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 n...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 theβ-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.展开更多
基金the German Research Foundation through CRC1052,CRC1423 and FOR2149(project numbers 209933838,421152132 and 246212759,respectively)to I.Lsupported by the German Research Foundation(project number 455890087)+2 种基金supported by the New Cornerstone Science Foundation(J.-P.S.)supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project(2024ZD0523100 to J.-P.S.)National Natural Science Foundation of China(32361163612 to J.-P.S.).
文摘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 theβ-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.
