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JNK1 regulates RANKL‐induced osteoclastogenesis via activation of a novel Bcl‐2‐Beclin1‐autophagy pathway

JNK1 plays an important role in osteoclastogenesis in response to the osteoclastogenic cytokine receptor activator for nuclear factor‐κB ligand (RANKL). JNK1 is widely accepted as an autophagy regulator under stress conditions. However, the role of JNK1‐mediated autophagy in osteoclastogenesis remains largely unknown. In the current study, our data showed that JNK1 inhibition by a pharmacological inhibitor or RNA interference significantly reduced the autophagic response induced by RANKL in osteoclast precursors (OCPs) derived from bone marrow‐derived macrophages. Overexpression of the key autophagy protein Beclin1 rescued autophagy deficiency and osteoclastogenesis in the presence of a JNK inhibitor (SP600125). In contrast, JNK activator (anisomycin)‐induced autophagy was blocked by Beclin1 knockdown in OCPs. In addition, JNK1 inhibition increased apoptosis and blocked autophagy, whereas overexpression of Beclin1 reversed the enhanced apoptosis induced by JNK1 inhibition in OCPs. Furthermore, RANKL could induce the phosphorylation of Bcl‐2, subsequently dissociating Beclin1 from the Bcl‐2‐Beclin1 complex, which could be blocked by JNK1 inhibition. Collectively, this study revealed that JNK1 regulated osteoclastogenesis by activating Bcl‐2‐Beclin1‐autophagy signaling in addition to the classic c‐Jun/activator protein 1 pathway, which provided the first evidence for the contribution of JNK1 signaling to OCP autophagy and the autophagic mechanism underlying JNK1‐regulated osteoclastogenesis. An important osteoclastogenesis‐regulating signaling pathway (JNK1‐Bcl‐2‐Beclin1‐autophagy activation) was identified, which provides novel potential targets for the clinical therapy of metabolic bone diseases.—Ke, D., Ji, L., Wang, Y., Fu, X., Chen, J., Wang, F., Zhao, D., Xue, Y., Lan, X., Hou, J. JNK1 regulates RANKL‐induced osteoclastogenesis via activation of a novel Bcl‐2‐Beclin1‐autophagy pathway. FASEB J. 33, 11082–11095 (2019). www.fasebj.org