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.
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