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Anticytokine Therapy for Osteoarthritis

Evidence to Date

Drugs & Aging volume 27, pages 95–115 (2010)Cite this article

Abstract

Several recent in vitro investigations and experimental studies performed in animal models of osteoarthritis (OA) sustained the previously held view that interleukin (IL)-1 or tumour necrosis factor-α (TNFα) disrupt the metabolism of synovial joint tissues. The evidence to date indicates that, in addition to IL-1 and TNFα, other pro-inflammatory cytokines, including IL-6, members of the IL-6 protein superfamily, IL-7, IL-17 and IL-18, can also promote articular cartilage extracellular matrix protein degradation or synergize with other cytokines to amplify and accelerate cartilage destruction. Most importantly, many of these cytokines have been implicated in causing synovial tissue activation and damage to subchondral bone as well as altering cartilage homeostasis in spontaneously occurring or surgically induced animal models of OA and in transgenic mice genetically primed to develop OA. In this regard, these pro-inflammatory cytokines may also play a significant role in the pathogenesis of human OA. However, attempts to modify the progression of human OA in well designed, controlled clinical trials with an IL-1 receptor antagonist protein (IRAP) have not been successful. Several anabolic cytokines (also termed growth factors), including transforming growth factor-β (TGF-β), insulin-like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF) and connective tissue growth factor (CTGF), have also been proposed as regulators of skeletal long bone growth and development as well as cartilage and bone homeostasis. TGF-β, IGF-1 and FGF-2, in particular, have been characterized as potential chondroprotective agents. Thus, enzymatic disruption and removal of these growth factors from cartilage extracellular matrix proteins, as in the case of TGF-β and FGF-2, or disruption of their function, as in the case of the enhanced binding of free IGF-1 with IGF binding proteins in OA joint synovial fluid, may compromise and ultimately be responsible for the inadequate repair of articular cartilage in OA. An improved understanding of the cellular and molecular mechanisms by which pro-inflammatory and/or anabolic cytokines alter both the structure and function of synovial joints may eventually result in the commercial development of disease-modifying OA drugs (DMOADs). Since the prevalence of OA is high in the elderly population, future development of DMOADs must also take into account potential differences in the way DMOADs would be metabolized in the older individual compared with younger people.

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  1. Department of Medicine, Division of Rheumatic Diseases, Department of Anatomy, Case Western Reserve University, School of Medicine & University Hospitals Case Medical Center, Cleveland, Ohio, USA

    Charles J. Malemud

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Malemud, C.J. Anticytokine Therapy for Osteoarthritis. Drugs Aging 27, 95–115 (2010). https://doi.org/10.2165/11319950-000000000-00000

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Keywords

  • Articular Cartilage
  • Synovial Fluid
  • Connective Tissue Growth Factor
  • Leukaemia Inhibitory Factor
  • Cartilage Explants