He Liang, Zhang Qiansen, You Yu, Sun Peng, Xu Ziwei, Li Rong, Wang Fanhua, Zhang Shaoying, He Jiangnan, Shen Juwen, Zhao Lei, Hong Yang, Li Yinghua, Liu Mingyao, Sun Jin-Peng, Wang Ning, Sun Yeqing, Yang Huaiyu, Luo Jian
Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, PR. China.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR. China.
Sci Adv. 2025 Jul 11;11(28):eads3829. doi: 10.1126/sciadv.ads3829.
Adhesion G protein-coupled receptors (GPCRs) play crucial roles in numerous physiological and pathological conditions. However, the functions of adhesion GPCRs remain poorly understood because of the lack of effective modulators. Here, we used the adhesion GPCR D1 (ADGRD1/GPR133) as a model to unveil a strategy for finding exogenous agonists that target adhesion GPCRs while revealing previously unidentified functions of ADGRD1. We identified the small molecule GL64 as a selective agonist of ADGRD1. GL64 activates ADGRD1 by mimicking the sequence. Using GL64 as a chemical tool, we demonstrated that ADGRD1 negatively regulates bone loss by inhibiting osteoclastogenesis. The cAMP-PKA-NFATC1 pathway was identified as the downstream signaling pathway of ADGRD1 in osteoclasts. Furthermore, administering GL64 prevented bone loss and suppressed osteoclast activity in the osteoporosis mouse model induced by ovariectomy. Our findings provide mechanistic insights into the activation of adhesion GPCRs by exogenous agonists and underscore the therapeutic potential of targeting ADGRD1 in osteoclast-related diseases.
粘附G蛋白偶联受体（GPCRs）在众多生理和病理状况中发挥着关键作用。然而，由于缺乏有效的调节剂，粘附GPCRs的功能仍知之甚少。在此，我们以粘附GPCR D1（ADGRD1/GPR133）为模型，揭示一种寻找靶向粘附GPCRs的外源性激动剂的策略，同时揭示ADGRD1此前未被发现的功能。我们鉴定出小分子GL64为ADGRD1的选择性激动剂。GL64通过模拟序列激活ADGRD1。使用GL64作为化学工具，我们证明ADGRD1通过抑制破骨细胞生成来负向调节骨质流失。cAMP-PKA-NFATC1途径被确定为破骨细胞中ADGRD1的下游信号通路。此外，在卵巢切除诱导的骨质疏松小鼠模型中，给予GL64可预防骨质流失并抑制破骨细胞活性。我们的研究结果为外源性激动剂激活粘附GPCRs提供了机制性见解，并强调了在破骨细胞相关疾病中靶向ADGRD1的治疗潜力。
