Role of zinc and zinc-modulated ion channels, ORAI1 and HCN in osteoclasts

Zinc is a trace element in the mammalian body, and increasing evidence is suggesting that it plays a critical role in bone development and in the differentiation of bone cells such as osteoblasts, osteoclasts, and chondrocytes. In vivo and in vitro studies have shown that zinc affects osteoclast differentiation. Zinc-sensitive ion channels have been reported. Zinc-related ion channel is ORAI1, which is a store-operated Ca 2+ entry channel subunit, and zinc inhibits the activity of this channel. ORAI1 channels play a significant role in regulating osteoclastic Ca 2+ oscillations during osteoclast differentiation. Knockdown of ORAI1 inhibited osteoclast differentiation. Zinc also inhibited osteoclastogenesis however, its inhibition was reduced by ORAI1 knockdown. Interestingly, zinc can change the osteoclastic membrane potential. Based on this, hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels were investigated and were found to be highly expressed in osteoclasts. High concentrations of zinc chloride increase Ih current which is generated by HCN channels, suggesting a complicated relationship between HCN channels and zinc. Zinc plays various roles in bone physiology through zinc-modulated ion channels. Signaling of these ion channels would be promising targets for treating skeletal diseases. 1200 analog-digital (Axon Instruments), using software (Axon Instruments). Voltage steps (from -30 to −150 mV) at holding