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Mechanisms of Disease: the link between RANKL and arthritic bone disease


Chronic inflammation and bone loss are closely linked pathophysiologic events. The most typical example of inflammatory bone loss is seen in patients with rheumatoid arthritis who develop systemic osteopenia as well as local breakdown of bone in the direct vicinity of inflamed joints. Understanding the mechanisms of arthritic bone degradation is crucial for designing therapies that can specifically protect joints from structural damage. Since osteoclast differentiation and activity are key events in arthritic bone damage, the signals that trigger osteoclastogenesis are potential therapeutic targets. Receptor activator of nuclear factor-κB (RANK) is activated by its ligand, RANKL, an essential molecule for osteoclast development: in the absence of RANKL or RANK, osteoclast differentiation from monocyte precursors does not occur. RANKL is expressed on T cells and fibroblasts within the synovial inflammatory tissue of patients with RA and its expression is regulated by proinflammatory cytokines. In animal models of arthritis, blockade of RANKL–RANK interactions, or a genetic absence of RANKL or RANK, protects against joint damage despite the presence of joint inflammation. Therefore, inhibition of RANKL is regarded as a promising future strategy for inhibiting inflammatory bone loss in patients with chronic inflammatory arthritis.

Key Points

  • Chronic synovial inflammation triggers local as well as generalized bone loss

  • The link between chronic inflammation and skeletal breakdown lies in the potential of synovial inflammatory tissue to induce the formation of osteoclasts

  • Receptor activator of NFκB ligand (RANKL) is an essential molecule for osteoclastogenesis

  • Therapeutic inhibition of RANKL is effective for preventing local bone erosion in animal models of arthritis

  • RANKL inhibition is therefore considered to be a promising therapeutic tool for protecting bone against arthritic damage

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Figure 1: Inflammatory cytokines lead to generalized osteopenia.
Figure 2: Osteoclasts at sites of bone erosion in rheumatoid arthritis.
Figure 3: RANKL induces RANK-dependent intracellular signaling pathways in osteoclasts.
Figure 4: Model of local bone resorption in arthritis.


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G Schett receives funding support from START Program of the Austrian Science Fund (FWF) of the Austrian Federal Ministry for Education, Science and Culture.

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Correspondence to Georg Schett.

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Schett, G., Hayer, S., Zwerina, J. et al. Mechanisms of Disease: the link between RANKL and arthritic bone disease. Nat Rev Rheumatol 1, 47–54 (2005).

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