Interleukin-1β promotes the LC3-mediated secretory function of osteoclast precursors by stimulating the Ca2+-dependent activation of ERK

Bone resorption by osteoclasts requires the release of secretory lysosomes containing cathepsin K, which degrades the organic bone matrix. The activity of this secretory function is determined by the level of lipidation of microtubule-associated protein 1 light chain 3 (LC3). Although the inflammatory cytokine IL-1β increases osteoclast activity, the underlying mechanism(s) remains undefined. In our present study, we found that IL-1β accelerates the release of cathepsin K from osteoclast precursors by increasing the cleavage and lipidation of LC3 and the subsequent formation of lipid-bound LC3-II containing secretory lysosomes. IL-1β increased LC3-II formation within osteoclast precursors through a process that is dependent on increases in the intracellular Ca2+ levels. In addition, IL-1β was found to act synergistically with RANKL to increase ERK activation in a Ca2+-dependent manner. More importantly, Atg7-deficient osteoclast precursors, which showed impaired lipidation of LC3-I, did not exhibit IL-1β-mediated increases in cathepsin K secretion. Thus, IL-1β promotes LC3-II formation through the Ca2+-dependent activation of ERK, which triggers the release of cathepsin K. These findings provide evidence for a molecular mechanism through which IL-1β enhances the secretory function of osteoclast precursors.