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.

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.