Isoprenaline and salbutamol inhibit pyroptosis and promote mitochondrial biogenesis in arthritic chondrocytes by downregulating β-arrestin and GRK2.

Rheumatoid arthritis and osteoarthritis overlap many molecular mechanisms of cartilage destruction. Wear and tear in cartilage is chondrocyte-mediated, where chondrocytes act both as effector and target cells. In current study, role ofβ2-AR was studied in chondrocytes both in vitro and in vivo. High grade inflammation in vitro and in vivo diseasemodels led to decline in anti-inflammatoryβ2-AR signaling and use of ß2-AR agonist attenuated arthritis symptoms. Detailed analysis in chondrocytes revealed that Isoprenaline (ISO) and Salbutamol (SBT) increased cell viability and relative Bcl-2 expression, meanwhile, decreased proteins levels of TNF-a, IL-6andIL-8 in arthritic chondrocytes when compared with control, respectively. SBT preserved physiological concentration of antioxidant enzymes (CAT, POD, SOD and GSH) in cartilage homogenates and ISO inhibited IL-1ß-mediated genotoxicity in arthritic chondrocytes. Moreover, β2-AR agonist increased mitochondrial biogenesis and proteoglycan biosynthesis by upregulating the gene expression of PGC1-a, NRF2 and COL2A1, Acan, respectively. ISO and SBT inhibited extracellular matrix (ECM) degradation by downregulating the gene expression of MMP1, MMP3, MMP9 and ADAMTS5 in vitro and in vivo study. In mechanism, β2-AR agonists decreasedβ-arrestin and GRK2 pathway, and as a resultmice receiving SBT did not exhibit severe disease. Hence our data suggestβ2-AR agonist administered at disease onset can inhibit receptor internalization by downregulating the expression ofβ-arrestin and GRK2 in chondrocytes. [ABSTRACT FROM AUTHOR]