. This characterization demonstrates that despite being a moderate OI model, the Amish G610C mouse model maintains a distinctly brittle phenotype and is well-suited for use in future intervention studies.

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Early Fracture Healing is Delayed in the Col1a2+/G610C Osteogenesis Imperfecta Murine Model

Cited by 10 publications

References 40 publications

Fracture Healing in Collagen-Related Preclinical Models of Osteogenesis Imperfecta

Fracture Healing in Collagen-Related Preclinical Models of Osteogenesis Imperfecta

Management of Endocrine Disease: Osteogenesis imperfecta: an update on clinical features and therapies

Morphological and mechanical characterization of bone phenotypes in the Amish G610C murine model of osteogenesis imperfecta

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