Published June 6, 2025 | Version v2
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The mechanosensitive adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) enhances bone formation

Creators

  • 1. Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany
  • 2. Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
  • 3. Institute of Anatomy, Medical Faculty, Leipzig University, Leipzig, Germany
  • 4. Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
  • 5. Institute for Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany
  • 6. Department of Pediatric Radiology, University of Leipzig, Leipzig, Germany
  • 7. Soft Matter Physics Division, Peter Debye Institute for Soft Matter Physics, University of Leipzig, Leipzig, Germany
  • 8. Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.

Description

Osteoporosis poses an increasing health and socioeconomic burden on aging societies. Current therapeutic options often present potentially severe side effects or lack long-term efficacy, underscoring the need for more effective treatments. Establishing novel drug targets requires an in-depth understanding of their physiological roles. Genome-wide association studies in humans link gene variants of the adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) to differences in bone mineral density and body height. Here, we describe the impact of GPR133/ADGRD1 on osteoblast differentiation and function. Constitutive and osteoblast-specific knockouts of Gpr133/Adgrd1 in mice result in reduced cortical bone mass and trabecularization in femurs and vertebrae—features characteristic of osteoporosis. This osteopenic phenotype in receptor-deficient mice is caused by suppressed osteoblast function, which allows for an increase in osteoclast activity. At the molecular level, GPR133/ADGRD1 influences osteoblast function and differentiation through a combined activation mechanism involving interaction with its endogenous ligand Tyrosine-protein kinase-like 7 (PTK7) and mechanical forces, which is shown in vitro through stretch assays and in vivo employing a mechanical loading experiment. In vitro analysis further shows that GPR133/ADGRD1-mediated osteoblast differentiation is driven by cAMP-dependent activation of the b-catenin signaling pathway. Activation of GPR133/ADGRD1 with the receptor-specific ligand AP-970/43482503 (AP503) promotes osteoblast function and differentiation both in vitro and in vivo, significantly alleviating osteoporosis in a mouse ovariectomy model. This renders GPR133/ADGRD1 a promising therapeutic target for osteoporosis and other diseases characterized by reduced bone mass.

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