# Osteoarthritis--The Role of Mesenchymal Stem Cells in Cartilage Regeneration
## 2 Etiopathogenesis
Metabolic syndrome is a cluster of cardiometabolic factors linked to cardiovascular disease and type 2 diabetes, including central obesity, dyslipidemia, impaired fasting glucose levels, and high blood pressure [41; 42]. Numerous studies have demonstrated that type 2 diabetes can alter the structure of the ECM, which subsequently sends a signal to chondrocytes, resulting in the degradation of the cartilage matrix [42]. Inactivity is a significant risk factor for OA that inhibits individuals from maintaining normal joint function [43]. Researchers between a sedentary lifestyle, obesity, a chronic inflammatory state, and the manifestation of osteoarthritis symptoms have identified a correlation. Maintaining cartilage and muscle mass requires regular mechanical stress, such as moderate to vigorous adapted physical activity (APA). The goal of APA is to reduce the associated risk factors (such as metabolic syndrome, obesity, sarcopenia, and chronic inflammation), as well as the most bothersome symptoms to the patient (e.g., pain, joint stiffness, and activity limitations). Being more active and less sedentary is a big part of reducing OA pain, physical function loss, and other symptoms, and it can also improve the quality of life (QOL). Numerous studies and meta-analyses have shown APA's effectiveness in OA [44,45]. Over the past few decades, dietary changes have led to an increase in the consumption of oxidizing foods and omega-6 fatty acids that promote inflammation [46]. Even though the direct link between dietary changes and OA is still up for debate, there is evidence that increasing fiber intake reduces knee pain in people with this condition [47]. Knee injuries considerably increase the likelihood of developing OA in athletically active young individuals. During the year, 41-51 percent of patients with a history of knee injury develop knee OA [48]. Inflammation is an important factor in cartilage breakdown [49]. Proinflammatory cytokines, which are significant mediators in the physiopathology of OA, alter the quantity and quality of cartilaginous ECM. Its pathophysiology has been linked primarily to IL-1\(\beta\) and TNF-\(\alpha\); other cytokines, such as IL-2, IL-6, IL-15, IL-17, and IL-21, as well as several chemokines, have been linked to the development of OA [50]. Researchers between a sedentary lifestyle, obesity, a chronic inflammatory state, and the manifestation of osteoarthritis symptoms have identified a correlation [50,51]. IL-1\(\beta\) and TNF-\(\alpha\) were discovered in increased amounts in OA patients' synovial fluid, cartilage, synovial membrane, and subchondral bone layer [50,52]. IL-1\(\beta\) causes joint cartilage to degrade and become inflammatory, resulting in cartilage loss. Many studies have demonstrated that IL-1\(\beta\) and TNF-\(\alpha\) have a direct effect on the formation of type II collagen and aggrecan in chondrocytes, resulting in the release of MMP-1, 3, and -13 [53,54]. TNF-\(\alpha\) and IL-1\(\beta\) also release proinflammatory cytokines such as IL-6, IL-17A, the C-X-X motif ligand 8 (CXXL8), vascular endothelial growth factor (VEGF) [55], and Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES) [56], when they are present in the bloodstream [57]. Anti-inflammatory chemicals TNF-\(\alpha\) and IL-1\(\beta\) are known to increase the production of A Disintegrin and Metalloproteines with Thromb motifs (ADAMTS), which break down aggregating molecules. The primary function of IL-1 and TNF-\(\alpha\) in the pathogenesis of OA is to maintain the inflammatory response by activating cascades that control the expression of essential pathway genes, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), Extracellular signal-Regulated Kinase (ERK), c-Jun N-terminal kinases (JNK), and p38 kinase. Additionally, they induce the production of ADAMTS and prostaglandinE2 (PGE2) in chondrocytes. The primary genetic regulatory genetic mechanism for catabolism in chondrocytes is NF-kB activation.