The mammalian osteopetroses are a diverse group of inherited bone disorders characterized by a generalized increase in skeletal mass resulting from reduced osteoclastic bone resorption. Various abnormalities in cellular and humoral immunity have been identified in osteopetrotic animals and children. Some osteopetrotic animal mutations represent unique in vivo models to explore interactions between the immune and skeletal systems. Specifically, we have been studying possible relationships between coexisting defects in immune cell and osteoclast functions in the osteopetrotic (op) rat. This laboratory recently demonstrated a defect in inflammation-primed macrophage activation resulting from the inability to convert serum vitamin D binding protein .(DBP) to a potent macrophage activating factor (DBP-MAF). This defect is due to the absence of an inducible beta-galactosidase isoenzyme associated with B cell membranes in op mutants. Furthermore, treatment of op mutants with exogenous DBP-MAF resulted in osteoclast activation. Collectively, these results support the hypothesis that DBP-MAF plays an important role in the pathogenesis of osteoclast hypofunction in some forms of osteopetrosis. Studies proposed in this application will test this hypothesis. B cells from normal rats will be transplanted into op mutants in an attempt to correct the B cell defect and cure osteopetrosis by restoring normal osteoclast function. Op mutants and normal rats will be treated with exogenous DBP-MAF at various doses and for different periods of time to; 1) determine if the excess skeletal mass can be completely resorbed in op mutants, and 2) test the effects of this novel factor on osteoclast function and skeletal modeling in normal rats. To gain a better understanding of the mechanism(s) of action of DBP-MAF proposed experiments will; l) examine structural requirements necessary for MAF activity, and 2) evaluate DBP-MAF binding to various immune cells and bone cells in situ. Finally, the powerful mRNA-differential display technique will be used to identify genes selectively expressed in bone from normal or osteopetrotic rats. These studies are expected to provide new clinical applications concerning the therapeutic management of osteopetrotic children and to broader aspects of skeletal pathology including inflammation-mediated osteopenias. As a direct application, exogenous DBP-MAF could be used to treat osteopetrotic children in an attempt to activate osteoclasts and reduce skeletal mass. Based on its potent osteoclast activating property, DBP-MAF may play a key role in mediating the bone loss often associated with chronic inflammatory diseases, such as periodontal disease, osteoarthritis and rheumatoid arthritis. Future studies aimed at developing methods to """"""""block"""""""" its osteolytic effect could be used therapeutically to inhibit inflammation- mediated bone loss.
