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The mechanosensitive adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) enhances bone formation

Juliane Lehmann¹, Hui Lin^2,3, 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

Abstract:

Osteoporosis represents an increasing health and socioeconomic burden on aging societies. Current therapeutic options often come with potentially severe side effects or lack long-term efficacy, highlighting the urgent need for more effective treatments. Identifying novel drug targets requires a thorough understanding of their physiological roles. Genome-wide association studies in humans have linked gene variants of the adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) to variations in bone mineral density and body height. In this study, we explore the impact of GPR133/ADGRD1 on osteoblast differentiation and function. Constitutive and osteoblast-specific knockouts of Gpr133/Adgrd1 in mice lead to reduced cortical bone mass and trabecularization in the femurs and vertebrae - features characteristic of osteoporosis. This osteopenic phenotype in receptor-deficient mice is caused by impaired osteoblast function, which, in turn, promotes increased osteoclast activity. At the molecular level, GPR133/ADGRD1 regulates osteoblast function and differentiation through a combined activation mechanism involving interaction with its endogenous ligand, protein tyrosine kinase 7 (PTK7), and mechanical forces. This is demonstrated in vitro through stretch assays and in vivo via a mechanical loading experiment. Further in vitro analysis shows that GPR133/ADGRD1-mediated osteoblast differentiation is driven by cAMP-dependent activation of the β-catenin signaling pathway. Activation of GPR133/ADGRD1 with the receptor-specific ligand AP-970/43482503 (AP503) enhances osteoblast function and differentiation, both in vitro and in vivo, significantly alleviating osteoporosis in a mouse ovariectomy model. These findings position GPR133/ADGRD1 as a promising therapeutic target for osteoporosis and other diseases characterized by reduced bone mass.

Insights

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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