G Protein-Coupled Receptors in Osteoarthritis: A Novel Perspective on Pathogenesis and Treatment

Abstract

G protein-coupled receptors (GPCRs) are transmembrane receptor proteins that trigger numerous intracellular signaling pathways in response to the extracellular stimuli. The GPCRs superfamily contains enormous structural and functional diversity and mediates extensive biological processes. Until now, critical roles have been established in many diseases, including osteoarthritis (OA). Existing studies have shown that GPCRs play an important role in some OA-related pathogenesis, such as cartilage matrix degradation, synovitis, subchondral bone remodeling, and osteophyte formation. However, current pharmacological treatments are mostly symptomatic and there is a paucity of disease-modifying OA drugs so far. Targeting GPCRs is capable of inhibiting cartilage matrix degradation and synovitis and up-regulating cartilage matrix synthesis, providing a new therapeutic strategy for OA. In this review, we have comprehensively summarized the structures, biofunctions, and the novel roles of GPCRs in the pathogenesis and treatment of OA, which is expected to lay the foundation for the development of novel therapeutics against OA. Even though targeting GPCRs may ameliorate OA progression, many GPCRs-related therapeutic strategies are still in the pre-clinical stage and require further investigation.

Identification and validation of immune-related genes in osteoarthritic synovial fibroblasts

“…Closely connected cytokine clusters in the OA-PPI network were identified using MCODE cluster analysis. We identified nine terms that were highly correlated with inflammatory signaling pathways, cell adhesion, and signal transduction, including the terms “G proton-coupled peptide receptor activity,” “PI3K-Akt signaling pathway,” and “ionotropic glutamate receiver complex.” G-protein-coupled receptors—transmembrane receptors that play pivotal roles in inflammation and immune responses [ 30 ], including in RA and OA—are involved in various OA pathologies, such as cartilage matrix degradation, synovitis, subchondral bone remodeling, and osteophyte formation [ 31 , 32 ]. Inhibition of G protein binding suppresses collagen-induced arthritis by reducing CD4+T cell productions [ 33 ].…”

CC chemokines and receptors in osteoarthritis: new insights and potential targets

“…The combination of CCLs and CCRs led to phenotypic changes through the biochemical cascades of G protein-coupled receptors [ 52 ], and this process, by negative feedback, formed a complex regulatory network. The nuclear factor-kappa B (NF-κB) signaling pathway regulated several CC chemokine family members, including CCL2, CCL4, CCL18, and CCL20 [ 53 – 55 ].…”