A role for TGFbeta(1) in osteoclast differentiation and survival.

Recently, tumour necrosis factor-related activation-induced cytokine (TRANCE) was shown to be necessary for osteoclast formation. We now report that TGF(beta), a cytokine enriched in bone matrix, is also required. TGF(beta) not only powerfully synergized with TRANCE for induction of osteoclast-like cells (OCL) from bone marrow precursors and monocytes, but OCL formation was abolished by recombinant soluble TGF(beta) receptor II (TGF(beta)sRII). Preincubation in TGF(beta) was as effective as simultaneous incubation with TRANCE. TGF(beta)-preincubation enhanced OCL formation at least partly by preventing the development of resistance to OCL-induction that otherwise occurs when precursors are incubated in M-CSF. OCL formed in TRANCE also showed more rapid apoptosis than OCL in TRANCE plus TGF(beta). Like TGF(beta), incubation on bone matrix prolonged and enhanced the sensitivity of precursors to OCL-induction by TRANCE, and this was reversed by TGF(beta)sRII. Taken together, this data is compelling evidence for a model in which TGF(beta) in matrix or released from bone-lining or other cells maintains and enhances the osteoclast-forming potential of precursors as they migrate towards sites of cell-bound TRANCE. Thus, the specific circumstances necessary for osteoclast formation and survival are TRANCE expression on osteoblastic cells and TGF(beta) in bone.