Implant loosening remains a major cause of delayed failure in joint replacement. Because such loosening occurs as a consequence of excess bone resorption resolution of this problem pivots on identifying the cells and resorptive mechanisms involved in bone matrix degradation. Recent work from this, and other laboratories, has shown that (i) osteoclasts resorb bone collagen using a lysosomal acid protease, (ii) osteoblasts may be involved in the resorptive phase of remodeling sine, in response to hormones, they produce both neutral collagenase and a potent collagenase inhibitor, and (iii) macrophages, which accumulate at sites of cemented implants, secrete a number of factors, including Interleukin-1, and prostaglandin E2, capable of stimulating resorptive activity. In the present application, experiments are described aimed at expanding and integrating these observations. Specifically, we propose to : (1) ISOLATE AND CHARACTERIZE THE ENZYME RESPONSIBLE FOR OSTEOCLAST-MEDIATED COLLAGENOLYSIS, (2) ASSESS THE INTRACELLULAR PROCESSING AND TRAFFICKING OF THE OSTEOCLAST COLLAGENOLYTIC ENZYME IN RESORPTIVE AND NON- RESORPTIVE OSTEOCLASTS, AND (3) EVALUATE THE CAPACITY OF MACROPHAGES TO (A) MODULATE OSTEOCLAST RESORPTIVE ACTIVITY AND (B) INFLUENCE SYNTHESIS OF OSTEOBLAST NEUTRAL COLLAGENASE AND COLLAGENASE INHIBITOR.
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