The role of GPCRs in bone diseases and dysfunctions

Luo, Jian; Sun, Ping; Siwko, Stefan; Liu, Mingyao; Xiao, Jianru

doi:10.1038/s41413-019-0059-6

Cited by 73 publications

(64 citation statements)

References 374 publications

(426 reference statements)

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

et al. 2020

Aging

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Osteoarthritis (OA) is a whole-joint disease with extremely high prevalence. In all treatment approaches of OA, blocking the degradation of the cartilage extracellular matrix is an important treatment. In OA, overexpression of derivative enzymes leads to excessive catabolism and reduced synthesis of cartilage including type II collagen and aggrecan, which results in irreversible destruction of the joint. SOX9 is a transcription factor that regulates the synthesis of type II collagen and aggrecan and is significantly downregulated in OA. GPR120 has been reported to affect the pathophysiology of OA. In this study, we used the GPR120 agonist GW9508 and TUG891 in ATDC5 chondrocytes exposed to interleukin (IL)-1β to investigate the involvement of GPR120 in SOX9mediated expression of type II collagen and aggrecan. Our findings show that agonism of GPR120 can reduce inflammation by inhibiting the expression of IL-6 and IL-8 induced by IL-1β. We also show that GW9508 and TUG891 rescue the expression of type II collagen and aggrecan by preventing the reduction of SOX9 expression. Additionally, we demonstrate that the effects of GW9508 on SOX9 expression are mediated through CREB and that GPR120 is indeed required for this effect. Thus, agonism of GPR120 by GW9508 might be a potential therapeutic strategy to halt or prevent cartilage degradation.

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Section: Discussionmentioning

confidence: 99%

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

Zhang

et al. 2020

Aging

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“…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).…”

Section: Npr3 Has Two Intergenic Bmd-risk Tier-1 Snps Upstream Of a Nmentioning

confidence: 83%

Prioritization of osteoporosis-associated GWAS SNPs using epigenomics and transcriptomics

Zhang

Deng

Shen

et al. 2020

Preprint

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Genetic risk factors for osteoporosis, a prevalent disease associated with aging, have been examined in many genome-wide association studies (GWAS). A major challenge is to prioritize transcription-regulatory GWAS-derived variants that are likely to be functional. Given the critical role of epigenetics in gene regulation, we have used an unusual epigenetics-and transcription-based approach to identify credible regulatory SNPs relevant to osteoporosis from 38 reported BMD GWAS. Using Roadmap databases, we prioritized SNPs based upon their overlap with strong enhancer or promoter chromatin preferentially in osteoblasts relative to 11 heterologous cell culture types. The selected SNPs also had to overlap open chromatin (DNaseI-hypersensitive sites) and DNA sequences predicted to bind to osteoblast-relevant transcription factors in an allele-specific manner. From >50,000 GWAS-derived SNPs, we identified 16 novel and credible regulatory SNPs (Tier-1 SNPs) for osteoporosis risk. Their associated genes, BICC1, LGR4, DAAM2, NPR3, or HMGA2, are involved in osteoblastogenesis or bone homeostasis and regulate cell signaling or enhancer function. Four of them are preferentially expressed in osteoblasts. BICC1, LGR4, and DAAM2 play important roles in canonical Wnt signaling, a pathway critical to bone formation and repair. The transcription factors that are predicted to bind to the Tier-1 SNP-containing DNA sequences also have bone-related functions. For the seven Tier-1 SNPs near the 5' end of BICC1, examination of eQTL overlap and the distribution of BMD-increasing alleles suggests that at least one SNP in each of two clusters contributes to inherited osteoporosis risk. Our study not only illustrates a method that can be used to identify novel BMD-related causal regulatory SNPs for future study, but also reveals evidence that some of the Tier-1 SNPs exert their effects on BMD risk indirectly through little-studied noncoding RNA genes, which in turn may control the nearby bone-related proteinencoding gene.

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Zhang¹,

Wang²,

Zhu³

et al. 2020

Int. J. Biol. Sci.

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G-protein-coupled receptors (GPCRs) are pivotal drug targets for many diseases. Coagulation Factor II Thrombin Receptor (F2R) is an important member of GPCR family that is highly expressed in osteoclasts. However, the role of F2r in osteoclasts is still unclear. Here, to examine the functions of F2r on osteoclast formation, differentiation, activation, survival, and acidification, we employed loss-of-function and gain-of-function approaches to study F2r using F2r-targeted short hairpin RNA (sh-F2r) lentivirus and overexpression plasmid pLX304-F2r lentivirus respectively, in mouse bone marrow cells (MBMs) induced osteoclasts. We used three shRNAs targeting F2r which had the ability to efficiently and consistently knock down the expression of F2r at different levels. Notably, F2r knockdown trigged a significant increase in osteoclast activity, number, and size, as well as promoted bone resorption and F-actin ring formation with increased osteoclast marker gene expression. Moreover, F2r overexpression blocked osteoclast formation, maturation, and acidification, indicating that F2r negatively regulates osteoclast formation and function. Furthermore, we investigated the mechanism(s) underlying the role of F2r in osteoclasts. We detected RANKL-induced signaling pathways related protein changes F2r knockdown cells and found significantly increased pAkt levels in sh-F2r infected cells, as well as significantly enhanced phosphorylation of p65 and IKBα in early stages of RANKL stimulation. These data demonstrated that F2r responds to RANKL stimulation to attenuate osteoclastogenesis through inhibiting the both F2r-Akt and F2r-NFκB signaling pathways, which lead a reduction in the expression of osteoclast genes. Our study suggests that targeting F2r may be a novel therapeutic approach for bone diseases, such as osteoporosis.

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The role of GPCRs in bone diseases and dysfunctions

Cited by 73 publications

References 374 publications

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

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

Prioritization of osteoporosis-associated GWAS SNPs using epigenomics and transcriptomics

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

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