Anti-inflammatory and osteoprotective effects of Shi-Wei-Ru-Xiang pills on collagen-induced arthritis in rats via inhibiting MAPK and STAT3 pathways

ETHNOPHARMACOLOGICAL RELEVANCEShi-Wei-Ru-Xiang pills (SW) as a tradition Tibetan medicine has been clinically proved effective in rheumatoid arthritis (RA) treatment. However, the underlying mechanism of SW remains unclear. AIM OF THE STUDYThis study aimed to investigate the anti-arthritic effect of SW and its possible mechanisms of action. MATERIALS AND METHODSA CIA rat model in vivo, and IL-1β-stimulated synoviocytes or chondrocytes and a co-culture system (IL-1β-stimulated synoviocytes/chondrocytes) in vitro were used to evaluate the effects of SW on the treatment of RA. Arthritic score, paw swelling rate, hematoxylin-eosin (HE) staining, and Safranin-O-Fast green (S-O) staining were used to evaluate the anti-arthritic activity of SW in CIA rats. TUNEL assay or flow cytometry were performed to measure chondrocytes apoptosis in vivo and invitro. The effects of SW on the expression and production of pro-inflammatory cytokines were assessed by qRT-PCR and Elisa. The inhibitory effects of SW on the phosphorylation of p38, Erk1/2, and STAT3 were analyzed by Western blot. RESULTSSW treatment significantly alleviated paw swelling, severity of arthritic and cartilage destruction in CIA rats. Moreover, SW decreased the expression of mRNAs of proinflammatory cytokines including TNF-α, IL-1β and IL-6 in the synovium, suppressed the production of these pro-inflammatory cytokines in serum and hind paws, downregulated the protein expression of p-p38, p-Erk1/2 and p-STAT3, and protected the chondrocytes apoptosis in CIA rats. Consistent with the results in vivo, SW also inhibited the activation of MAPK and STAT3 pathways, suppressed the expression of pro-inflammatory cytokines in IL-1β-stimulated synoviocytes, and attenuated chondrocytes apoptosis in IL-1β-stimulated chondrocytes. In the co-culture system, SW pre-treatment in IL-1β-stimulated synoviocytes exhibited inhibition of chondrocytes apoptosis, which was associated with attenuation of inflammation in synoviocytes. CONCLUSIONThese results suggested that the underlying mechanisms by which SW exerts its anti-arthritis effect may be related to the reduction of proinflammatory cytokine levels, inhibition of p38, Erk1/2 and STAT3 phosphorylation, and attenuating of chondrocyte apoptosis.