Inflammation in osteoarthritis

Abstract

Purpose of review: This review focuses on the novel stress-induced and proinflammatory mechanisms underlying the pathogenesis of osteoarthritis, with particular attention to the role of synovitis and the contributions of other joint tissues to cellular events that lead to the onset and progression of the disease and irreversible cartilage damage.

Recent findings: Studies during the past 2 years have uncovered novel pathways that, when activated, cause the normally quiescent articular chondrocytes to become activated and undergo a phenotypic shift, leading to the disruption of homeostasis and ultimately to the aberrant expression of proinflammatory and catabolic genes. Studies in animal models and retrieved human tissues indicate that proinflammatory factors may be produced by the chondrocytes themselves or by the synovium and other surrounding tissues, even in the absence of overt inflammation, and that multiple pathways converge on the upregulation of aggrecanases and collagenases, especially MMP-13. Particular attention has been paid to the contribution of synovitis in posttraumatic joint injury, such as meniscal tears, and the protective role of the pericellular matrix in mediating chondrocyte responses through receptors, such as discoidin domain receptor-2 and syndecan-4. New findings about intracellular signals, including the transcription factors NF-κB, C/EBPβ, ETS, Runx2, and hypoxia-inducible factor-2α, and their modulation by inflammatory cytokines, chemokines, adipokines, Toll-like receptor ligands, and receptor for advanced glycation end-products, as well as CpG methylation and microRNAs, are reviewed.

Summary: Further work on mediators and pathways that are common across different models and occur in human osteoarthritis and that impact the osteoarthritis disease process at different stages of initiation and progression will inform us about new directions for targeted therapies.

Figure 1. Key mediators involved in proinflammatory events in osteoarthritis

In response to alterations in the joint environment, inflammation-induced and stress-induced signaling pathways may be activated in the synovium and cartilage resulting in the production of cytokines, chemokines, adipokines, Toll-like receptor (TLR) ligands, and other inflammatory mediators such as nitric oxide. This may occur also in response to alterations in the pericellular matrix or the release of damage-associated molecular patterns, which are TLR and RAGE ligands. The consequent upregulation of cartilage-degrading proteinases by extracellular matrix (ECM) proteins or ECM degradation products can further promote catabolic activation, phenotypic shift, and apoptosis.