Abstract only The amiloride‐sensitive epithelial sodium channels (ENaC) are essential for maintaining sodium homeostasis, transducting mechanical stimuli, and sensing acidosis. The expression of ENaC in bone and the correlation of Na content with bone disease have been reported. We thus studied the distribution and regulation of ENaC by cGMP/PKG signal in normal and cGK knockout mouse bone and primary cultured osteoblasts. Our immunostaining and RT‐PCR results showed that three ENaC subunits, namely , α , β and γ were expressed in osteoblasts of normal mice. Amiloride‐sensitive Na currents were detected in primary osteoblasts clamped in whole‐cell mode. Furthermore, we found that 8‐pCPT‐cGMP (0.2mM, 24hr) stimulated ENaC channel activity in oocytes (P<0.05, n=9). On the other hand, regulation of ENaC expression by cGMP was examined by comparing the protein expression levels of ENaC in normal and cGKII knockout mice. The protein expression levels for ENaC, as measured by densitometry of Western blot strikingly reduced in cGKII knockout mice which are dwarfs (P<0.05, n=3). Similar observations were seen in immunohistochemical images. Our results suggest that regulation of ENaC channel expression and function by cGMP/cGKII signal pathway may be a potential target for developing pharmaceutical intervention for metabolic bone diseases. Supported by HL87017 and National Natural Science Foundation of China 30740085.