OSTEOPETROSIS IN MICE LACKING HEMATOPOIETIC TRANSCRIPTION FACTOR PU.1

Osteoclasts are multinucleated cells and the principal resorptive cell s of bone. Although osteoclasts are of myeloid origin(1), the role of haematopoietic transcription factors in osteoclastogenesis has not bee n explored. Here we show that messenger RNA for the myeloid- and B-cel l-specific transcription factor PU.1 progressively increases as marrow macrophages assume the osteoclast phenotype in vitro. The association between PU.1 and osteoclast differentiation was confirmed by demonstr ating that PU.1 expression increased with the induction of osteoclasto genesis by either 1,25-dihydroxyvitamin D-3 or dexamethasone. Consiste nt with the participation of PU.1 in osteoclastogenesis, we found that the development of both osteoclasts and macrophages is arrested in PU .1-deficient mice. Reflecting the absence of osteoclasts, PU.1(-/-) mi ce exhibit the classic hallmarks of osteopetrosis, a family of sclerot ic bone diseases(2). These animals were rescued by marrow transplantat ion, with complete restoration of osteoclast and macrophage differenti ation, verifying that the PU.1 lesion is intrinsic to haematopoietic c ells. The absence of both osteoclasts and macrophages in PU.1-mutant a nimals suggests that the transcription factor regulates the initial st ages of myeloid differentiation, and that its absence represents the e arliest developmental osteopetrotic mutant yet described.