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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE298885 | GEO | 2025/06/04

REPOSITORIES: GEO

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Project description:This a model from the article: Mathematical model of paracrine interactions between osteoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone. Komarova SV. Endocrinology.2005 Aug;146(8):3589-95. 15860557, Abstract: To restore falling plasma calcium levels, PTH promotes calcium liberation from bone. PTH targets bone-forming cells, osteoblasts, to increase expression of the cytokine receptor activator of nuclear factor kappaB ligand (RANKL), which then stimulates osteoclastic bone resorption. Intriguingly, whereas continuous administration of PTH decreases bone mass, intermittent PTH has an anabolic effect on bone, which was proposed to arise from direct effects of PTH on osteoblastic bone formation. However, antiresorptive therapies impair the ability of PTH to increase bone mass, indicating a complex role for osteoclasts in the process. We developed a mathematical model that describes the actions of PTH at a single site of bone remodeling, where osteoclasts and osteoblasts are regulated by local autocrine and paracrine factors. It was assumed that PTH acts only to increase the production of RANKL by osteoblasts. As a result, PTH stimulated osteoclasts upon application, followed by compensatory osteoblast activation due to the coupling of osteoblasts to osteoclasts through local paracrine factors. Continuous PTH administration resulted in net bone loss, because bone resorption preceded bone formation at all times. In contrast, over a wide range of model parameters, short application of PTH resulted in a net increase in bone mass, because osteoclasts were rapidly removed upon PTH withdrawal, enabling osteoblasts to rebuild the bone. In excellent agreement with experimental findings, increase in the rate of osteoclast death abolished the anabolic effect of PTH on bone. This study presents an original concept for the regulation of bone remodeling by PTH, currently the only approved anabolic treatment for osteoporosis. The model reproduces Figures 1B and 2A of the reference publication. To obtain the figures 1B, the parameter g21 needs changes. To obtain the figures 1A, the parameters g21, g12 and k2 need to changed. For details look at the curation tab. The initial concentration of Osteoclasts (x1) is corrected to 1.06066 from 10.06066. This model was taken from the CellML repository and automatically converted to SBML. The original model was: CellMLdetails The original CellML model was created by: Lloyd, Catherine, May c.lloyd@auckland.ac.nz The University of Auckland The Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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

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