The role of GPCRs in bone diseases and dysfunctions

Abstract

The superfamily of G protein-coupled receptors (GPCRs) contains immense structural and functional diversity and mediates a myriad of biological processes upon activation by various extracellular signals. Critical roles of GPCRs have been established in bone development, remodeling, and disease. Multiple human GPCR mutations impair bone development or metabolism, resulting in osteopathologies. Here we summarize the disease phenotypes and dysfunctions caused by GPCR gene mutations in humans as well as by deletion in animals. To date, 92 receptors (5 glutamate family, 67 rhodopsin family, 5 adhesion, 4 frizzled/taste2 family, 5 secretin family, and 6 other 7TM receptors) have been associated with bone diseases and dysfunctions (36 in humans and 72 in animals). By analyzing data from these 92 GPCRs, we found that mutation or deletion of different individual GPCRs could induce similar bone diseases or dysfunctions, and the same individual GPCR mutation or deletion could induce different bone diseases or dysfunctions in different populations or animal models. Data from human diseases or dysfunctions identified 19 genes whose mutation was associated with human BMD: 9 genes each for human height and osteoporosis; 4 genes each for human osteoarthritis (OA) and fracture risk; and 2 genes each for adolescent idiopathic scoliosis (AIS), periodontitis, osteosarcoma growth, and tooth development. Reports from gene knockout animals found 40 GPCRs whose deficiency reduced bone mass, while deficiency of 22 GPCRs increased bone mass and BMD; deficiency of 8 GPCRs reduced body length, while 5 mice had reduced femur size upon GPCR deletion. Furthermore, deficiency in 6 GPCRs induced osteoporosis; 4 induced osteoarthritis; 3 delayed fracture healing; 3 reduced arthritis severity; and reduced bone strength, increased bone strength, and increased cortical thickness were each observed in 2 GPCR-deficiency models. The ever-expanding number of GPCR mutation-associated diseases warrants accelerated molecular analysis, population studies, and investigation of phenotype correlation with SNPs to elucidate GPCR function in human diseases.

Agonism of GPR120 prevented IL-1β-induced reduction of extracellular matrix through SOX-9

“…For example, a 2019 review reported that there are presently 92 different GPCRs known to be involved in bone function and disease, including GPR120. This includes GPR120-mediated bone remodeling in OA [21,22]. Another study demonstrated the involvement of GPR120 activation in determining whether bone marrow mesenchymal stem cells differentiate into adipocytes or osteocytes [23].…”

Prioritization of osteoporosis-associated GWAS SNPs using epigenomics and transcriptomics

“…This gene encodes a cell membrane receptor that can regulate Wnt signaling and is implicated in both embryonic bone development and postnatal bone remodeling. (35) Rs10835153 and most of the other BMD-associated SNPs in this region were far downstream of LGR4 and closer to the littlestudied CCDC34 protein-encoding gene and to BBOX1-AS1 than to the LGR4 TSS ( Fig. 4C) but neither (36) for chromatin folding for the fetal lung fib cell line IMR-90; HMEC gave a similar profile (not shown).…”

F2r negatively regulates osteoclastogenesis through inhibiting the Akt and NFκB signaling pathways

“…Thrombin is the natural ligand of F2r [40,41]. Currently, GPCRs remain a major target for bone related diseases drug discovery [38,39,42,43]. F2r has been the object of large-scale drug development programs since the 1990s, and Vorapaxar and drotrecogin-α are approved F2rtargeted therapeutics [20].…”