Activation of dopamine receptor D1 promotes osteogenic differentiation and reduces glucocorticoid-induced bone loss by upregulating the ERK1/2 signaling pathway.

ABSTRACT

BACKGROUND: The inhibition of osteogenic differentiation is a major factor in glucocorticoid-induced bone loss, but there is currently no effective treatment. Dopamine, a major neurotransmitter, transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. Although the relevance of the neuroendocrine system in bone metabolism has emerged, the precise effects of dopamine receptor signaling on osteoblastogenesis remain unknown. METHODS: In vitro, western blotting and immunofluorescence staining were used to observe the expression of dopamine receptors in MC3T3-E1 and BMSCs cells treated with dexamethasone (Dex). In addition, Alizarin red S (ARS) and alkaline phosphatase (ALP) staining and western blotting were used to evaluate the effect of D1R activation on osteogenic differentiation in Dex-induced MC3T3-E1 cells via the ERK1/2 signaling pathway. In vivo, micro-CT and hematoxylin and eosin (H&E), toluidine blue and immunohistochemical staining were used to determine the effect of D1R activation on Dex-induced bone loss. RESULTS: We demonstrated that the trend in D1R but not D2-5R was consistent with that of osteogenic markers in the presence of Dex. We also demonstrated that the activation of D1R promoted Dex-induced osteogenic differentiation by activating the ERK1/2 pathway in vitro. We further demonstrated that a D1R agonist could reduce Dex-induced bone loss, while pretreatment with a D1R inhibitor blocked the effect of a D1R agonist in vivo. CONCLUSIONS: Activation of D1R promotes osteogenic differentiation and reduces Dex-induced bone loss by activating the ERK1/2 pathway. Hence, D1R could serve as a potential therapeutic target for glucocorticoid-induced osteoporosis.