Osteoarthritis (OA) is among the most common joint disorders worldwide and a significant contributor to patient morbidity and impaired functional status, leading to major socioeconomic burden ^[1][2][3]. The prevalence of OA worldwide over the period 1990–2019 increased by a striking 114% ^[4]. These numbers, however, vary widely, mainly owing to the definition used (clinical vs. radiographic OA), the population sampled and the affected joints ^[1]. The knee is the joint most frequently involved in OA, followed by interphalangeal joints of the hand and the hip ^[5]. Risk factors include genetics, age, sex, mechanical load, obesity/metabolic syndrome and others. Obesity-related OA, also more broadly described as metabolic-syndrome-associated OA, is a complex condition that not only stems from the increased mechanical load on weight-bearing joints (such as the knee and hip) but the systemic effects of obesity-induced inflammation that further increase the risk of OA in other areas (such as the hand) ^[2][3].

2. Epidemiology and Pathogenesis of Knee Osteoarthritis

Knee OA is a progressive multifactorial disease associated with chronic pain, reduced mobility and increased patient morbidity ^[5]. Almost four fifths of the total OA burden worldwide is attributed to knee OA, and this burden increases with obesity and age ^[6][7]. Incidence and prevalence vary substantially among countries due to the impact of geographical location, development, income and other socioeconomic factors, and were estimated to be around 86.7 million worldwide and around 654.1 million worldwide in 2020, respectively ^[7]. An analysis of OA distribution among regions based on geography and income (assessed through the sustainable development index—SDI) over the period 1990–2019 revealed that the knee was the predominantly affected joint in all geographical regions apart from high-income North America and Eastern Europe, where it was superseded by hand OA ^[4]. In addition, prevalence of radiographic knee OA was higher than that of symptomatic or self-reported cases ^[7]. Females are more commonly affected, with prevalence ranging from 19% to 24.5% (mean 21.7%), while in males, it falls within the range 10.2–13.8% (mean 11.9%). Clinical OA is defined based on history and examination and can be classified according to various criteria, the most recognized of which are those of the American College of Rheumatology (ACR), which consider the presence of crepitus, morning stiffness and bone enlargement ^[1]. Radiographic OA is usually assessed based on the Kellgren and Lawrence score, which takes into consideration joint space loss and the presence of osteophytes, sclerosis and cysts and grades disease severity on a scale from 0 to 4 (Table 1) ^[1][8].

Grade	Description
Grade 1	Doubtful narrowing of the joint space with possible osteophyte formation.
Grade 2	Possible narrowing of the joint space with definite osteophyte formation.
Grade 3	Definite narrowing of joint space, moderate osteophyte formation, some sclerosis and possible deformity of bony ends.
Grade 4	Severe narrowing of the joint space, large osteophyte formation, with marked sclerosis and definite deformity of bone ends.

