Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation

The differentiation of cells of the monocytic lineage into mature osteoclas ts (OC) is specifically induced by the tumor necrosis factor-related factor , RANKL (receptor activator of NF-kappaB ligand; also known as OPGL, ODF, o r TRANCE). Because inhibition of osteoclastogenesis is one of the main mech anisms by which estrogen (E2) prevents bone loss, it is likely that E2 may regulate either the production of, or the target cell responsiveness to RAN KL. We found that E2 decreases the differentiation into OC of both murine b one marrow monocytes and RAW 264.7 cells, a monocytic line, by downregulati ng the activation of Jun N-terminal kinase 1 (JNK1). Diminished JNK1 activi ty results in decreased nuclear levels of the key osteoclastogenic transcri ption factors, c-Fos and c-Jun, and lower binding of these transcriptional inducers to DNK Thus, one novel mechanism by which E2 down-regulates osteoc lastogenesis is by decreasing the responsiveness of OC precursors to RANKL.