Rapid Publication Requirement of pp6Oc-8rc Expression for Osteoclasts to Form Ruffled Borders and Resorb Bone in Mice

Targeted disruption of the c-src proto-oncogene in mice has shown that src expression is required for normal bone resorp-tion, since the src-deficient mutants develop osteopetrosis. To evaluate the mechanisms by which src-deficiency affects osteo-clast function, we treated src-deficient mice with the stimulants of bone resorption, IL-1, parathyroid hormone, and parathy-roid hormone-related protein, and analyzed the effects by quan-titative bone histomorphometry and electron microscopy. In-creased numbers of multinucleated cells with the morphologi-cal characteristics of osteoclasts appeared on bone surfaces, but these cells did not form ruffled borders or normal resorp-tion lacunae. To confirm these in vivo findings, we cultured src-mutant bone marrow cells on dentine slices in the presence of 1,25 dihydroxyvitamin D3. Increased numbers ofmultinucle-ated cells were formed, but unlike normal murine bone marrow cells, they did not form resorption pits. These results indicate that osteoclasts appear in the absence of pp6Or, but that pp6OC expression is required for mature osteoclasts to form ruffled borders and resorb bone. (J. Clin. Invest. 1992. 90:1622-1627.) Key words: osteopetrosis * proto-oncogene. histomorphometry * electron microscopy * calciu