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

描述（由申请人提供）：与年龄相关的和病理性骨折仍然是一个重要的公共卫生问题，每年影响超过1000万美国人，它们造成大量的死亡率、发病率和经济成本。目前临床上主要通过骨密度（bone mineral density， BMD）测量骨量来评估骨折风险，但低骨折风险组和高骨折风险组的骨密度存在大量重叠，提示骨质量可能在确定骨脆性方面发挥重要作用。骨质量的某些方面是通过骨微结构、微损伤积累和骨基质材料特性（BMMP）来反映的，每一个都被证明对骨脆弱性有重要贡献。转化生长因子-2 （TGF-2）信号通过抑制Runx2调控BMMP和全骨骨折抵抗，但TGF-2和Runx2的下游靶点尚不清楚。基质金属蛋白酶13 （Matrix metalloproteinase-13, MMP-13）可能是TGF-2和Runx2影响基质金属蛋白酶13的途径之一。初步研究表明，TGF-2在成骨细胞培养中直接调节MMP-13， MMP-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MMP-13可能在TGF-2调节骨折抵抗中发挥作用。因此，我们假设基质金属蛋白酶-13是TGF-2调控骨基质材料特性的下游靶点。本研究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进行年龄相关和病理性骨折的诊断、治疗和预防。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The research work proposed here aims to address the mechanisms of regulation of bone fracture resistance. The increased understanding of the role of matrix metalloproteinase-13 in the TGF-2 regulation of bone matrix material properties would allow the precise manipulation of the regulatory processes of healthy bone maintenance. Furthermore, the results may lead to improved therapies and strategies for the prevention and treatment of age-related and pathological bone fragility.