Down-regulation of protease-activated receptor 2 ameliorated osteoarthritis in rats through regulation of MAPK/NF-κB signaling pathwayin vivoandin vitro

Abstract

Recently, protease-activated receptor 2 (PAR2) has been proved to be involved in the inflammatory response including osteoarthritis (OA). In the present study, we found that PAR2 antagonist could remarkably improve the pathological condition of OA rats in vivo. In addition, we also found that PAR2 antagonist could suppress the production of inflammatory factors (TNF-α and Cox-2), decrease the levels of MMP-1 and MMP-13, and restrain the levels of P62 proteins and aggravate the expression of LC3-II both in vivo and in vitro. Besides, in vitro, PAR2 antagonist could increase the proliferation and colony formation of chondrocytes induced with IL-1β. Moreover, PAR2 antagonist could decrease the expression of expressions of p-p38, p-IκBα and p-NF-κB in vitro. However, PAR2 agonist exhibited the opposite effects. Furthermore, SB203580, a p38 MAPK inhibitor, could remarkably promote the proliferation of chondrocytes induced with IL-1β, could alleviate the production of TNF-α and Cox-2, could down-regulate the protein expressions of MMP-1 and MMP-13, and could decrease the expression of P62 and increase the expressions of LC3-II of chondrocytes induced with IL-1β. Importantly, SB203580 could reverse the effects of PAR2 agonist on the functions of chondrocytes induced with IL-1β. Taken together, the present data suggest that down-regulation of PAR2 can ameliorate OA through inducing autophagy via regulation of MAPK/NF-κB signaling pathway in vivo and in vitro, and PAR2 can be considered as a potential candidate to treat OA.

Protease Activated Receptors and Arthritis

“…Measured levels of PAR-2 correlated with the severity of the synovitis, suggesting that PAR-2 is relevant in joint disease where there is ongoing inflammation. In other experiments, blocking PAR-2 reduced pannus invasion and proliferation, decreased the release of IL-17, IL-1β, and TNF-α, and ameliorated signs of OA via regulation of the MAPK/NF-kB pathway [50,98,99].…”

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

“…The results above suggest that PAR-2 plays a vital role in the occurrence and progression of OA. Therefore, the PAR-2 antagonist AZ3451 inhibits chondrocyte apoptosis to improve OA by activating chondrocyte autophagy by regulating the P38/MAPK, NF-κB, and PI3K/AKT/mTOR signaling pathways ( Huang et al, 2019 ; Yan et al, 2020 ).…”

“…Destruction or mutation of GPCRs can lead to bone and joint dysfunction or diseases in humans, and most of these phenotypes have been validated in mouse models ( Luo et al, 2019 ). Furthermore, emerging evidence has shown that GPCRs regulate the progression of OA by modulating cartilage matrix degradation, synovial inflammation, subchondral bone remodeling, osteophyte formation, chondrocyte hypertrophy, cartilage angiogenesis, and chondrocyte apoptosis ( Jones et al, 2006 ; Yan et al, 2020 ; Mlost et al, 2021 ; Wang et al, 2021 ). However, the detailed mechanisms underlying the regulatory responses remain unclear.…”

The Activation Fragment of PAR2 Is Increased in RA and Modulated in Response To Anti-IL-6R Treatment

“…Other studies have investigated the effect of PAR2 antagonists in a pre-clinical aspect and showed that PAR2 blockage reduced disease progression and improved synovitis in adjuvant-induced monoarthritic mice models 21 . In addition to that, Yan et al found that down-regulation of PAR2 could ameliorate OA through suppressing the release of in ammatory factors and proteases and promoting chondrocytes proliferation via regulation of MAPK/NF-κB signaling 22 . Furthermore, apart from PAR2 contribution to synovitis and cartilage destruction, a mice study from 2015 has been clearly shown that PAR2 contributes to osteophyte formation via its presence in proliferative and hypertrophic chondrocytes 23 .…”