Transforming growth factor-β coordinately induces suppressor of cytokine signaling 3 and leukemia inhibitory factor to suppress osteoclast apoptosis

Local release of TGF-βduring times of high bone turnover leads to elevated levels within the bone microenvironment, and we have shown that TGF-β suppresses osteoclast apoptosis. Therefore, understanding the influences of TGF-β on bone resorbing osteoclasts is critical to the design of therapies to reduce excess bone loss. Hereweinvestigated the mechanisms by which TGF-βsustains suppression of osteoclast apoptosis. We found TGF-βrapidly increased leukemia inhibitory factor (LIF) expression and secretion by phosphorylated mothers against decapentaplegic-dependent and -independent signaling pathways. TGF-β also induced suppressor of cytokine signaling 3 (SOCS3) expression, which was required for TGF-β or LIF to promote osteoclast survival by. Blocking LIF or SOCS3 blocked TGF-β promotion of osteoclast survival, confirming that LIF and SOCS3 expression are necessary for TGF-β-mediated suppression of osteoclast apoptosis. Investigation of the mechanisms by which LIF promotes osteoclast survival revealed that LIF-induced expression of Bcl-X_L and repressed Bcl-2 interacting domain expression by activating MAPK kinase, AKT, and nuclear factor-κB pathways. Suppression of Janus kinase/signal transducer and activator of transcription signaling further increased Bcl-X _Lexpression and enhance dosteoclast survival,supporting that this pathway is not involvedin prosurvival effects of TGF-βand LIF.These data show that TGF-β coordinately induces LIF and SOCS3 to promote prosurvival signaling. This alters the ratio of prosurvival Bcl2 family member Bcl-X _L to proapoptotic family member Bcl-2 interacting domain, leading to prolonged osteoclast survival.