C-Src-dependent transactivation of PDGFR contributes to TNF-α-induced MMP-9 expression and functional impairment in osteoblasts

Chia Lan Tsai, Wei Chung Chen, I-Ta Lee, Pei Ling Chi, Shin Ei Cheng, Chuen Mao Yang

研究成果: 雜誌貢獻文章

16 引文 斯高帕斯(Scopus)

摘要

Matrix metalloproteinases (MMPs), MMP-9 especially, have been shown to be induced by cytokines, including tumor necrosis factor-α (TNF-α) and may contribute to bone inflammatory diseases and postnatal bone modeling and remodeling. However, the mechanisms underlying MMP-9 expression induced by TNF-α in osteoblasts remain unclear. Here, we showed that in MC3T3-E1 cells, TNF-α induced MMP-9 gene expression determined by real-time PCR, zymography, and promoter assay. TNF-α-mediated responses were attenuated by pretreatment with the inhibitor of protein tyrosine kinase (PTK; genistein), c-Src (PP1), PDGFR (AG1296), PI3K (LY294002), Akt (SH-5), MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), or AP-1 (Tanshinone IIA) and transfection with siRNA of c-Src, PDGFR, p85, Akt, c-Jun, or ATF2. Moreover, TNF-α also time-dependently stimulated phosphorylation of c-Src and PDGFR and c-Src/PDGFR complex formation, which were reduced by pretreatment with PP1 or AG1296. TNF-α-stimulated Akt phosphorylation was inhibited by genistein, PP1, AG1296, LY294002, or SH5. We further demonstrated that TNF-α stimulated ERK1/2, p38 MAPK, and JNK1/2 phosphorylation via a c-Src-dependent PDGFR/PI3K/Akt pathway. TNF-α stimulated AP-1 activation, including c-Jun and ATF2 phosphorylation and AP-1 transcription activity via MAPK-dependent pathways. In addition, TNF-α-induced MMP-9 promoter activity was mediated through an AP-1 binding domain of the MMP-9 promoter region. Finally, we found that up-regulation of MMP-9 contributes to MMP-mediated type I collagen degradation and osteoblasts detachment. These results suggested that TNF-α-induced MMP-9 expression is mediated through a c-Src-dependent PDGFR transactivation and PI3K/Akt cascade linking to MAPK-mediated activation of AP-1 (c-Jun/ATF2) and leading to functional impairment in osteoblasts.
原文英語
頁(從 - 到)186-197
頁數12
期刊Bone
60
DOIs
出版狀態已發佈 - 三月 1 2014
對外發佈Yes

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ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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