The Role of MMP-13 in the TGF-beta Regulation of Bone Matrix Material Properties

与年龄相关的和病理性骨折仍然是一个重大的公共卫生问题，每年影响着1000多万美国人，它们会导致大量的死亡、致病和经济损失。目前，临床上用骨密度(BMD)测量的骨量来评估骨折的风险，但低风险组和高风险组的BMD有很大的重叠，这表明骨质量可能在确定骨脆性方面发挥重要作用。骨质量的某些方面通过骨微结构、微损伤累积和骨基质材料特性(BMMPs)来反映，每一方面都被证明是导致骨脆性的重要因素。转化生长因子-2的信号转导通过抑制Runx2的表达来调节骨基质金属蛋白酶和全骨的抗折性，但其下游靶点尚不清楚。基质金属蛋白酶-13(MMP13)是转化生长因子-2和Runx2影响BMMPs的可能途径之一。初步研究表明，在成骨细胞培养中，转化生长因子-2直接调节基质金属蛋白酶-13，而基质金属蛋白酶-13缺陷小鼠的长骨表现出脆性增加的表型。综上所述，初步数据表明，基质金属蛋白酶-13可能在转化生长因子-2对骨折抗性的调节中发挥作用。因此，我们假设基质金属蛋白酶-13是转化生长因子-2在骨基质材料特性调节中的下游靶点。这项建议旨在确定指定和调节骨基质材料特性的分子机制，长期目标是利用这些知识来诊断、治疗和预防与年龄相关的和病理性骨折。

Age-related and pathological fractures continue to be a significant public health issue that affects more than 10 million Americans annually, and they cause substantial mortalities, morbidities, and economic costs. Currently, the risk of fracture is clinically assessed by bone mass as measured by bone mineral density (BMD), but there are substantial overlaps in the BMD of low and high fracture risk groups, suggesting that bone quality may play a significant role in the determination of bone fragility. Some aspects of bone quality are reflected through bone micro-architecture, microdamage accumulation, and bone matrix material properties (BMMP), and each has been shown to contribute significantly to bone fragility. The signaling of transforming growth factor-2 (TGF-2) regulates BMMP and whole-bone fracture resistance through the repression of Runx2, but the downstream targets of TGF-2 and Runx2 remain unknown. Matrix metalloproteinase-13 (MMP-13) is one possible pathway by which TGF-2 and Runx2 affect BMMP. Preliminary studies show that TGF-2 directly regulate MMP-13 in osteoblastic culture, and MMP-13 deficient mice show a phenotype of increased fragility in their long bones. Taken together, the preliminary data the MMP-13 could play a role in the TGF-2 regulation of bone fracture resistance. We thus hypothesize that matrix metalloproteinase-13 is a downstream target of TGF-2 in the regulation of bone matrix material properties. This proposal aims to identify molecular mechanisms that specify and regulate bone matrix material properties, with the long-term goal of harnessing this knowledge towards the diagnosis, treatment, and prevention of age-related and pathological fractures.