Enhanced turnover of subchondral trabecular bone is a hallmark of rheumatoid arthritis (RA) and it results from an imbalance between bone resorption and bone formation activities. To investigate the formation and activation of osteoclasts which mediate bone resorption, a Fas-deficient MRL/Ipr mouse model which spontaneously develops autoimmune arthritis and exhibits decreased bone mass was studied. Various assays were performed on subchondral trabecular bone of the temporomandibular joint (TMJ) from MRL/lpr mice and MRL+/+ mice. Initially, greater osteoclast production was observed in vitro from bone marrow macrophages obtained from MRL/lpr mice due to enhanced phosphorylation of NF-kappa B, as well as Akt and MAPK, to receptor activator of nuclear factor-kappa B ligand (RANKL). Expression of sphingosine 1-phosphate receptor 1 (SIP1) was also significantly upregulated in the condylar cartilage. S1P(1) was found to be required for S1P-induced migration of osteoclast precursor cells and downstream signaling via Rac1. When SN50, a synthetic NF-kappa B-inhibitory peptide, was applied to the MRL/Ipr mice, subchondral trabecular bone loss was reduced and both production of osteoclastogenesis markers and sphingosine kinase (Sphk) 1/S1P(1) signaling were reduced. Thus, the present results suggest that Fas/S1P(1) signaling via activation of NF-kappa B in osteoclast precursor cells is a key factor in the pathogenesis of RA in the TMJ. (C) 2017 Elsevier Inc. All rights reserved.