The Role of Innate Immunity in Osteoarthritis and the Connotation of "Immune-joint" Axis: A Narrative Review.

Osteoarthritis (OA) is a degenerative disease that results in constriction of the joint space due to the gradual deterioration of cartilage, alterations in subchondral bone, and synovial membrane. Recently, scientists have found that OA involves lesions in the whole joint, in addition to joint wear and tear and cartilage damage. Osteoarthritis is often accompanied by a subclinical form of synovitis, which is a chronic, relatively low-grade inflammatory response mainly mediated by the innate immune system. The "immune-joint" axis refers to an interaction of an innate immune response with joint inflammation and the whole joint range. Previous studies have underestimated the role of the immune-joint axis in OA, and there is no related research. For this reason, this review aimed to evaluate the existing evidence on the influence of innate immune mechanisms on the pathogenesis of OA. The innate immune system is the body's first line of defense. When the innate immune system is triggered, it instantly activates the downstream inflammatory signal pathway, causing an inflammatory response, while also promoting immune cells to invade joint synovial tissue and accelerate the progression of OA. We have proposed the concept of the "immune-joint" axis and explored it from two aspects of Traditional Chinese Medicine (TCM) theory and modern medical research, such as the innate immunity and OA, macrophages and OA, complement and OA, and other cells and OA, to enrich the scientific connotation of the "immune-joint" axis.

Prebiotics alleviate cartilage degradation and inflammation in post-traumatic osteoarthritic mice by modulating the gut barrier and fecal metabolomics.

Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degeneration, subchondral bone sclerosis, synovial hyperplasia and inflammation as the main pathological manifestations. This study aims to investigate the protective effect of prebiotics in post-traumatic osteoarthritic (PTOA) mice by modulating the gut barrier and fecal metabolomics. The results suggested that cartilage degeneration, osteophyte formation and inflammation were significantly reduced by prebiotics in PTOA mice. In addition, the gut barrier was protected by the increased expression of tight junction proteins ZO-1 and occludin in the colon. High-throughput sequencing found that 220 fecal metabolites were affected by joint trauma, 81 of which were significantly recovered after probiotic intervention, and some metabolites (valerylcarnitine, adrenic acid, oxoglutaric acid, etc.) were closely associated with PTOA. Our study demonstrates that prebiotics can delay the progression of PTOA by regulating the metabolites of the gut microbiota and protecting the gut barrier, which is expected to be an intervention method for PTOA.

Zhuifeng tougu capsules inhibit the TLR4/MyD88/NF-κB signaling pathway and alleviate knee osteoarthritis: In vitro and in vivo experiments.

Background: Knee osteoarthritis (KOA), a chronic degenerative disease, is mainly characterized by destruction of articular cartilage and inflammatory reactions. At present, there is a lack of economical and effective clinical treatment. Zhuifeng Tougu (ZFTG) capsules have been clinically approved for treatment of OA as they relieve joint pain and inflammatory manifestations. However, the mechanism of ZFTG in KOA remains unknown. Purpose: This study aimed to investigate the effect of ZFTG on the TLR4/MyD88/NF-κB signaling pathway and its therapeutic effect on rabbits with KOA. Study design: In vivo, we established a rabbit KOA model using the modified Videman method. In vitro, we treated chondrocytes with IL-1ß to induce a pro-inflammatory phenotype and then intervened with different concentrations of ZFTG. Levels of IL-1ß, IL-6, TNF-α, and IFN-γ were assessed with histological observations and ELISA data. The effect of ZFTG on the viability of chondrocytes was detected using a Cell Counting Kit-8 and flow cytometry. The protein and mRNA expressions of TLR2, TLR4, MyD88, and NF-κB were detected using Western blot and RT-qPCR and immunofluorescence observation of NF-κB p65 protein expression, respectively, to investigate the mechanism of ZFTG in inhibiting inflammatory injury of rabbit articular chondrocytes and alleviating cartilage degeneration. Results: The TLR4/MyD88/NF-κB signaling pathway in rabbits with KOA was inhibited, and the levels of IL-1ß, IL-6, TNF-α, and IFN-γ in blood and cell were significantly downregulated, consistent with histological results. Both the protein and mRNA expressions of TLR2, TLR4, MyD88, NF-κB, and NF-κB p65 proteins in that nucleus decreased in the ZFTG groups. Moreover, ZFTG promotes the survival of chondrocytes and inhibits the apoptosis of inflammatory chondrocytes. Conclusion: ZFTG alleviates the degeneration of rabbit knee joint cartilage, inhibits the apoptosis of inflammatory chondrocytes, and promotes the survival of chondrocytes. The underlying mechanism may be inhibition of the TLR4/MyD88/NF-kB signaling pathway and secretion of inflammatory factors.

