Role of Voltage-gated Potassium Channel, Kv7.3 in Osteoblast Maturation and Mineralization

Abstract

KCNQ channel is one of the voltage-gated potassium (Kv) channels. The functions of Kv7 channels in muscles, neurons and sensory cells are well characterized. However, the function in osteoblast cells has not been investigated. The present study demonstrated that Kv7.3 channel could regulate osteoblast differentiation. First, expression of Kv7 channels was examined in MG-63 and Saos-2 osteoblast cells. All subtypes of Kv7 channels, including Kv7.1, Kv7.2, Kv7.3, Kv7.4 and Kv7.5, were expressed in MG-63 cells, and Kv7.3 and Kv7.5 channels existed in Saos-2 cells. The results illustrated that the expression of Kv7.3 channel, which was highly expressed in MG-63 and Saos-2 cells, changed during osteoblastic differentiation at the mRNA and protein levels. Inhibition of Kv7.3 by linopirdine or XE991 increased the matrix mineralization during osteoblast differentiation. This was confirmed by the increase in mRNA of alkaline phosphatase, osteocalcin, transcription factor, osterix, and by the deposition of type 1 collagen proteins in MG-63 cells. Furthermore, the extracellular glutamate secreted by osteoblasts was measured to investigate its effect on the matrix mineralization in MG-63 osteoblast cells. Blockade of Kv7.3 promoted the release of glutamate via the phosphorylation of extracellular signal-regulated kinase 1/2-mediated up-regulation of synapsin. On the other hand, activation of Kv7.3 using flupirtine did not produced notable changes in matrix mineralization during osteoblast differentiation. In conclusion, these results suggest that blockade of Kv7.3 channels could enhance the matrix mineralization during osteoblast differentiation. Although further studies are required to clarify the underlying mechanisms, the present study implicates that Kv7.3 channel can be a possible target of bone-loss-related diseases.