Acid sphingomyelinase regulates osteoclastogenesis by modulating sphingosine kinases downstream of RANKL signaling

Acid sphingomyelinase (ASM) was identified as a gene induced by NFAT2 activation in osteoclasts. Sup- pression of ASM expression in bone marrow macrophages by knockdown enhanced c-Fos/NFAT2 expres- sion, increasing the number of TRAP-positive multinucleated cells in vitro. SphK1 was upregulated during the late stage of osteoclastogenesis, while SphK2 expression remained constant. SphK1 was downregu- lated following ASM knockdown, while SphK2 levels were unchanged. Experiments using shRNA and cat- alytically-inactive form demonstrated inhibitory and stimulatory activities on osteoclast formation of SphK1 and SphK2, respectively. These results suggest that ASM regulates osteoclastogenesis by modulat- ing the balance between SphK1 and SphK2 downstream of RANKL signaling.