Nodakenin attenuates cartilage degradation and inflammatory responses in a mice model of knee osteoarthritis by regulating mitochondrial Drp1/ROS/NLRP3 axis.

Osteoarthritis (OA) is a common degenerative disease with few treatments. In traditional Chinese medicine (TCM), Radix Angelicae biseratae (RAB) is commonly used to treat OA. Nodakenin (Nod) is one main coumarin active component in RAB and exhibits anti-inflammatory, anti-oxidative, and anti-apoptotic effects. Reactive oxygen species (ROS) produced by mitochondria play a vital role in the pathogenesis of OA. We hypothesized that Nod might ameliorate cartilage degradation and inflammatory responses by regulating the mitochondrial Drp1/ROS/NLRP3 axis. With this, the effects of Nod on a mouse model of knee OA and activated primary chondrocytes were assessed. The results showed that Nod intervention improved bone volume, lowered trabecular separation, and increased trabecular number in the subchondral bone. Nod decreased the Osteoarthritis Research Society International (OARSI) scores and increased collagen II-positive areas in the articular cartilage of the tibial plateau. Compared with OA mice, Nod-treated animals exhibited lower levels of inflammatory factors in the serum and synovitis of the knee joint. In vitro results indicated that Nod suppressed dynamin-related protein 1 (Drp1) phosphorylation and massive ROS production by Drp1-dependent mitochondrial fission in lipopolysaccharide-stimulated chondrocytes. Moreover, Nod inhibited the mRNA levels of inflammatory cytokines (COX 2, IL-1ß, and TNF-α), nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, and matrix metalloproteinase 13 expression in activated chondrocytes. In conclusion, Nod attenuates cartilage degradation and inflammatory responses in mice with OA by regulating the mitochondrial Drp1/ROS/NLRP3 axis, suggesting its potential for OA therapy.

Baicalein Alleviates Osteoarthritis Progression in Mice by Protecting Subchondral Bone and Suppressing Chondrocyte Apoptosis Based on Network Pharmacology.

As life expectancy increases, Osteoarthritis (OA) is becoming a more frequently seen chronic joint disease. The main characteristics of OA are loss of articular cartilage, subchondral bone sclerosis, and synovial inflammation. Baicalein (Bai), a traditional Chinese medicine extracted from Scutellaria baicalensis Georgi, has been demonstrated to exert notable anti-inflammatory effects in previous studies, suggesting its potential effect in the treatment of OA. In this study, we first predicted the action targets of Bai, mapped target genes related to OA, identified potential anti-OA targets for Bai, performed gene ontology (GO) enrichment, and KEGG signaling pathway analyses of the action targets, and analyzed the molecular docking of key Bai targets. Additionally, the effect and potential mechanism of Bai against OA were verified in mouse knee OA models induced by destabilized medial meniscus (DMM) surgery. GO and KEGG analyses showed that 19 anti-OA targets were mainly involved in the response to oxidative stress, the response to hypoxia and apoptosis, and the PI3K-Akt and p53 signaling pathways. Molecular docking results indicated that BAX, BCL 2, and Caspase 3 enriched in the apoptotic signaling pathway have high binding affinity with Bai. Validation experiments showed that Bai can significantly attenuate the loss of articular cartilage (OARSI score), suppress synovial inflammation (synovitis score), and ameliorate subchondral bone resorption measured by micro-CT. In addition, Bai notably inhibited the expression of apoptosis-related proteins in articular cartilage (BAX, BCL 2, and Caspase 3). By combining network pharmacology with experimental validation, our study identifies and verifies the importance of the apoptotic signaling pathway in the treatment of OA by Bai. Bai may have promising application and potential therapeutic value in OA treatment.