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. Suppression of ASM expression in bone marrow macrophages by knockdown enhanced c-Fos/NFAT2 expression, 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 downregulated following ASM knockdown, while SphK2 levels were unchanged. Experiments using shRNA and catalytically-inactive form demonstrated inhibitory and stimulatory activities on osteoclast formation of SphK1 and SphK2, respectively. These results suggest that ASM regulates osteoclastogenesis by modulating the balance between SphK1 and SphK2 downstream of RANKL signaling.

Research highlights
► ASM as a NFAT2-inducible gene in osteoclasts downstream of RANKL signaling.
► ASM differentially modulated the expression of SphK1 and SphK2.
► SphK1 and SphK2 play negative and positive roles on osteoclastogenesis, respectively.
► The ASM-SphK axis functions in conjunction with the c-Fos/NFAT2 pathway.