Transcriptional Regulation of Articular Chondrocyte Function and Its Implication in Osteoarthritis

Abstract

Osteoarthritis (OA) is characterized by joint pain and stiffness with radiographic evidence of joint space narrowing, osteophytes, and subchondral bone sclerosis. Current treatments primarily target symptomatic control of OA, including pharmacologic therapy, local joint injection, and surgical interventions. Pharmaceuticals such as nonsteroidal antiinflammatory drugs (NSAIDs) and Acetaminophen are aimed to control inflammation and pain by blocking potent inflammatory cytokine pathways. Joint injections including glucocorticoids and hyaluranan-based formulations attempt to control inflammatory mediators locally and improve the glucosaminoglycan concentration within the joint space. Surgical procedures such as debridement, microfracture, osteochondral autografting, and autologous chondrocyte transplantation are currently employed to stimulate articular cartilage repair and delay the need for joint replacement. However, all these therapies are aimed at symptomatic control and have limited impact on impeding or reversing the progression to advanced OA. Therefore, interest has been high in development of structure or disease-modifying OA drugs (DMOADs) aimed at slowing, halting, or reversing the progression of structural damage of articular cartilage. A large number of candidate DMOADs have been tested but none have been approved by American or European regulatory agencies (Hellio Le Graverand-Gastineau, 2009; Lotz & Kraus, 2010). A critical barrier in drug development for OA is that molecular and cellular mechanisms for the development of OA, especially the mechanisms that control the activity of adult articular chondrocytes, remain unclear. Overexpression of proinflammatory cytokines such as Interleukin-1┚ (IL-1┚) and tumor necrosis factor-┙ (TNF-┙) (Goldring, 2001; Fernandes et al., 2002), matrix-degrading proteinases such as matrix metalloproteinases (MMPs) (Burrage et al., 2006) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) (Glasson et al., 2005; Karsenty, 2005; Stanton et al., 2005), and nitric oxide (Pelletier et al., 2000; Haudenschild et al., 2008; Lotz, 1999) may cause cartilage degradation. However, no single cytokine or proteinase can stimulate all the metabolic reactions observed in OA. Due to the involvement of multiple proteinases and proinflammatory cytokines in the pathogenesis of OA, a candidate DMOAD that inhibits a single proteinase or inflammatory