OSTEOBLAST MEDIATED TURNOVER OF COLLAGENASE IN BONE

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DESCRIPTION (Adapted from the Applicant's Abstract): The principal investigator, Nicola Partridge, Ph.D., proposes to examine the mechanism of the binding, internalization and degradation of the resorptive enzyme, collagenase-3 (a.k.a., metalloproteinase 13, MMP-13) following its elaboration from the osteoblast during resorption. It is hypothesized that there is a specific receptor, the collagenase-3 receptor, which binds to collagenase-3, resulting in endocytosis that triggers a further interaction of collagenase-3 with the low-density lipoprotein receptor-related protein (LRP). The precise concentration, and hence, the biological activity of MMP-3 depends on a balance between its secretion and its receptor-mediated uptake. Based upon preliminary data that the putative receptor may be a novel lectin, the applicant proposes four Specific Aims. First, she proposes to express and examine the regulation of the collagenase-3 receptor. Secondly, she proposes to mutate the receptor to determine its functional domains that interact with collagenase-3. Thirdly, she will study the interaction of the collagenase-3 molecule with LRP. Finally, she proposes to determine the domains of the collagenase-3 molecule that bind the collagenase-3 receptor and the LRP receptor. Critical new information on the biology of this important molecule may be derived from these studies.