EFFECTS OF VITAMIN-D-BINDING PROTEIN-MACROPHAGE ACTIVATING FACTOR (DBP-MAF) INFUSION ON BONE-RESORPTION IN 2 OSTEOPETROTIC MUTATIONS

Osteopetrosis is a heterogeneous group of bone diseases characterized by an excess accumulation of bone and a variety of immune defects, Ost eopetrosis (op) and incisors absent (ia) are two nonallelic mutations in the rat which demonstrated these skeletal defects as a result of re duced bone resorption. Osteopetrotic (op) rats have severe sclerosis a s a result of reduced numbers of osteoclasts which are structurally ab normal, The sclerosis in ia rats is not as severe as in op mutants; th ey have elevated numbers of osteoclasts, but they are also morphologic ally abnormal, lacking a ruffled border, Both of these mutations have defects in the inflammation-primed activation of macrophages, They dem onstrate independent defects in the cascade involved in the conversion of vitamin D binding protein (DBP) to a potent macrophage activating factor (DBP-MAF), Because this factor may also play a role in the path ogenesis of osteoclastic dysfunction, the effects of ex vivo-generated DBP-MAF were evaluated on the skeletal system of these two mutations, Newborn ia and op rats and normal littermate controls were injected w ith DBP-MAF or vehicle once every 4 days from birth until 2 weeks of a ge, at which time bone samples were collected to evaluate a number of skeletal parameters, DBP-MAF treated op rats had an increased number o f osteoclasts and the majority of them exhibited normal structure, The re was also reduced bone volume in the treated op animals and an assoc iated increased cellularity of the marrow spaces, The skeletal scleros is was also corrected in the ia rats; the bone marrow cavity size was significantly enlarged and the majority of the osteoclasts appeared no rmal with extensive ruffled borders, Superoxide production was enhance d to normal levels in the osteoclasts from the treated ia animals as w ell, These studies demonstrate that the skeletal defects in both mutat ions can be improved with exogenous DBP-MAF and that this protein is i nvolved in the pathogenesis of the disease.