Osteoarthritis

OA is a complex and multi-factorial disease with numerous genetic, biological, and biochemical components that affect the entire joint, including synovium, meniscus (in the knee), periarticular ligaments, and subchondral bone.[21] The exact aetiology is unknown.

Age, hereditary predisposition, female sex, joint anatomy and/or misalignment, and obesity are associated with increased risk of OA.[9][10][15][16][18][19][22][23][24][25][26][27][28]

Articular congenital deformities or trauma to the joint also increase the risk of developing OA.[22][29][30]

High bone mineral density and low oestrogen status, such as in post-menopausal women, may be associated with higher risk of knee and hip OA.[10]

The preceding factors might lead to a joint environment that is susceptible to trauma and to external mechanical stressors that are exacerbated by certain physical activities.

Local mechanical factors, such as periarticular muscle weakness, joint anatomy and misalignment, and structural joint abnormality (e.g., meniscal tear), further facilitate the progression of the disease.[21][22][26][27][31][32]

The internal and external factors combined lead eventually to a failed joint.[2][33]

In the affected joint, there is a failure in maintaining the homeostatic balance of the cartilage matrix synthesis and degradation, resulting from reduced formation or increased catabolism.[34]

A number of factors may contribute:

Inflammatory mediators play a role as potential drivers of joint tissue destruction. The number of pro-inflammatory mediators reported in the synovial fluid and tissue affected by OA is increasing.[35][36][37][38][39]
Connective tissue growth factor (CTGF) is present in osteophytes of late-stage OA. CTFG is usually up-regulated in synovial fluid of OA that stimulates the production of inflammatory cytokines. Evidence has demonstrated CTFG also activates nuclear factor-κB, increases the production of chemokines and cytokines, and up-regulates matrix metalloproteinases-3 (MMP-3) that in turn leads to the reduction in proteoglycan contents in joint cartilage. Thereby creating an imbalance in cartilage homeostasis which may contribute to the pathogenesis of OA by developing synovial inflammation and cartilage degradation.[40]
Matrix metalloproteinases (e.g., collagenase), enzymes that catalyse both collagen and proteoglycan degradation, are found in increased concentrations in OA cartilage.[41]
Nitric oxide may activate metalloproteinases, thereby playing a role in cartilage degradation.
Anabolic cytokine levels, such as those of insulin-like growth factors (IGF-I), are decreased in OA.[42][43][44]
Aberrant chondrocyte metabolism is a response to changes in the inflammatory microenvironment and may play a key role in cartilage degeneration and OA progression. Under conditions of environmental stress, chondrocytes shift from oxidative phosphorylation to glycolysis, a process regulated by the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) pathways.[45]
Leptin is able to modulate the production of inflammatory mediators in immune cells of patients with OA, and it has been demonstrated to participate in the onset and progression of OA. One meta-analysis reported greater levels of circulating leptin in OA patients compared with the control group, and that synovial leptin levels were greater in patients with OA compared with healthy participants.[46] In addition, LEPR rs113710 polymorphism was linked to an increased risk of developing OA.[46]

The osteoarthritic process involves not only the cartilage but also other joint structures, resulting in bone remodelling and bone marrow lesions of the subchondral bone, synovial inflammation, capsular stretching and periarticular muscle weakness, and ligament laxity.[21]

The Janus Kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) is a signalling pathway which is instrumental in the osteoarticular system, including cartilage, subchondral bone, and synovium. There is evidence to suggest this signalling plays a significant role in the progression of OA.[47]

The above elements, in addition to trauma, can lead to focal stress and eventual cartilage loss. This can further alter the joint anatomy, predisposing it to the potentially detrimental effects of mechanical factors and physical activity, by redistributing and increasing the focal loading in the joint. For example, in knee OA, genu varum (bow-legs) and genu valgum (knock-knees) are associated with increased risk of structural deterioration of the joint.[33][48]

Osteoarthritis classification by disease aetiology[3][4]

Primary (idiopathic): no preceding injury to the joint; further categorised into localised OA, which mostly affects the hands, knee, hip, or foot (especially the first metatarsophalangeal), or generalised OA, usually affecting the hands and another joint.
Secondary: an antecedent insult to the joint, such as a congenital abnormality (e.g., congenital hip dysplasia); trauma; inflammatory arthropathies (e.g., rheumatoid arthritis, chronic gout); and ongoing strenuous physical activities or occupations could lead to joint damage over time.

Kellgren-Lawrence radiographic classification of osteoarthritis[5][6]

Has been used as a research tool in epidemiological studies of osteoarthritis.

Grade 0 (none): no radiological findings of osteoarthritis
Grade 1 (doubtful): doubtful joint space narrowing and possible osteophytic lipping
Grade 2 (minimal): definite osteophytes and possible joint space narrowing
Grade 3 (moderate): moderate multiple osteophytes, definite narrowing of joint space and some sclerosis, and possible deformity of bone ends
Grade 4 (severe): large osteophytes, marked narrowing of joint space, severe sclerosis, and definite deformity of bone ends.

Pathophysiology

Classification

Osteoarthritis classification by disease aetiology[3][4]

Kellgren-Lawrence radiographic classification of osteoarthritis[5][6]