Bone matrix protein osteocalcin (OC) was shown to support the development of learning and memory and also prevent anxiety-like behaviors in mice. Although the involvement of GPR158 as the candidate receptor for OC has been reported, the direct effect of OC on the neuronal cells are still unclear. In this study, we investigated both morphological and functional effects of OC on neurons using a model cell line, rat pheochromocytoma cell line PC12 cells.
We detected relatively high expression of GPR158 at both mRNA and protein level, while the expression of the other OC receptor GPRC6A was barely detected in PC12 cells. Treatment of PC12 cells with OC induced transient phosphorylation of ERK, indicated the existence of functional OC receptor in the cells. Proliferation of PC12 cells was promoted in the the presence of 5 to 50 ng/mL of OC. NGF-induced neurite outgrowth was up-regulated by treating the cells with OC. Apoptosis of PC12 cells induced by H₂O₂ was observed as the cleavage of PARP and was suppressed in the presence of OC. The results suggested that OC has direct effect on neuronal morphology and proliferation and also functional cell survival by binding to GPR158 and modulation of downstream intracellular signaling.