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Chloroquine and osteoclastogenesis; the role of TRAF3 and potential for future therapeutics
DOI:10.1038/bonekey.2014.34
The proinflammatory cytokine tumor necrosis factor (TNF) acts as a direct stimulant of osteoclastogenesis but also boosts cellular levels of NF-κB p100, which decreases the formation of osteoclasts mediated through both TNF and RANKL. This poorly understood mechanism, which involves TNF receptor-associated receptor 3 (TRAF3), is explored by Xiu et al.
Transgenic mice with an osteoclast-specific deletion of TRAF3 showed increased production of osteoclasts with resultant osteoporosis; a result of enhanced canonical and noncanonical NF-κB signaling. RANKL was shown to act through the lysosome/autophagy system to degrade TRAF3, so the researchers then explored the effect of chloroquine, a potent inhibitor of this system.
Chloroquine enhanced expression of TRAF3 in osteoclast precursors, so reducing osteoclast formation normally stimulated by RANKL. Wild-type mice treated with chloroquine showed no reduction in basal bone resorption but osteoclast activation following PTH treatment or ovariectomy was inhibited. This effect was not seen in Traf3 knockout mice. Lyosomal degradation induced by TRAF3 and RANKL was dependent on the transcription factor gene RelB, which regulates expression of the autophagy regulator beclin 1 (BECN1).
The authors suggest that there is therapeutic potential here; drug candidates that could raise levels of TRAF3 in osteoclast precursors could reduce bone destruction in osteoporosis and other bone diseases.
Editor’s comment: This work further elucidates the signaling pathway of the surprisingly antagonistic effects of TNF on RANKL-mediated osteoclastogenesis, and may provide a proof-of-concept for the development of novel anti-resorptives.
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