Abstract
RANKL induces osteoclastogenesis via JNK1 signal that exerts an anti-apoptotic effect during osteoclastogenesis. However, the classic downstream c-Jun/AP-1 pathway is not included in anti-apoptosis of JNK1. Thus, the detail mechanism underlying JNK1-resisted apoptosis remains unknown during RANKL-induced osteoclastogenesis. RANKL-induced autophagy results in the degradation of the osteoclastogenesis-inhibitor TRAF3, and TRAF3 is thought as a regulator of apoptosis. Given the key effect of JNK1 in mediating autophagy, our study aims to investigate the significance of TRAF3 in bridging JNK1-mediated autophagy and apoptotic resistance during osteoclastogenesis. In this study, by using Bone Marrow-derived macrophages (BMMs) as osteoclast precursors (OCPs), we found that RANKL-induced TRAF3 degradation was significantly suppressed by JNK inhibitor (SP600125), which was restored by overexpression of Beclin1 (key autophagic protein). Nevertheless, TRAF3 silencing partially reversed the reduced osteoclastogenesis under SP600125 intervention. Besides, OCP apoptosis was positively regulated by TRAF3 overexpression, regardless of the application of autophagy inhibitor or SP600125. Remarkably, the enhanced apoptosis caused by the pharmacological inhibition of Beclin1 was reversed by TRAF3 silencing. Together, these results suggest that JNK1-mediated autophagy could promote RANKL-induced osteoclastogenesis via enhancing TRAF3 degradation. Importantly, JNK1 could prevent OCP apoptosis through autophagy-TRAF3 signaling, which provides more potential targets for clinical treatment of pathological bone loss.