Crosstalk between STAT3 and RANK signaling pathways during osteoclastogenesis (174.7)

Abstract

Abstract Osteoclasts are a specialized cell type in the bone marrow microenvironment with a critical role in bone resorption. Osteoclasts develop from macrophage precursors in response to RANK ligand (RANKL) stimulation. Osteopenia and pathologic fractures frequently occur in patients with Hyper IgE syndrome, which is caused by loss-of-function mutations in STAT3 . How impaired STAT3 function translates to these clinical features is not understood. We found that mice with conditional Stat3 deletion in bone marrow have increased osteoclast numbers in vivo; therefore, we examined STAT3 function in RANKL-induced osteoclast differentiation from bone marrow macrophages (BMMs). We found that STAT3 negatively regulates RANK signaling by inhibiting TRAF6 ubiquitination and activation of the downstream signaling proteins NF-κB, JNK and p38 MAPK. Stat3-deficient BMMs show enhanced osteoclast gene expression and osteoclast formation in vitro. STAT3 is induced in BMMs by M-CSF, not RANKL, suggesting that M-CSF signal transduction via STAT3 conditions osteoclast precursors for appropriate RANK-RANKL signaling. We identified the deubiquitinase Uch37 as a STAT3-dependent gene regulating osteoclastogenesis. Thus, our data suggest STAT3 restrains osteoclast development and bone resorption by mediating the amplitude of RANK signaling via Uch37 regulation.