Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations

Abstract

Osteoarthritis (OA) has traditionally been classified as a noninflammatory arthritis; however, the dichotomy between inflammatory and degenerative arthritis is becoming less clear with the recognition of a plethora of ongoing immune processes within the OA joint and synovium. Synovitis is defined as inflammation of the synovial membrane and is characteristic of classical inflammatory arthritidies. Increasingly recognized is the presence of synovitis in a significant proportion of patients with primary OA, and based on this observation, further studies have gone on to implicate joint inflammation and synovitis in the pathogenesis of OA. However, clinical OA is not one disease but a final common pathway secondary to many predisposing factors, most notably age, joint trauma, altered biomechanics, and obesity. How such biochemical and mechanical processes contribute to the progressive joint failure characteristic of OA is tightly linked to the interplay of joint damage, the immune response to perceived damage, and the subsequent state of chronic inflammation resulting in propagation and progression toward the phenotype recognized as clinical OA. This review will discuss a wide range of evolving data leading to our current hypotheses regarding the role of immune activation and inflammation in OA onset and progression. Although OA can affect any joint, most commonly the knee, hip, spine, and hands, this review will focus primarily on OA of the knee as this is the joint most well characterized by epidemiologic, imaging, and translational studies investigating the association of inflammation with OA.

Keywords: Osteoarthritis; inflammation; innate Immunity.

Figure 1.

Inflammatory cytokines are associated with osteoarthritis. Relative cytokine levels in serum and synovial fluid (SF) samples from patients with osteoarthritis (OA) or rheumatoid arthritis (RA) and in serum samples from healthy individuals (normal sera). Cytokine levels were measured with a multiplex bead-based immunoassay. Samples from individual patients are listed above the heatmap, and the individual cytokines are listed to the right of the heatmap. β-NGF, β nerve growth factor; CTACK, cutaneous T-cell attracting chemokine; FGF, fibroblast growth factor; GM-CSF, granulocyte macrophage colony-stimulating factor; GROα, growth-regulated oncogene α; G-CSF, granulocyte colony-stimulating factor; HGF, hepatocyte growth factor; IFN, interferon; IL, interleukin; IL-1ra, interleukin-1 receptor antagonist; IL-2Rα, interleukin-2 receptor α chain; IP-10, interferon γ induced protein 10; LIF, leukemia inhibitory factor; MCP, monocyte chemotactic protein; M-CSF, macrophage colony-stimulating factor; MIG, monokine induced by interferon γ; MIP-1, macrophage inflammatory protein; SCF, stem cell factor; SCGF-β, stem cell growth factor β; SDF-1α, stromal cell-derived factor 1α; VEGF, vascular endothelial growth factor. (Reproduced from Sohn et al. [2012] with permission).

Figure 2.

Schematic representation of chronic inflammation as a mediator of osteoarthritis. Following joint trauma or overuse, tissue damage results in the production of damage-associated molecular patterns (DAMPs), including cartilage extracellular matrix (ECM) breakdown products and intracellular alarmins that signal through pattern recognition receptors on synovial macrophages, fibroblast-like synoviocytes (FLS), or chondrocytes to induce the local production of inflammatory mediators. Inflammation-induced angiogenesis and increased vascular permeability results in the subsequent influx of plasma proteins also capable of functioning as DAMPs. Acute and chronic production of inflammatory mediators promote further cartilage degradation either directly or indirectly through their induction of proteolytic enzymes, amplifying a vicious cycle of innate immune activation in osteoarthritis.