The mechanosensitive adhesion G protein-coupled receptor GPR133/ADGRD1 enhances bone formation – a potential new target for osteoporosis treatment

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. Here, we describe the impact of the adhesion G protein-coupled receptor GPR133/ADGRD1 on osteoblast differentiation and function. Constitutive and osteoblast-specific knockouts of GPR133/ADGRD1 in mice result in reduced cortical bone mass and increased trabecularization in femurs and vertebrae—features characteristic of osteoporosis. Genome-wide association studies in humans link GPR133/ADGRD1 gene variants to differences in bone mineral density and body height. At the molecular level, GPR133/ADGRD1 influences osteoblast function and differentiation through a combined activation mechanism involving interaction with its endogenous ligand PTK7 and mechanical forces. In vitro analysis shows that osteoblast differentiation is driven by cAMP-dependent activation of the b-catenin signaling pathway. Activation of GPR133/ADGRD1 with the receptor-specific ligand 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. Comparative RNA-Seq profiling of wildtype and Gpr133/ADGRD1-deficient hearts from C57BL/6J mice. The embryonic stem cell line carrying the Adgrd1tm1a(EUCOMM)Wtsi allele was purchased from the European Conditional Mouse Mutagenesis Program (EUCOMM) and injected into 129/SV/J blastocysts. The chimeric mice were crossed with WT C57BL/6J mice for more than 12 generations to exclude potential strain-related effects.