# Osteoarthritis--The Role of Mesenchymal Stem Cells in Cartilage Regeneration
## 2 Etiopathogenesis
OA has been linked to an elevated risk of cardiovascular and atherosclerotic diseases [28; 29; 30]. Furthermore, people with lower-limb OA are more likely to feel depressed because of the pain, the most common and severe complication of this disease [15]. OA has become increasingly prevalent over the past few decades, with environmental change being the primary culprit. Four critical environmental factors are linked to its etiology [31; 32]: obesity, metabolic syndrome, dietary alterations, and physical inactivity. A genetic component has long been known, especially in OA involving several joints. Numerous genes have been explicitly linked to OA, while many others have been identified as connected with contributory variables, such as heightened inflammation and obesity [13]. Genetic susceptibility is an important risk factor for primary OA, which accounts for around 30% to 65% of the risk [15; 33; 34]. The genetic risk factors have been significantly enhanced in our comprehension by recent genome-wide association studies (GWAS). As of 2019, 90 genetic risk loci associated with osteoarthritis (OA) have been identified. Among this set of hypothetical genes, no genes associated with inflammation were identified; instead, there is a notable abundance of growth factor clusters. The genetic differences discussed above include TGF-family genes, which consist of ligands (TGFB1, GDF5), latent binding proteins (LTBP1, LTBP3), and signaling molecules (SMAD3). The FGF family is also present. The findings together emphasize the significance of the loss of reparative characteristics inside the joint in the progression of osteoarthritis [35]. However, in order to understand the molecular mechanism by which these polymorphisms raise the risk of OA, functional studies are necessary. Functional investigations of these locations will be influenced by incorporating genetic variations with genome-wide datasets of cartilage allelic imbalance, chromatin states, and open chromatin areas. The characterization of new chondrocyte subtypes and the systematic identification of all microRNAs (miRNAs), long noncoding RNAs (IncRNAs), and circular RNAs (circRNAs) present in OA cartilage have been accomplished by RNA sequencing investigations [36; 37]. Early-onset OA may be caused by infrequent mutations in monogenetic illnesses linked to OA. On the other hand, late-onset OA is often distinguished by a multifaceted clinical presentation consisting of prevalent DNA variations and other risk factors [35]. The involvement of genes within the BMP (bone morphogenetic protein) and WNT (wingless type) signaling pathways has been associated with the pathogenesis of OA. In animal research, a robust association has been shown between OA and two specific genes, GDF5 (growth and differentiation factor 5) and FRZB (frizzled-related protein), wound in the articular cartilage [13]. Genetic factors have a significant role in heritable developmental abnormalities and skeletal anomalies, which may lead to congenital misalignment of joints. These factors have the potential to cause harm to the cartilage and integrity of the joint [13]. Age is commonly considered to be the most important independent risk factor for OA, although the underlying processes and related variables remain unknown [14; 15; 33]. An imbalance in the synthesis and activity of catabolic mediators leads to the breakdown and loss of joint cartilage in aged cells. People's cartilage and other joint tissues, such as the synovium, subchondoral bone, and muscles, all change as they get older [36; 37]. Obesity is a significant risk factor, especially for knee OA, because it puts more pressure on the joints that hold up the body [32]. It is a prevalent illness projected to impact 20% of the global population by 2030 [38; 39]. It is a well-established risk factor for the progression and development of OA. Overweight people are more likely to get knee OA [40], because their weight puts mechanical stress on the joints that support them and because adipokines cause low-grade systemic inflammation.