ELP2 negatively regulates osteoblastic differentiation impaired by tumor necrosis factorα in MC3T3-E1 cells through STAT3 activation.

Abstract

Tumor necrosis factor‐α (TNF‐α) is a pluripotent signaling molecule. The biological effect of TNF‐α includes slowing down osteogenic differentiation, which can lead to bone dysplasia in long‐term inflammatory microenvironments. Signal transducer and activator of transcription 3 (STAT3)‐interacting protein 1 (StIP1, also known as elongator complex protein 2, ELP2) play a role in inhibiting TNF‐α‐induced osteoblast differentiation. In the present study, we investigated whether and how ELP2 activation mediates the effects of TNF‐α on osteoblastic differentiation. Using in vitro cell cultures of preosteoblastic MC3T3‐E1 cells, we found that TNF‐α inhibited osteoblastic differentiation accompanied by an increase in ELP2 expression and STAT3 activation. Forced ELP2 expression inhibited osteogenic differentiation of MC3T3‐E1 cells, with a decrease in the expression of osteoblast marker genes, alkaline phosphatase activity, and matrix mineralization capacity. In contrast, ELP2 silencing ameliorated osteogenic differentiation in MC3T3‐E1 cells, even after TNF‐α stimulation. The TNF‐α‐induced inhibitory effect on osteoblastic differentiation was therefore mediated by ELP2, which was associated with Janus kinase 2 (JAK2)/STAT3 activation. These results suggest that ELP2 is upregulated at the differentiation of MC3T3‐E1 cells into osteoblasts and inhibits osteogenic differentiation in response to TNF‐α through STAT3 activation.