Interaction Between Activating Transcription Factor 4 and Interleukin 6 Dictates Osteoclast Differentiation and Activity

Osteoclast functioning determines homeostasis of bone texture, healing speed after bone injury, and integrity after bone remodeling. Osteoclastogenesis is tightly controlled by transcriptional factors and cytokine-mediated signaling. The activating transcription factor 4 (Atf4) and interleukin 6 (IL6) have been considered to be involved in osteoclastogenesis, but their interaction on osteoclast differentiation is still largely unclear. Here we aimed to investigate their interaction on osteoclast differentiation and activity. Through lentiviral overexpression and siRNA transfection, we showed that Atf4 regulated osteoclastogenesis by upregulating the expression of osteoclast markers, including Nfatc1, c-Fos, Dcst1, Mmp2 and 9, and cathepsin K. Atf4-mediated osteoclastogenesis was largely dependent on activation of IL6 signaling through the direct binding of Atf4 to the IL6 promoter by ChIP assay. Atf4-IL6 axis activated the Jak1/Stat3 signaling to promote the formation of large, multinucleated osteoclasts. Taken together, these results indicate the important interaction between Atf4 and IL6 signaling on osteoclast differentiation beyond canonical MCSF and RANKL signaling and emphasize the multi-regulatory mechanism of Atf4-mediated osteoclastogenesis, which provides us with understanding of osteoporotic diseases and cues for therapeutic strategies.