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

Liang He1, Qiansen Zhang2, Yu You1

  • 1Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, PR. China.

Science Advances
|July 11, 2025
PubMed

Insights

Researchers identified GL64, a novel agonist for adhesion G protein-coupled receptor D1 (ADGRD1). This discovery reveals ADGRD1

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cell Biology

Background:

  • Adhesion G protein-coupled receptors (GPCRs) are vital in health and disease.
  • Understanding adhesion GPCR functions is limited by a lack of specific modulators.

Purpose of the Study:

  • To develop a strategy for identifying exogenous agonists targeting adhesion GPCRs.
  • To explore the functions of adhesion GPCR D1 (ADGRD1/GPR133).

Main Methods:

  • Small molecule screening to identify ADGRD1 agonists.
  • Utilizing the identified agonist (GL64) as a chemical probe.
  • Investigating ADGRD1's role in osteoclastogenesis and bone loss using cellular and mouse models.

Main Results:

  • GL64 was identified as a selective agonist for ADGRD1, mimicking the stachel sequence.
  • ADGRD1 was found to negatively regulate bone loss by inhibiting osteoclastogenesis via the cAMP-PKA-NFATC1 pathway.
  • GL64 administration in an osteoporosis mouse model prevented bone loss and reduced osteoclast activity.

Conclusions:

  • A novel strategy for activating adhesion GPCRs with exogenous agonists was established.
  • ADGRD1 plays a significant role in regulating bone metabolism.
  • Targeting ADGRD1 presents therapeutic potential for osteoclast-related diseases like osteoporosis.

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