Overexpression of c-Fos reverses osteoprotegerin-mediated suppression of osteoclastogenesis by increasing the Beclin1-induced autophagy.

Abstract

Osteoclastogenesis requires the involvement of transcription factors and degrading enzymes, and is regulated by upstream and downstream signalling. However, c‐Fos how regulates osteoclastogenesis through autophagy remain unclear. This study aimed to explore the role of c‐Fos during osteoprotegerin (OPG)‐mediated suppression of osteoclastogenesis. We found that the number of osteoclasts and the expression of c‐Fos, MMP‐9, CAⅡ, Src and p62 were decreased after treated with OPG, including attenuation the PI3K/Akt and the TAK1/S6 signalling pathways, but the expression of Beclin1 and LC3Ⅱ were increased. Knockdown of Beclin1 could reverse the expression of c‐Fos and MMP‐9 by activating the PI3K/Akt signalling pathway, but inhibiting the autophagy and the TAK1/S6 signalling pathway. In addition, inhibition of autophagy using the PI3K inhibitor LY294002 did not rescues OPG‐mediated suppression of osteoclastogenesis, but caused reduction of the expression of c‐Fos and CAⅡ by attenuating the autophagy, as well as the PI3K/Akt and the TAK1/S6 signalling pathways. Furthermore, continuous activation of c‐Fos could reverse OPG‐mediated suppression of osteoclastogenesis by activating the autophagy and the PI3K/Akt and the TAK1/S6 signalling pathways. Thus, overexpression of c‐Fos could reverse OPG‐mediated suppression of osteoclastogenesis via activation of Beclin1‐induced autophagy, indicating c‐Fos might serve as a new candidate for bone‐related basic studies.