Inflammation-dependent activation of NCOA2 associates with p300 and c-MYC/Max heterodimer to transactivate RUNX2-AS1 and mediate RUNX2 downstream bone differentiation genes in the pathology of septic nonunion.

Chen Li, Yi-Hong Qian

Cytokine 2022 Oct

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Septic nonunion (SN) is a common bone disorder caused by the failure of fracture healing. Local inflammation in fracture sites often causes SN; however, little is known about the molecular mechanisms of SN pathology. Herein, we identified a significant upregulation of the long non-coding RNA (lncRNA) RUNX2-AS1 (Runt-related Transcription Factor 2-Antisense 1) in the biopsies of SN patients. Overexpression or knockdown of RUNX2-AS1 in vitro could inhibit or induce, respectively, the expression of RUNX2 and RUNX2-downstream target genes, including ALPL (Alkaline Phosphatase), COL1A1 (Collagen Type I Alpha 1 Chain), IBSP (Integrin Binding Sialoprotein), MMP13 (Matrix Metallopeptidases), and SPP1 (Secreted Phosphoprotein 1), which are involved in bone differentiation. Mechanically, we demonstrated that a transcription factor c-MYC could assemble a transcriptional complex with its partner Max, a histone acetyltransferase p300, and nuclear receptor coactivator 2 (NCOA2), and this complex then bound to the promoter of RUNX2-AS1 to transactivate its expression. The mRNA and protein levels of NCOA2 were dose-dependently increased by treatment with lipopolysaccharide(LPS), a well-known inflammation trigger. LPS exposure increased the enrichment of the NCOA2-p300-c-MYC/Max complex on the RUNX2-AS1 promoter to activate its expression, thereby downregulating the expression of RUNX2 and RUNX2-downstream target genes. Depletion of NCOA2 reversed the expression of RUNX2-AS1, RUNX2, and RUNX2 target genes following LPS exposure. Taken together, our results demonstrate a new signaling pathway that contributes to the pathology of SN and may aid in preventing SN progression. Copyright © 2022 Elsevier Ltd. All rights reserved.

Citation

Chen Li, Yi-Hong Qian. Inflammation-dependent activation of NCOA2 associates with p300 and c-MYC/Max heterodimer to transactivate RUNX2-AS1 and mediate RUNX2 downstream bone differentiation genes in the pathology of septic nonunion. Cytokine. 2022 Oct;158:155992