Acid-sensing ion channel 1a is involved in acid-induced osteoclastogenesis by regulating activation of the transcription factor NFATc1.

It has been known that osteoclastogenesis is induced by extracellular acidosis-evoked the rise of intracellular calcium ([Ca(2+)]i), which regulate activation of the transcription factor nuclear factor of activated T cells c1 (NFATc1). However, the acid-sensing ion channels (ASICs) involved remain largely unknown. Here, we show that ASIC1a, ASIC1b, ASIC2a, and ASIC3 are expressed in rat osteoclasts, and only ASIC1a is highly upregulated in response to acidosis. Both the ASIC1a-specific blocker PcTX1 and specific siRNA significantly reduce this increase in acid-induced [Ca(2+)]i and acid-induced nuclear translocation of NFATc1, and inhibit acid-induced osteoclast differentiation and bone resorption. These findings show that ASIC1a-mediated calcium entry plays a critical role in osteoclastogenesis by regulating activation of the NFATc1.