Inhibitory effect of chloroquine on bone resorption reveals the key role of lysosomes in osteoclast differentiation and function

抄録

The lysosome is an acidic compartment containing certain hydrolytic enzymes necessary for the intracellular digestion of macromolecules. In terms of the activity of bone-resorbing osteoclasts, the secretion of lysosomal vesicles containing protons and matrix-degrading proteinases into the resorption lacunae is essential. Chloroquine (CQ), one of the lysosomotropic agents, has an immunosuppressive effect and is used for the treatment for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the direct effect of CQ on osteoclasts has not been reported. Here, we show that CQ suppresses the bone resorbing activity of osteoclasts by inhibition of the acidification in the lysosomes, as well as osteoclast differentiation in vitro. CQ treatment ameliorates the bone loss induced by RANKL injection in mice. These results suggest that CQ has a bone-increasing effect by inhibiting osteoclast differentiation and function. In addition, a lysosomal proton pump inhibitor bafilomycin A1 also inhibits osteoclast differentiation. Thus, this study revealed the importance of the lysosomes in osteoclast differentiation and function in vivo as well as in vitro, suggesting the therapeutic efficacy of immunosuppressive CQ in osteoclast-mediated bone loss or destruction.