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

描述（由申请人提供）：脊柱相关和病理性骨折仍然是一个重大的公共卫生问题，每年影响超过1000万美国人，并且它们导致大量死亡率、发病率和经济成本。目前，临床上通过骨矿物质密度（BMD）测量的骨量来评估骨折风险，但低骨折风险组和高骨折风险组的BMD存在大量重叠，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性质（BMMP）反映，并且每一个都已被证明对骨脆性有显著贡献。转化生长因子-2（transforming growth factor-2，TGF-2）通过抑制Runx 2的表达来调节骨基质金属蛋白酶（BMMP）和全骨骨折抵抗力，但TGF-2和Runx 2的下游靶点尚不清楚。基质金属蛋白酶-13（MMP-13）是TGF-2和Runx 2影响BMMP的一个可能途径。初步研究表明，TGF-2直接调节成骨细胞培养中的MMP-13，并且MMP-13缺陷小鼠在其长骨中显示出增加的脆性表型。综上所述，初步数据显示MMP-13可能在TGF-2调节骨折阻力中发挥作用。因此，我们假设基质金属蛋白酶-13是TGF-2调节骨基质材料性质的下游靶点。该提案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，治疗和预防年龄相关和病理性骨折。

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.