The pathologic changes that occur in osteoarthritis joints are fibrillation and degradation of the articular cartilage, thickening of the subchondral bone, formation of osteophytes, inflammation of the synovium (synovitis), degeneration of ligaments and menisci, and hypertrophy of the joint capsule.

These mediators promote macroscopic inflammation, including synovitis, and can drive cartilage matrix catabolism, but some also promote cartilage remodelling and repair. The number and diversity of inflammatory mediators in OA joints, the paradoxical roles of some of these mediators in tissue damage and repair, and the physiological roles of some mediators in host defence, means targeting individual mediators for OA therapy is difficult.

Several inflammatory pathways and mechanisms are likely to contribute to the pathogenesis of OA. In this paradigm, injury or overuse, often in the context of other risk factors, triggers a vicious cycle of local tissue damage, failed tissue repair, and low-grade inflammation involving a number of molecular components and mechanisms in the joint. This low-grade inflammation contributes to or mediates progressive cartilage loss, pain, and joint dysfunction.

An inflammatory state is present in osteoarthritis (OA), produced either by the secretion of cytokines from the synovium or, in the context of obesity, indirectly from adipose tissue. These cytokines are involved in the degradation of cartilage by inducing the local secretion of MMPs and ADAMTSs via the activation of signalling pathways, mainly MAPK and NF-κB pathways. Cytokines can also activate the afferent arc of the vagus nerve. After integration of these signals at the brain level, the efferent arc is activated leading to the release of acetylcholine into the microenvironment of the chondrocyte. Acetylcholine binding to its receptors blunts MAPK and NF-kB pathways and thus inhibits cartilage degradation. This cholinergic anti-inflammatory reflex arc can also be externally activated by implanting an external device close to the vagus nerve that delivers electrical stimulation.

Left: Normal, smooth surface, heavy red stain of proteoglyans, no increase or decrease in chondrocytes and one well-defined tidemark. Right: Osteoarthritis, disrupted cartilage surface, proliferation of chondrocytes with many pyknotic chondrocytes (indicating cell death), sparse red stain of proteoglycans that is only present around chondrocytes, and duplicated tidemark invaded by blood vessels.

The mineralized tissues beneath the articular cartilage are sometimes referred to collectively as subchondral bone or subchondral mineralized tissues, but in reality include different kinds of tissues that vary compositionally, architecturally, physiologically and mechanically. The subchondral plate is dense cortical bone, but the subchondral cancellous bone beneath it is quite porous. The distinction between these tissues is important because they change in different ways and at different times during the development of osteoarthritis (OA). In early-stage OA, the subchondral plate becomes thinner as a consequence of an increased remodelling rate. At the same time, cancellous bone is lost as the trabecular plates become thinner and more rod-like. In late-stage disease, the subchondral plate thickens, but the subchondral cancellous bone remains osteopenic. The calcified cartilage begins to advance into the articular cartilage in late-stage disease, leaving a footprint of multiple tidemarks as the mineralization front advances. This creates an even thicker mineralized plate, and reduces the thickness of the non-mineralized articular cartilage which cannot replace itself. This is accompanied by a loss of aggrecan beginning superficially in the articular cartilage (shown by a change in stain color), and surface fibrillation. The sum result of these changes is subchondral sclerosis (that includes both the subchondral plate and calcified cartilage) and thinner, more fibrillated articular cartilage.

Bone remodelling involves the coordinated activity of osteoclasts that resorb the bone and osteoblasts that mediate bone formation. Osteocytes regulate bone remodelling in response to mechanical stimuli via direct cell–cell signalling with osteoblasts and osteoclasts and by the release of soluble mediators. For example, in response to increased mechanical loading, secretion of sclerostin, a WNT pathway inhibitor, by osteocytes decreases. Decreased secretion of sclerostin results in increased WNT signalling and enhanced osteoblast-mediated bone formation. Conversely, unloading results in increased secretion of receptor activator of nuclear factor-κB (RANK; also known as TNFRSF11A) ligand (RANKL; also known as TNFSF11), which leads to enhanced osteoclast differentiation and increased bone resorption. OPG, osteoprotegerin (also known as TNFRSF11B).

Chondrocytes in osteoarthritis (OA) switch from oxidative phosphorylation to glycolysis as their main source of energy metabolism. In osteoarthritic joints, chondrocytes are exposed to proinflammatory cytokines and microenvironmental alterations, including hypoxia and nutrient stress. Mitochondrial metabolism is impaired and reactive oxygen species (ROS) accumulate, causing damage to mitochondria which inhibits AMPK signalling and activity, downregulate SIRT1 and decrease levels of PGC1α, the master regulator of mitochondrial biogenesis.

Products of cartilage breakdown that are released into the synovial fluid are phagocytosed by synovial cells, amplifying synovial inflammation. In turn, activated synovial cells in the inflamed synovium produce catabolic and proinflammatory mediators that lead to excess production of the proteolytic enzymes responsible for cartilage breakdown, creating a positive feedback loop. The inflammatory response is amplified by activated synovial T cells, B cells and infiltrating macrophages. To counteract this inflammatory response, the synovium and cartilage may produce anti-inflammatory cytokines. In addition to these effects on cartilage inflammation and breakdown, the inflamed synovium contributes to the formation of osteophytes via BMPs.

Products that are released from the cartilage matrix and/or the chondrocytes in response to adverse mechanical forces and other factors induce the release of products that deregulate chondrocyte function via paracrine and autocrine mechanisms. Catabolic enzymes, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), released by chondrocytes degrade the cartilage matrix, releasing cartilage degradation products that, along with the other pro-inflammatory chondrocyte derived-products, act on the synovium to induce inflammation and the release of pro-inflammatory products that feedback on chondrocytes to further deregulate their function. COX2, cyclooxygenase 2; DAMP, damage-associated molecular pattern; NO, nitric oxide; NOS2, nitric oxide synthase 2; OA, osteoarthritis; PGE₂, prostaglandin E₂; RAGE, receptor for advanced glycation end-products; TLR, Toll-like receptor.