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-alpha is one of the most potent osteoclastogenic
cytokines produced in
inflammation and is pivotal in the pathogenesis of RA. Production of
tumor necrosis factor-alpha (
TNF-alpha) and other proinflammatory
cytokines in RA is largely CD4(+) T-cell dependent and mostly a result of
interferon-gamma (IFN-gamma) secretion. Synovial T cells contribute to
synovitis by secreting IFN-gamma 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-kappaB ligand (RANKL). In rheumatoid synovium, fibroblasts also provide an abundant source of RANKL. Furthermore,
TNF-alpha 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-alpha acts directly to stimulate osteoclast differentiation of macrophages and myeloid progenitor cells. In addition,
TNF-alpha 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-alpha 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-alpha 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 for RA.