Activin A is an essential cofactor for osteoclast induction

Recently, receptor activator of NF-kappa B ligand (RANKL) was shown to be n ecessary for osteoclast formation. We now report that activin A, a cytokine enriched in bone matrix and secreted by osteoblasts and osteoclasts, power fully synergized with RANKL for induction of osteoclast-like cells (OCL) fr om bone marrow precursors depleted of stromal cells. Moreover, OCL formatio n in RANKL was virtually abolished by soluble type II A activin receptors ( ActR-II(A)), suggesting that activin A is essential for OCL formation. Acti vin A was most effective when precursors were exposed to RANKL and activin A simultaneously: resistance to OCL-induction that occurs when precursors a re pre-incubated in M-CSF was reduced. Incubation on bone matrix also enhan ced the sensitivity of precursors to OCL-induction by RANKL; and this was p revented by soluble ActR-II(A). Thus, activin A in bone matrix, or released from osteoblastic or other cells, enhances the osteoclast-forming potentia l of precursors and synergizes with RANKL in inducing osteoclastic differen tiation, (C) 2000 Academic Press.