THE PHYSIOLOGY OF IGFBP DEGRADING PROTEINASES IN BONE

骨是一个动态的器官，它经历平衡的、持续的重组，需要骨形成（骨吸收）和骨吸收（骨吸收）。 这两个过程之间的相互作用称为耦合。 在骨中，胰岛素样生长因子（IGF-I和IGF-II）是骨形成中重要的有丝分裂原。 然而，这些生长因子的作用受高亲和力IGF结合蛋白（IGFBP 1-6）的调节。 最近的数据显示，当与可溶性IGFBPs结合时，IGFs不能与其细胞表面受体相互作用。 相反，当IGFBPs被蛋白酶降解或当它们与基质分子复合时，它们对IGF的亲和力降低，使得IGF可与细胞表面I型IGF受体相互作用。 我们推测IGFBP降解蛋白酶和IGF/IGFBP复合物之间的相互作用在骨偶联过程中起着不可或缺的作用。 例如，许多参与骨吸收的蛋白酶，如基质金属蛋白酶（MMP），也降解IGFBPs。IGFBPs的降解反过来导致IGF的释放，从而在骨形成中起到合成代谢剂的作用。 本提案的总体目标是阐明哪些蛋白酶参与了两种重要的骨源性IGFBP-4和IGFBP-5的降解，并确定它们对骨细胞中IGF合成代谢作用的总体贡献。 所提出的研究旨在a）了解MMP对IGFBP-5降解的作用以及该IGFBP的降解如何影响成骨细胞中IGF的生物利用度; B）阐明新型L56蛋白酶在IGFBP-4降解中的作用，并确定调节其在骨中的产生和活性的因子;以及c）利用新方法鉴定和克隆人骨中新型IGFBP降解蛋白酶。 更好地了解参与IGFBP降解的蛋白酶及其在IGF作用中的生理作用，将有助于开发治疗干预措施，通过增加IGF生物利用度或减少各种骨病（例如骨质疏松症和代谢性骨病）中的骨吸收来增强骨形成。

Bone is a dynamic organ which undergoes a balanced, ongoing reorganization requiring both bone formation (anabolism) and bone resorption (catabolism). The interplay between these two processes is referred to as coupling. In bone, insulin-like growth factors (IGF-I and IGF-II) are important mitogens in bone formation. These growth factors' actions are, however, modulated by high affinity IGF-binding proteins (IGFBP 1-6). Recent data shows that when bound to soluble IGFBPs, IGFs are unable to interact with their cell surface receptors. In contrast, when IGFBPs are degraded by proteinases or when they are complexed with matrix molecules, their affinity for IGFs is lowered, making IGFs available to interact with cell surface type I IGF receptors. We hypothesize that the interplay between IGFBP-degrading proteinases and IGF/IGFBP complexes plays an integral role in the process of bone coupling. For instance, many of the proteinases involved in bone resorption, such as matrix metalloproteinases (MMPs), also degrade IGFBPs. Degradation of IGFBPs, in turn, results in the release IGFs to function as anabolic agents in bone formation. The overall objective of this proposal is to clarify which proteinases are involved in the degradation of two important bone-derived IGFBPs, IGFBP-4 and IGFBP-5, and to determine their overall contribution to the anabolic actions of IGFs in bone cells. The proposed studies are designed to a) understand the roles of MMPs on IGFBP-5 degradation and how degradation of this IGFBP affects IGF bioavailability in osteoblasts; b) clarify the role of the novel L56 proteinase in IGFBP-4 degradation and define the factors which regulate its production and activity in bone; and c) utilize new methodologies to identify and clone novel IGFBP-degrading proteinases in human bone. A better understanding of the proteinases involved in IGFBP degradation and their physiologic role in IGF action will allow for development of therapeutic interventions to enhance bone formation by increasing IGF biovailability or by decreasing bone resorption in a variety of bone disorders such as osteoporosis and metabolic bone diseases.