Dataset Information

ERK1/2 drives IL-1?-induced expression of TGF-?1 and BMP-2 in torn tendons.

ABSTRACT: Diseased and injured tendons develop fibrosis, driven by factors including TGF-?, BMPs and CTGF. IL-1? and its signal transducer Erk1/2 are known to regulate TGF-? expression in animal tendons. We utilised tissues and cells isolated from patients with shoulder tendon tears and tendons of healthy volunteers to advance understanding of how inflammation induces fibrosis in diseased human tendons. ERK1/2 expression was reduced in torn (diseased) compared to healthy patient tendon tissues. We next investigated the fibrotic responses of tendon-derived cells isolated from healthy and diseased human tendon tissues in an inflammatory milieu. IL-1? treatment induced profound ERK1/2 signalling, TGFB1 and BMP2 mRNA expression in diseased compared to healthy tendon-derived cells. In the diseased cells, the ERK1/2 inhibitor (PD98059) completely blocked the IL-1?-induced TGFB1 and partially reduced BMP2 mRNA expression. Conversely, the same treatment of healthy cells did not modulate IL-1?-induced TGFB1 or BMP2 mRNA expression. ERK1/2 inhibition did not attenuate IL-1?-induced CTGF mRNA expression in healthy or diseased tendon cells. These findings highlight differences between ERK1/2 signalling pathway activation and expression of TGF-?1 and BMP-2 between healthy and diseased tendon tissues and cells, advancing understanding of inflammation induced fibrosis during the development of human tendon disease and subsequent repair.

SUBMITTER: Morita W

PROVIDER: S-EPMC6908634 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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ERK1/2 drives IL-1β-induced expression of TGF-β1 and BMP-2 in torn tendons.

Morita Wataru W Snelling Sarah J B SJB Wheway Kim K Watkins Bridget B Appleton Louise L Carr Andrew J AJ Dakin Stephanie G SG

Scientific reports 20191212 1

Diseased and injured tendons develop fibrosis, driven by factors including TGF-β, BMPs and CTGF. IL-1β and its signal transducer Erk1/2 are known to regulate TGF-β expression in animal tendons. We utilised tissues and cells isolated from patients with shoulder tendon tears and tendons of healthy volunteers to advance understanding of how inflammation induces fibrosis in diseased human tendons. ERK1/2 expression was reduced in torn (diseased) compared to healthy patient tendon tissues. We next in ...[more]

PMID: 31831776

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Project description:In patients who were treated with exogenous BMP-2 to repair bone fractures or defects, the levels of the inflammatory cytokines such as TNF-α and IL-1β in sera are significantly elevated, which may affect the outcome of bone regeneration. Mitogen-activated protein kinase (MAPK) cascades such as extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase 1/2 (JNK1/2) have a crucial role in osteogenic differentiation and are activated by both BMP-2 and TNF-α/IL-1β. However, previous studies suggested that the effects of BMP-2 and TNF-α/IL-1β in osteoblastic differentiation are opposite. Here, we investigated the exact role of MAPKs in a BMP-2 and TNF-α/IL-1β co-existed condition. Treatment with TNF-α/IL-1β inhibited BMP-2-induced alkaline phosphatase activity, calcium deposition, osteogenic transcriptional factor Runx2, and the expression of osteogenic markers in C2C12 and MC3T3-E1 cells. This inhibitory effect was independent of the canonical BMP/Smad pathway, suggesting the presence of an alternate regulatory pathway for BMP-2-induced Runx2 activity and subsequent osteoblastic differentiation. We then confirmed that BMP-2, TNF-α, and IL-1β alone can activate p38, ERK1/2, and JNK1/2, respectively. However, only inhibition of p38 and ERK1/2 signaling were required to modulate BMP-2-induced Runx2 expression. Finally, we determined that TNF-α/IL-1β decreased BMP-2-induced Runx2 expression through the activation of p38 and ERK1/2 signaling. Furthermore, strong activation of p38 and ERK1/2 signaling by transfection with CA-MKK3 or CA-MEK1 inhibited BMP-2-induced Runx2 expression and osteoblastic differentiation in C2C12 and MC3T3-E1 cells. Based on these results, we conclude that TNF-α/IL-1β- and BMP-2-activated p38 and ERK1/2 signaling have opposing roles that converge on Runx2 to regulate osteoblastic differentiation. The elucidation of these mechanisms may hasten the development of new strategies and improve the osteoinductive efficacy of BMP-2 in the clinic to enhance osteoblastic differentiation and bone formation.

Dataset Information

ERK1/2 drives IL-1?-induced expression of TGF-?1 and BMP-2 in torn tendons.

Publications

ERK1/2 drives IL-1β-induced expression of TGF-β1 and BMP-2 in torn tendons.

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