The growing array of innate inflammatory ignition switches in osteoarthritis

Abstract

Osteoarthritis (OA) is the most common form of arthritis and is a major cause of chronic pain and disability. We currently lack disease-modifying OA medical therapeutics that effectively slow or halt the progression to destruction and failure of articular cartilage. Importantly, OA is a disease of the whole joint, including not only meniscal fibrocartilage and hyaline articular cartilage, but also subchondral bone, periarticular musculature, tendons and ligaments, articular adipose tissue, synovium, and synovial fluid (SF). Clinically, varying degrees of synovitis and joint effusion in OA contribute to signs and symptoms of inflammation (1). Multiple lines of evidence suggest that OA progression is promoted by low-grade innate articular inflammation and by synovitis (1,2). “Conventional” inflammatory cytokines expressed in cartilage and synovium likely play a role, and interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), IL-6, IL-8, and IL-17 are among the players in synovitis (1,2). The report by Nair et al in this issue of Arthritis & Rheumatism reveals increased levels of soluble CD14 (sCD14) in SF to be a biomarker of innate inflammation in patients undergoing arthroscopic knee meniscectomy for treatment of meniscal tears (3). Investigators in this group previously characterized this population as “enriched for patients with preradiographic disease” (4), given the associated symptoms, synovitis, and evidence of articular cartilage damage detected by arthroscopy.

Figure 1

The position of soluble CD14 (sCD14) in the larger innate inflammatory network in osteoarthritis (OA). This schematic illustrates how elevated synovial fluid sCD14 is present in the “whole joint organ” in early OA associated with meniscal injury, arthroscopically detectable synovitis, clinical symptoms, and the first onset of hyaline articular cartilage damage, prior to plain radiographic evidence of OA. Many innate inflammatory factors, including sCD14 and the others cited here, ignite or enhance noxious responses of cultured synovial fibroblasts and chondrocytes. Hence, these same factors have the potential to help switch on OA after cartilage injury (left) and affect the progression of OA (right). However, the right side of the schematic shows that experimental manipulation of certain mediators in the highlighted innate inflammatory network has yielded surprisingly mixed results to date for OA progression in animal models. In this sense, OA is another example of the “double-edged” sword of innate inflammation in tissue damage versus repair, and the innate inflammation likely embraces synovium and may involve sCD14. DAMPs = damage-associated molecular patterns; PRRs = pattern-recognition receptors; RAGE = receptor for advanced glycation end products; TLR-2 = Toll-like receptor 2; MMPs = matrix metalloproteinases.