Involvement of receptor activator of NFκB ligand and tumor necrosis factor-α in bone destruction in rheumatoid arthritis

• Published in: Bone 2002-02, Vol.30 (2), p.340-346
• Main Authors: Romas, E, Gillespie, M.T, Martin, T.J
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Diseases of the osteoarticular system; Inflammatory joint diseases; Medical sciences; Osteoclast; Receptor activator of NF-κB (RANK) ligand; Rheumatoid arthritis (RA); T cells; TNF-α; Tumor necrosis factor-α
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/S8756-3282(01)00682-2

Bone loss represents a major unsolved problem in rheumatoid arthritis (RA). The skeletal complications of RA consist of focal bone erosions and periarticular osteoporosis at sites of active inflammation, and generalized bone loss with reduced bone mass. New evidence indicates that osteoclasts are key mediators of all forms of bone loss in RA. TNF-α is one of the most potent osteoclastogenic cytokines produced in inflammation and is pivotal in the pathogenesis of RA. Production of tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines in RA is largely CD4 + T-cell dependent and mostly a result of interferon-γ (IFN-γ) secretion. Synovial T cells contribute to synovitis by secreting IFN-γ and interleukin (IL)-17 as well as directly interacting with macrophages and fibroblasts through cell-to-cell contact mechanisms. Activated synovial T cells express both membrane-bound and soluble forms of receptor activator of NF-κB ligand (RANKL). In rheumatoid synovium, fibroblasts also provide an abundant source of RANKL. Furthermore, TNF-α and IL-1 target stromal-osteoblastic cells to increase IL-6, IL-11, and parathyroid hormone-related protein (PTHrP) production as well as expression of RANKL. In the presence of permissive levels of RANKL, TNF-α acts directly to stimulate osteoclast differentiation of macrophages and myeloid progenitor cells. In addition, TNF-α induces IL-1 release by synovial fibroblasts and macrophages, and IL-1, together with RANKL, is a major survival and activation signal for nascent osteoclasts. Consequently, TNF-α and IL-1, acting in concert with RANKL, can powerfully promote osteoclast recruitment, activation, and osteolysis in RA. The most convincing support for this hypothesis has come from in vivo studies of animal models. Protection of bone in the presence of continued inflammation in arthritic rats treated with osteoprotegerin (OPG) supports the concept that osteoclasts mediate bone loss, providing further evidence that OPG protects bone integrity by downregulating osteoclastogenesis and promoting osteoclast apoptosis. Modulation of the RANKL/OPG equilibrium in arthritis may provide additional skeletal benefits, such as chondroprotection. The nexus between T-cell activation, TNF-α overproduction, and the RANKL/OPG/RANK ligand-receptor system points to a unifying paradigm for the entire spectrum of skeletal pathology in RA. Strategies that address osteoclastic bone resorption will represent an important new facet of therapy fo