Inhibitory regulation of osteoclast differentiation by interleukin-3 via regulation of c-Fos and Id protein expression

Interleukin‐3 (IL‐3) is produced under various pathological conditions and is thought to be involved in the pathogenesis of inflammatory diseases; however, its function in bone homeostasis under normal conditions or nature of the downstream molecular targets remains unknown. Here we examined the effect of IL‐3 on osteoclast differentiation from mouse and human bone marrow‐derived macrophages (BMMs). Although IL‐3 can induce osteoclast differentiation of multiple myeloma bone marrow cells, IL‐3 greatly inhibited osteoclast differentiation of human BMMs isolated from healthy donors. These inhibitory effects of IL‐3 were only observed at early time points (days 0 and 1). IL‐3 inhibited the expression of c‐Fos and NFATc1 in BMMs treated with RANKL. However, IL‐3‐mediated inhibition of osteoclast differentiation was not completely reversed by ectopic expression of c‐Fos or NFATc1. Importantly, IL‐3 induced inhibitor of DNA binding/differentiation (Id)1 in hBMMs, while Id2 were sustained during osteoclast differentiation of mBMMs treated with IL‐3. Ectopic expression of NFATc1 in Id2‐deficient BMMs completely reversed the inhibitory effect of IL‐3 on osteoclast differentiation. Furthermore, inflammation‐induced bone erosion was markedly inhibited by IL‐3 administration. Taken together, our results suggest that IL‐3 plays an inhibitory role in osteoclast differentiation by regulating c‐Fos and Ids, and also exerts anti‐bone erosion effects. J. Cell. Physiol. 227: 1851–1860, 2012. © 2011 Wiley Periodicals, Inc.