This work is devoted to the investigation of biochemical mechanisms of cartilage remodeling in experimental osteoarthritis (ОА). We conducted a comprehensively evaluated gut microbiota status; histological changes in knee articular cartilages; changes of blood serum metabolic biochemical markers and expression of main genes responsible for cartilage matrix remodeling; biochemical markers and expression of genes responsible for the development of inflammatory responses, maintenance of prooxidant-antioxidant balance; and changes of signal transduction pathways in cartilage tissue in monoiodoacetate-induced experimental osteoarthritis upon the administration of chondroitin sulfate (CS) and probiotic (PB).
It was found that experimental OA causes dysbiosis of rat colon accompanied by degenerative and dystrophic changes in cartilage and subchondral bone of knee joints. We also registered the increase in blood levels of main biochemical markers of cartilage metabolism, which play an important role in cartilage degradation and remodeling: cartilage oligomeric matrix protein, aggrecan, cathepsin K, chitinase-3-like-protein-1 and matrix metalloproteinases-1, 2, 3, 8. At the same time, we detected changes in rat cartilage and blood serum under experimental OA: increased levels of prostaglandin E2; upregulation of Ptgs2 (cyclooxygenase-2), Nos2 (inducible nitric oxide synthase) and Tgfb1 (transforming growth factor beta 1), which are involved in the development of inflammatory responses; increased levels of catabolic pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8, IFN-γ) and TGF-β with simultaneous decrease in anabolic anti-inflammatory IL-4, IL-10 and IGF-1; intensification of free radical production: increase in the amount of superoxide anion, hydrogen peroxide and products of lipid and protein oxidation; antioxidative defense disorders: increased activity of superoxide dismutase and catalase with elevated levels of oxidized glutathione, simultaneous downregulation of glutathione peroxidase, glutathione transferase and glutathione reductase combined with decrease in reduced glutathione, which was interpreted as both systemic and local inflammation and oxidative stress. We also detected downregulation of main cartilage matrix genes Col2a1, Acan, Comp, and upregulation of Tlr2, Tlr4, Nfkb1 involved in signaling, in the cartilage of rats upon the experimental OA.
Administration of CS and PB to the experimental animals with induced OA resulted in correction of colon microbiota; partial recovery of morphological and functional state of joints, structural elements of cartilage matrix, biochemical markers of cartilage metabolism and inflammation, prooxidant-antioxidant homeostasis. Colon microbiota appeared to participate in biochemical mechanisms of articular cartilage remodeling in experimental OA model through TLR-2/4-mediated NF-κB inflammatory pathway. We found that chondroitin sulfate and probiotic show anti-inflammatory, anti-oxidative and pro-regenerative activity both through the normalization of gut microbiota and the activation of cartilage anabolism in rats upon monoiodoacetate-induced experimental osteoarthritis.
The results of our experimental study are summarized in a conceptual framework describing the role of gut microbiota in biochemical regulation of articular cartilage remodeling upon the experimental osteoarthritis.