While historically knee OA has been considered a disease primarily involving structural modifications to the joint cartilage and the subchondral bone, the synovial membrane, ligaments, muscles and Hoffa’s fat pad are also affected, thus leading to the concept of OA as a ‘whole joint disease’ ^[9][10]. Articular cartilage is composed of connective tissue cells known as chondrocytes situated in an extracellular matrix (ECM) built of water (more than 70%) and organic components including collagen type II, aggrecan, decorin, fibromodulin, glycosaminoglycans (chondroitin sulfate and keratan sulfate) and glycoproteins. Generally, the structural elements of the ECM are organized in the following manner: proteoglycan aggregates containing chondroitin sulfate and keratan sulfate bound to aggrecan as the ‘core protein’, which is connected to a backbone of hyaluronic acid, along with other ECM components are entrapped in a network formed by collagen type II fibrils ^[10][11]. All these components are produced by chondrocytes and this process is finely regulated through the action of proteolytic enzymes and is further regulated by mechanical loading through membrane-bound mechanoreceptors ^[10][12]. Changes in the cartilage ECM are among the first manifestations of OA. These include the cleavage of aggrecan from the hyaluronic acid backbone by proteinases of the ADAMTS family, particularly ADAMTS-4 and ADAMTS-5, as well as the disruption of the collagen network by matrix metalloproteinases (MMP), mainly MMP-13, which has a distinct avidity for collagen type II ^[13][14]. Proliferation and hypertrophy of chondrocytes aimed at restoring the cartilaginous matrix instead lead to release of pro-inflammatory mediators such as tumor necrosis factor-alpha (TNFα), interleukin 1β (IL-1β) and interleukin 6 (IL-6), which accelerate the degradation of the matrix and may activate the adjacent synovium ^[10][15]. Apart from articular cartilage, other structures of the knee joint are also affected in OA. Subchondral bone alterations are critical in the pathogenesis of OA and differ in early and late-stage OA ^[16]. Early changes are characterized by a deterioration of the subchondral plate, with compromised subchondral trabeculae, increased porosity and decreased bone density. On the contrary, subchondral sclerosis, increased trabecular thickness and decreased trabecular separation are all features of late-stage OA ^[16][17]. Two major histopathological alterations found in OA joints include bone marrow lesions, which correlate with knee OA severity ^[18] and subchondral bone cysts, which are usually found in weight-bearing regions of the joint and show a multitude of osteoblasts, osteoclasts and osteoprogenitor cells, suggesting a high degree of bone turnover ^[19]. Moreover, these cellular types show their own alterations in the knees of OA patients. For instance, osteoblasts in the OA subchondral bone have higher alkaline phosphatase activity and produce higher levels of insulin-like growth factor 1 (IGF1), transforming growth factor β1 (TGFβ1), receptor activator of nuclear factor kappa beta-ligand (RANKL) and vascular endothelial growth factor (VEGF) compared to normal osteoblasts ^[17]. Synovitis is a common finding in knee OA, which can be present in early as well as more advanced stages and is associated with pain, functional impairment and structural progression ^[10][20]. Multiple inflammatory mediators have been found in the synovial fluid of OA patients, including C-reactive protein (CRP), TNFα, IL-1β, IL-6, TGFβ1, VEGF, various fibroblast growth factors (FGFs), leukotrienes, prostaglandins and others ^[20][21]. In addition, synovial inflammation leads to influx of macrophages, T- and B-lymphocytes and mast cells ^[22]. The number of these cells and the expression of cytokines, however, have been described as moderate and lower than those in rheumatoid arthritis (RA) ^[22]. Interestingly, synovial inflammation induced by cartilage damage drives structural damages further in a vicious cycle by an increased production of proteolytic enzymes ^[23].

3. Risk Factors

Generally, risk factors for the development of OA can be divided into person-level factors and joint-level factors (Table 2) ^[1].

Person-Level Factors	Joint-Level Factors
Genetics	Knee injury
Old age	Mechanical loading
Female gender	Repetitive joint use
Obesity/metabolic syndrome	Muscle weakness
Dietary habits	Joint laxity
Socioeconomic factors	Bone density

Old age is a major risk factor that contributes to the development of knee OA in multiple ways, including oxidative stress, muscle weakening and sarcopenia, decreased mobility and impaired proprioception ^[1][4]. In addition, genetics are thought to play a role in approximately 40% of cases of knee OA, in particular, genes encoding the vitamin D receptor, collagen type II, IGF1 and growth differentiation factor 5 ^[24]. The role of dietary habits, smoking and alcohol consumption is not yet clear. As mentioned above, females are more commonly affected by knee OA than males. Females generally tend to have narrower femurs, thinner patellae, greater angle of insertion of the quadriceps tendon and smaller tibial condyles—all factors that alter knee kinematics ^[25].  At the joint level, particular repetitive joint movements have been associated with a higher risk for knee OA. Prolonged and frequent squatting predisposes elderly individuals to tibiofemoral knee OA. Moreover, occupational activities involving squatting or kneeling more than two hours daily were associated with two-fold significantly increased risk of moderate to severe radiographic knee OA ^[26]. Injuries and tears to the ligamentous apparatus of the joint, including meniscal lesions, lead to decreased resistance to mechanical forces, including shear stress, tension and compression ^[10]. Rupture of the anterior cruciate ligament (ACL) in particular causes joint instability and is responsible for early OA developing in 10 to 15 years in 13% of cases. When such injuries are combined with damage to collateral ligaments, menisci, cartilage and/or subchondral bone, this percentage may rise to as high as 40% ^[27].