Fatty acid sensing GPCR (GPR84) signaling safeguards cartilage homeostasis and protects against osteoarthritis. (February 2021)

• Record Type: Journal Article
• Authors: Wang, Fanhua; Ma, Lu; Ding, Yi; He, Liang; Chang, Mingzhi; Shan, Yingquan; Siwko, Stefan; Chen, Geng; Liu, Yuwei; Jin, Yunyun; Peng, Xiaochun; Luo, Jian
• Is Part Of: Pharmacological research. Volume 164(2021)
• Publication Date: 2021-02
• Subjects: ACAN Aggrecan -- Adamts5 a disintegrin and metalloproteinase with thrombospondin motifs -- ANOVA One way analysis of variation -- BMD bone mineral density -- BV/TV bone volume per tissue volume -- cDNA Complementary DNA -- Col2a1 collagen type II alpha 1 chain -- Col10a1 collagen type X alpha 1 chain -- DMM destabilization of the medial meniscus -- ECM extracellular matrix -- FBS fetal bovine serum -- FFA free fatty acid -- GADPH Glyceraldehyde 3-phosphate dehydrogenase -- GPCR G protein–coupled receptor -- GZ growth plate zone -- H&E hematoxylin and eosin -- HZ hypertrophic zones -- IHC immunohistochemistry -- IL-1 interleukin 1 -- IL-1β interleukin 1 beta -- IL-6 interleukin 6 -- MAPK mitogen-activated protein kinase -- Mmp3 matrix metalloproteinase 3 -- Mmp12 matrix metalloproteinase 12 -- Mmp13 matrix metalloproteinase 13 -- MCFA medium-chain fatty acid -- MFC medial femoral condyle -- MTP medial tibial plateau -- NF-κB nuclear factor-κB -- OA osteoarthritis -- OARSI Osteoarthritis Research Society International -- OSM oncostatin M -- Prg4 proteoglycan 4 -- PZ proliferating zone -- P1 Postnatal day 1 -- RZ resting zone -- RNAi RNA interfere -- RT-qPCR real-time quantitative PCR -- SBP subchondral bone plate -- siRNA small interfering RNA -- Sox9 SRY-box -- S.D standard deviation -- Tb.N trabecular number -- Tb.Th trabecular thickness -- Tb.Sp trabecular spacing -- TV total tissue volume -- WT wild-type -- 6-OAU 6-n-octylaminouracil; IL-1β (PubChem CID: 123872) -- Lauric acid (PubChem CID: 3893) -- 6-OAU (PubChem CID: 10354234); Fatty acid -- GPR84 -- Osteoarthritis -- Cartilage -- ECM -- Cartilage anabolism and catabolism; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105406
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: It is well known that free fatty acids (FFAs) have beneficial effects on the skeletal system, however, which fatty acid sensing GPCR(s) and how the GPCR(s) regulating cartilage development and osteoarthritis (OA) pathogenesis is largely unknown. In this study, we found Gpr84, a receptor for medium-chain FFAs (MCFA), was the only FFA-sensing GPCR in human and mouse chondrocytes that exhibited elevated expression when stimulated by interleukin (IL)-1β. Gpr84- deficiency upregulated cartilage catabolic regulator expression and downregulated anabolic factor expression in the IL-1β-induced cell model and the destabilization of the medial meniscus (DMM)-induced OA mouse model. Gpr84 −/− mice exhibited an aggravated OA phenotype characterized by severe cartilage degradation, osteophyte formation and subchondral bone sclerosis. Moreover, activating Gpr84 directly enhanced cartilage extracellular matrix (ECM) generation while knockout of Gpr84 suppressed ECM-related gene expression. Especially, the agonists of GPR84 protected human OA cartilage explants against degeneration by inducing cartilage anabolic factor expression. At the molecular level, GPR84 activation inhibited IL-1β-induced NF-κB signaling pathway. Furthermore, deletion of Gpr84 had little effect on articular and spine cartilaginous tissues during skeletal growth. Together, all of our results demonstrated that fatty acid sensing GPCR (Gpr84) signaling played a critical role in OA pathogenesis, and activation of GPR84 or MCFA supplementation has potential in preventing the pathogenesis and progression of OA without severe cartilaginous side effect.