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Elevated interleukin-6 (IL-6) perpetuates chronic synovitis1,5,6*
*Based on pre-clinical, ex-vivo, and clinical data.
RA leads to increased bone destruction. In the clinical evaluation of synovial fluid from patients with RA, it was determined that the ratio of receptor activator of nuclear factor kappa-ß ligand (RANKL) to osteoprotegerin (OPG) reflects osteoclast function, and a higher ratio of RANKL to OPG is correlated to osteoclast hyperactivity and bone resorption in RA joints.1,9,19,21-24
IL-6 can affect the RANKL/OPG ratio through 2 mechanisms during RA inflammation by directly stimulating25,26:
IL-6 induces macrophages/monocytes to produce IL-1 and tumor necrosis factor-α (TNF-α). IL-17, IL-1, and TNF-α all stimulate effector T-cell proliferation and activation, which contribute to tissue damage in RA. Importantly, these newly formed, activated T cells can express RANKL.27
Therefore, the increased number of T cells expressing RANKL increases the ratio of RANKL to OPG and enhances osteoclast function.28
This increased osteoclast function shifts the balance of bone resorption/formation toward resorption, resulting in reduced bone mineral density in patients with RA. Elevated IL-6 signaling also inhibits bone regeneration by affecting osteogenesis.1,10,19,29,30
Increased bone resorption activity is associated with RA and translates to articular bone damage and systemic bone loss.31-33
Adapted from Choy 2012.
Schematic view of a normal joint (a)
and a joint affected by RA (b)
IL-6 activates and increases proliferation of FLSs of the synovial intimal, or inner lining.2,9,35,36 The invasive properties of FLSs have been shown to correlate with radiologic and histological damage in RA.37
Under normal conditions, FLSs secrete proteins that help build the extracellular collagen network, which is responsible for cushioning in joints.35 In RA, however, FLSs:
IL-6 is both produced by and activates FLSs.2,9,34,36
Adapted from Ota 2014 and Kimura 2010.
IL-6 and the positive feedback loop26,40-44
Serum IL-6 levels are at their highest in the early morning hours when patients with RA most often experience articular pain and stiffness, as well as functional disability.45-47
Adapted from Crofford 1997.
Early morning levels of IL-6: nearly 4 times higher in patients with RA45
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