Dopamine D1 Receptor Contributes to Glucocorticoid‐Associated Osteonecrosis of Femoral Head Protection Through the ATF3/CHOP Axis to Inhibit Osteoblastic Apoptosis

Abstract The nervous system plays a pivotal regulatory role in the maintenance of bone homeostasis, and the protective effects of dopamine and its receptors on bone metabolism are emerging. Despite these protective roles, the functional contribution of dopaminergic signaling, particularly through specific receptor subtypes, remains unexplored in glucocorticoid (GC)‐associated osteonecrosis of the femoral head (ONFH) pathogenesis. Here, the dopamine D1 receptor (DRD1), a G protein‐coupled receptor with few identified bone‐related functions, is identified as a positive regulator of GC‐induced apoptosis. The dopamine levels in the serum of GC‐associated ONFH patients are significantly lower than those in the normal population. The protein and gene expression levels of DRD1 and the number of DRD1‐positive cells are abnormally elevated in the pathological state of GC‐associated ONFH, and DRD1 is expressed in osteoblasts. Overexpression of DRD1 attenuates GC‐induced osteogenic inhibition and apoptosis in vivo and in vitro. Mechanistically, overexpression of DRD1 elevates cAMP levels, activates downstream protein kinase A, and inhibits GC‐induced endoplasmic reticulum stress and apoptosis through the ATF3/CHOP signaling pathway, thus improving bone homeostasis. Importantly, Madopar, an FDA‐approved dopaminergic agent, inhibits GC‐induced osteoblastic apoptosis and ONFH via DRD1. Collectively, this study not only deciphers a previously unrecognized DRD1‐mediated neuro‐osteogenic axis but also repurposes an FDA‐approved drug (Madopar) for precision ONFH management.