2. Academic Validation
  3. Exogenous activation of the adhesion GPCR ADGRD1/GPR133 protects against bone loss by negatively regulating osteoclastogenesis

Exogenous activation of the adhesion GPCR ADGRD1/GPR133 protects against bone loss by negatively regulating osteoclastogenesis

  • Sci Adv. 2025 Jul 11;11(28):eads3829. doi: 10.1126/sciadv.ads3829.
Liang He 1,  Qiansen Zhang 2,  Yu You 1,  Peng Sun 3,  Ziwei Xu 2,  Rong Li 1,  Fanhua Wang 1,  Shaoying Zhang 2,  Jiangnan He 2,  Juwen Shen 2,  Lei Zhao 1,  Yang Hong 4,  Yinghua Li 4,  Mingyao Liu 2,  Jin-Peng Sun 5 6,  Ning Wang 7 8,  Yeqing Sun 1,  Huaiyu Yang 2,  Jian Luo 1
Affiliations

Affiliations

  • 1 Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, PR. China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR. China.
  • 3 Key Laboratory of Adolescent Health Assessment and Exercise Intervention of the Ministry of Education, East China Normal University, Shanghai, P. R. China.
  • 4 Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, P. R. China.
  • 5 Advanced Medical Research Institute, Cheeloo College of Medicine, NHC Key Laboratory of Otorhinolaryngology, the Laboratory of New Cornerstone Investigator, Shandong University, Jinan, China.
  • 6 Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, China.
  • 7 Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
  • 8 The Mellanby Centre for Musculoskeletal Research, Division of Clinical Medicine, University of Sheffield, Sheffield, UK.
PMID: 40644539 DOI: 10.1126/sciadv.ads3829
Abstract

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 stachel 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.

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