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The mechanosensitive adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) enhances bone formation
Juliane Lehmann1, Hui Lin2,3, Zihao Zhang4
1Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany. juliane.lehmann@medizin.uni-leipzig.de.
Signal Transduction and Targeted Therapy
|June 29, 2025
Summary
Adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) is crucial for bone health. Targeting GPR133/ADGRD1 with AP503 shows promise for treating osteoporosis by enhancing osteoblast function.
Area of Science:
- Bone Biology and Endocrinology
- Cellular and Molecular Medicine
- Pharmacology and Drug Discovery
Background:
- Osteoporosis poses a significant health burden, necessitating novel therapeutic strategies.
- Existing osteoporosis treatments have limitations, increasing the demand for effective alternatives.
- Genome-wide association studies suggest a link between GPR133/ADGRD1 gene variants and bone mineral density.
Purpose of the Study:
- To investigate the role of GPR133/ADGRD1 in osteoblast differentiation and function.
- To elucidate the molecular mechanisms underlying GPR133/ADGRD1's regulation of bone metabolism.
- To evaluate the therapeutic potential of targeting GPR133/ADGRD1 for osteoporosis treatment.
Main Methods:
- Generation of constitutive and osteoblast-specific Gpr133/Adgrd1 knockout mice.
- In vitro and in vivo experiments assessing osteoblast function and differentiation under mechanical stimulation.
- Analysis of signaling pathways, including cAMP and β-catenin, involved in GPR133/ADGRD1 activation.
- Pharmacological intervention using GPR133/ADGRD1-specific ligand AP503 in an ovariectomy-induced osteoporosis mouse model.
Main Results:
- Gpr133/Adgrd1 deficiency in mice resulted in reduced bone mass and osteopenic phenotypes.
- Impaired osteoblast function and increased osteoclast activity were observed in receptor-deficient mice.
- GPR133/ADGRD1 regulates osteoblast function via interaction with PTK7 and mechanical forces, activating the cAMP/β-catenin pathway.
- Treatment with AP503 significantly improved bone mass and alleviated osteoporosis in a mouse model.
Conclusions:
- GPR133/ADGRD1 plays a critical role in maintaining bone homeostasis by regulating osteoblast function.
- The GPR133/ADGRD1-PTK7-mechanical force axis is a key regulator of osteoblast differentiation.
- Targeting GPR133/ADGRD1 with agonists like AP503 represents a promising therapeutic strategy for osteoporosis.
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