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Irisin promotes proliferation but inhibits differentiation in osteoclast precursor cells

The receptor activator of NF‐κB ligand‐induced osteoclast differentiation has a critical role in the process of bone metabolism. Overactivation of osteoclastogenesis may result in a series of diseases. Irisin, a novel myokine, which was first reported in 2012, has been proposed to mediate the beneficial metabolic effects of exercise. Studies have demonstrated that irisin targets osteoblasts by promoting osteoblast proliferation and differentiation; how ever, the underlying mechanism regarding the effect of irisin on osteoclasts remains elusive. Using 2 types of osteoclast precursor cells, RAW264.7 cells and mouse bone marrow monocytes, we showed that irisin promoted osteoclast precursor cell proliferation but inhibited osteoclast differentiation. Irisin down‐regulated the expression of osteoclast differentiation marker genes, including receptor activators of NF‐κB, nuclear factor of activated T cells, cytoplasmic 1, cathepsin K, and tartrate‐resistant acid phosphatase (TRAP), as well as decreasing the number of TRAP‐positive multinucleated cells and hydroxyapatite resorption pits. Furthermore, we showed that irisin sup pressed the NF‐κB signaling pathway, but activated the p38 and JNK signaling pathways. In the presence of an inhibitor of p38 and JNK, irisin‐induced promotion of RAW264.7 cell proliferation was attenuated. However, irisin‐ induced inhibition of osteoclast differentiation was not affected by either the p38 or JNK signaling pathway. Our study suggested the direct effect of irisin on osteoclastogenesis and revealed the mechanism responsible for the therapeutic potential of irisin in bone metabolism disease.—Ma, Y., Qiao, X., Zeng, R., Cheng, R., Zhang, J., Luo, Y., Nie, Y., Hu, Y., Yang, Z., Zhang, J., Liu, L., Xu, W., Xu, C. C., Xu, L. Irisin promotes proliferation but inhibits differentiation in osteoclast precursor cells. FASEB J. 32, 5813–5823 (2018). www.fasebj.org