THE PHYSIOLOGY OF IGFBP DEGRADING PROTEINASES IN BONE

骨是一个动态的器官，它经历着平衡的、持续的重组，需要骨形成(合成代谢)和骨吸收(分解代谢)。这两个过程之间的相互作用称为耦合。在骨组织中，胰岛素样生长因子(IGF-I和IGF-II)是骨形成过程中重要的有丝分裂原。然而，这些生长因子的作用是由高亲和力的IGF结合蛋白(IGFBP1-6)调节的。最近的数据显示，当IGF与可溶性IGFBPs结合时，不能与其细胞表面受体相互作用。相反，当IGFBPs被蛋白酶降解或与基质分子络合时，它们对IGFS的亲和力降低，使IGFS可与细胞表面I型IGF受体相互作用。我们推测，IGFBP降解酶和IGF/IGFBP复合体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，许多与骨吸收有关的蛋白酶，如基质金属蛋白酶(MMPs)，也能降解IGFBPs。IGFBPs的降解反过来导致释放的IGFS在骨形成中作为合成代谢剂发挥作用。本研究的总体目标是阐明IGFBP-4和IGFBP-5这两种重要的骨源性IGFBP-4和IGFBP-5这两种重要的骨源性IGFBPs的降解过程，并确定它们对IGFS在骨细胞中的合成代谢作用的总体贡献。这些研究旨在a)了解MMPs在IGFBP-5降解中的作用以及IGFBP在成骨细胞中的降解如何影响IGFBP-4的生物利用度；b)阐明新型L56蛋白酶在IGFBP-4降解中的作用，并确定其在骨骼中的产生和活性的调节因素；以及c)利用新的方法来鉴定和克隆人骨中新的IGFBP降解蛋白。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，通过提高IGF的生物利用度或通过减少各种骨骼疾病(如骨质疏松症和代谢性骨骼疾病)的骨吸收来促进骨形成。

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.