## 5 Degradation of Articular Cartilage  
AC can succumb to a variety of pathologies, from rare disease entities to one of the most common: osteoarthritis [290, 291]. OA is considered a disease of the entire knee joint, which includes cartilage degradation as well as subchondral bone remodelling, fibrosis and inflammation of the SM, degenerative changes to the meniscus and ligaments and pathological changes to the subchondral fat pad [292, 293, 294, 295, 296]. The main risk factors for OA are gender, genetic predisposition, age, joint injury, obesity and diabetes [297, 298, 299]. Currently, there are no effective disease-modifying therapies; the only known therapeutic option is joint endoprosthesis at an advanced stage of the disease [300]. One of the main factors limiting the quality of life of patients affected by OA is pain as a consequence of mechanopathology and chronic inflammation [301, 302]. In the progression of osteoarthritis, one of the earliest changes is a disruption of the molecular structure and a change in the composition of the extracellular matrix, due to mechanical stress, genetic predisposition or chronic inflammation [287, 303, 304, 305]. Even in the early stages of OA, a decrease in AC stiffness and an increase in its permeability are observed, which may contribute to an acceleration of the degradation process [306]. Initial changes include a loss of proteoglycans, as well as an increase in tissue hydration. Damage to the matrix induces proliferation and increased chondrocyte synthesis activity, thus enabling temporary maintenance or partial restoration of AC structure in some cases [306]. Under physiological conditions, chondrocytes are metabolically dormant, whereas in OA, they become active and adopt a hypertrophic phenotype [291]. This results in the deregulation of pro-inflammatory and catabolic genes, and in consequence, uprequlation of MMPs production [307]. Catabolic activity can be exacerbated by changes in key signalling pathways (TGF-\(\beta\), Wnt/\(\beta\)-catenin, Notch, Ihh, FGF), as well as by mutations in genes encoding extracellular matrix components [308]. Overproduction of ECM-degrading enzymes consequently leads to irreversible damage to its structure and function [309]. AC degradation is not always irreversible; in some cases, the synovial joint may show the ability to partially rebuild the cartilaginous surface [306; 310]. Although the incidence of such a regenerative response is not clearly defined, clinical studies have shown the possibility of spontaneous AC restoration in patients with complete AC loss [306]. In contrast, this phenomenon requires further study, mainly focusing on identifying the determinants of such a response. A characteristic feature of OA is the destruction of AC resulting from a disruption of homeostasis, with catabolic activity predominating [291]. This process results in proliferation, hypertrophy and apoptosis of chondrocytes, increased angiogenesis, as well as matrix calcification and pathological replication of flow markers [304; 307; 311; 312]. The main cellular phenomena include loosening and degradation of the ECM due to mechanical damage and increased MMP activity, which affects the initiation of the inflammatory cascade and denaturation of mainly collagen II, while loss of elasticity is also noticeable, as is the formation of ruptures and loss of proteoglycans [305; 307]. As the disease progresses, the collagen/aggrecan ratio is disrupted, and the composition of collagen changes from type II to type I, which negatively affects collagen networks, weakening them [291]. A reduction in the water content with increased cross-linking of collagen in the matrix compromises the mechanical properties of the tissue. The decrease in stiffness and mechanical strength of the AC makes it more susceptible to damage and promotes the development of degenerative changes [313; 314; 315; 316]. Proteoglycan aggregates become smaller, and the aggregate molecules become shorter and less numerous within the aggregates [317; 318; 319; 320].