Fractures show delayed healing and increased possibility of re-fracture in OI murine models.

在 OI 小鼠模型中，骨折显示愈合延迟且再次骨折的可能性增加。

• 批准号: 9758632
• 负责人: Jennifer Zieba
• 金额: $ 5.03万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2020-01-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758632
• 关键词: Adult; Affect; Architecture; Biological; Biomechanics; Bone Matrix; Bone Regeneration; Bone callus; COL1A1 gene; COL1A2 gene; Cartilage; Characteristics; Child; Childhood; Chondrocytes; Clinical; Clinical Data; Clinical Trials; Collagen; Collagen Type I; Complex; Contralateral; Data; Data Analyses; Defect; Deformity; Development; Developmental Bone Diseases; Disease; Exhibits; Extracellular Matrix; Foundations; Fracture; Fracture Healing; Future; Genes; Genetic; Goals; Human; Hydroxylation; Impaired wound healing; Impairment; Individual; Inherited; Knowledge; Literature; Methodology; Modeling; Molecular; Mus; Mutation; Operative Surgical Procedures; Osteogenesis; Osteogenesis Imperfecta; Osteotomy; Patients; Phenotype; Population; Process; Proteins; Reporting; Research; Resistance; Signal Transduction; Structure; Testing; Tibial Fractures; Torsion; Transforming Growth Factor beta; Work; bisphosphonate; bone; bone healing; bone mass; bone quality; bone strength; cartilage development; clinical practice; experience; fracture risk; healing; improved; in vivo; insight; long bone; member; microCT; mouse model; novel; tibia; treatment effect; virtual

Project Summary/Abstract Osteogenesis Imperfecta (OI) is the most common genetic bone dysplasia. It is characterized by bone deformities and fractures caused by low bone mass and impaired bone quality. Roughly 85-90% of cases are dominantly inherited and result from mutations in genes encoding type I collagen (COL1A1 and COL1A2), the major protein of the bone matrix. 10-15% of OI cases are recessively inherited and the majority result from mutations in members of the prolyl-3-hydroxylation complex including Cartilage Associated Protein (CRTAP). OI patients are at an increased risk of fracture throughout their lifetimes. Delayed healing and non-union has been reported in 24% of fractures and 52% of osteotomies in OI patients, higher than in the healthy population yet there have been few studies concerning the molecular mechanisms behind these healing abnormalities. Thus, there is an unmet need to better understand the mechanisms by which OI affects fracture healing. It is my goal to determine to what extent the fracture healing process differs in OI and how anti-TGFβ treatment may normalize or improve fracture healing and healed bone quality in murine models. I have observed a decrease in callus size and strength indicating a delay in fracture healing in Crtap–/– mice. It is my hypothesis that OI fractures undergo suboptimal healing and that this process results in ultimately weaker bone leading to the increased possibility of re-fracture. Using both Col1a2+/G610C and Crtap–/– mice (dominant and recessive models of OI, respectively), I will model long bone fracture healing using open tibial fracture surgery. I will determine the differences in OI fracture healing when compared to wild-type by collecting fractured tibia at multiple timepoints to observe fracture callus cartilage development and composition changes throughout the healing process. Additionally, I will analyze the architectural and biomechanical structure of the OI callus to determine the effect of the OI phenotype on the strength of healing/fully healed bone. Finally, our group demonstrated increased TGFβ signaling in OI bone using both Col1a2+/G610C and Crtap–/– OI mouse models that contributes to the low bone mass/quality phenotype. We further showed that anti-TGFβ treatment improves bone mass and quality in both OI mouse models. Therefore, I will investigate the effect of anti-TGFβ treatment on callus composition, callus strength, and healed bone strength/quality in OI and WT mice. Currently, anti-TGFβ anabolic treatments are in clinical trials yet their effect on fracture healing has not been assessed. Therefore, the knowledge gained from this study will be entirely novel and of high importance to the field of OI management. Furthermore, both Col1a2+/G610C and Crtap–/– mice model OI via mutations in collagen or collagen processing and the effect of extracellular matrix structure on fracture healing is poorly understood. By understanding fracture healing in OI, the results will have broad significance for basic fracture healing research. This proposal will not only confirm and elucidate abnormal healing in OI, it will also identify the mechanism behind these differences as well as assess the effect of a current therapy on the healing process.

项目总结/摘要 成骨不全症（OI）是最常见的遗传性骨发育不良。它的特点是骨 由低骨量和骨质受损引起的畸形和骨折。大约85-90%的病例是 显性遗传并由编码I型胶原蛋白（COL 1A 1和COL 1A 2）的基因突变引起， 骨基质的主要蛋白质。10-15%的OI病例是重复遗传的，大多数是由以下原因引起的： 脯氨酰-3-羟基化复合物的成员中的突变，包括软骨素相关蛋白（CRTAP）。 OI患者在其一生中骨折的风险增加。延迟愈合和骨不连 在OI患者中，24%的骨折和52%的截骨术中报告，高于健康人群 然而，关于这些愈合异常背后的分子机制的研究很少。 因此，有一个未满足的需要，以更好地了解OI影响骨折愈合的机制。是 我的目标是确定骨折愈合过程在多大程度上与OI不同，以及抗TGF β治疗 可以使小鼠模型中的骨折愈合和愈合的骨质量正常化或改善。我观察到 骨痂大小和强度的降低表明Crtap-/-小鼠骨折愈合延迟。我假设 OI骨折的愈合不理想，这一过程最终导致骨质变弱， 再次骨折的可能性增加。使用Col 1a 2 +/G610 C和Crtap-/-小鼠（显性和隐性） 模型的OI），我将使用开放性胫骨骨折手术模拟长骨骨折愈合。我会 通过收集骨折的胫骨，确定OI骨折愈合与野生型相比的差异， 多个时间点观察骨折骨痂软骨发育和组成变化， 愈合过程此外，我将分析OI骨痂的结构和生物力学结构， 确定OI表型对愈合/完全愈合骨强度的影响。最后，我们的团队 使用Col 1a 2 +/G610 C和Crtap-/- OI小鼠模型证实OI骨中TGFβ信号传导增加 导致低骨量/骨质量表型。我们进一步表明，抗TGF β治疗 改善两种OI小鼠模型的骨量和质量。因此，我将研究抗TGF β 治疗对OI和WT小鼠的骨痂组成、骨痂强度和愈合的骨强度/质量的影响。 目前，抗TGF β合成代谢治疗处于临床试验中，但其对骨折愈合的作用尚未被证实。 评估。因此，从这项研究中获得的知识将是全新的，对 OI管理领域。此外，Col 1a 2 +/G610 C和Crtap-/-小鼠均通过胶原蛋白突变建立OI模型， 或胶原蛋白加工，而细胞外基质结构对骨折愈合的影响知之甚少。 通过对骨不连骨折愈合的了解，其结果对骨折的基础愈合具有广泛的意义 research.这项建议不仅将确认和阐明OI的异常愈合，还将确定 这些差异背后的机制，以及评估当前治疗对愈合过程的影响。