Endothelin‑1 induces oncostatin M expression in osteoarthritis osteoblasts by trans‑activating the oncostatin M gene promoter via Ets‑1

Wu,Ren; Wang,Wanchun; Huang,Guoliang; Mao,Xinzhan; Chen,You; Tang,Qi; Liao,Lele

doi:10.3892/mmr.2016.4960

Endothelin‑1 induces oncostatin M expression in osteoarthritis osteoblasts by trans‑activating the oncostatin M gene promoter via Ets‑1

Authors:
- Ren Wu
- Wanchun Wang
- Guoliang Huang
- Xinzhan Mao
- You Chen
- Qi Tang
- Lele Liao
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Affiliations: Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
Published online on: March 2, 2016 https://doi.org/10.3892/mmr.2016.4960
Pages: 3559-3566

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Abstract

Oncostatin M (OSM) contributes to cartilage degeneration in osteoarthritis (OA) and was demonstrated to be expressed in OA osteoblasts. Endothelin‑1 (ET‑1) is implicated in the degradation of OA articular cartilage, and osteoblast proliferation and bone development. In the present study, the effects of ET‑1 on OSM expression in human OA osteoblasts were investigated, to the best of our knowledge, for the first time. Primary human OA osteoblasts were treated with ET‑1 (1, 5, 10, 20 and 30 nM) for 0.5, 1, 2, 3 and 4 h with or without the selective ETA receptor (ETAR) antagonist, BQ123, ETB receptor antagonist, BQ788 or the phosphatidylinositol 3‑kinase (PI3K) inhibitor, BKM120. ET‑1 treatment induced OSM mRNA expression, and the intracellular and secreted protein levels of OA osteoblasts in a dose‑dependent manner. This effect was suppressed by BQ123 and BKM120, but not BQ788 administration. In combination with electrophoretic mobility shift assays, deletional and mutational analyses on the activity of a human OSM promoter/luciferase reporter demonstrated that ET‑1 induced OSM expression in OA osteoblasts by trans‑activating the OSM gene promoter through specific binding of Ets‑1 to an Ets‑1 binding site in the OSM promoter in an ETAR‑ and PI3K‑dependent manner. Furthermore, ET‑1 treatment increased the expression of Ets‑1 in a dose‑dependent manner, however the knockdown of Ets‑1 suppressed the ET1‑induced expression of OSM in OA osteoblasts. In conclusion, the present study demonstrated that ET‑1 induces the expression of OSM in OA osteoblasts by trans‑activating the OSM gene promoter primarily through increasing the expression level of Ets‑1 in an ETAR‑ and PI3K‑dependent manner. The current study suggested novel insights into the mechanistic role of ET‑1 in the pathophysiology of OA.

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