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Connective tissue growth factor is a target of notch signaling in cells of the osteoblastic lineage.

ABSTRACT: Connective tissue growth factor (Ctgf) or CCN2 is a protein synthesized by osteoblasts necessary for skeletal homeostasis, although its overexpression inhibits osteogenic signals and bone formation. Ctgf is induced by bone morphogenetic proteins, transforming growth factor ? and Wnt; and in the present studies, we explored whether Notch regulated Ctgf expression in osteoblasts. We employed Rosa(Notch) mice, where the Notch intracellular domain (NICD) is expressed following the excision of a STOP cassette, placed between the Rosa26 promoter and NICD. Notch was activated by transduction of adenoviral vectors expressing Cre recombinase (Ad-CMV-Cre). Notch induced Ctgf mRNA levels in a time dependent manner and increased Ctgf heterogeneous nuclear RNA. Notch also destabilized Ctgf mRNA shortening its half-life from 13h to 3h. The effect of Notch on Ctgf expression was lost following Rbpj? downregulation, demonstrating that it was mediated by Notch canonical signaling. However, downregulation of the classic Notch target genes Hes1, Hey1 and Hey2 did not modify the effect of Notch on Ctgf expression. Wild type osteoblasts exposed to immobilized Delta-like 1 displayed enhanced Notch signaling and increased Ctgf expression. In addition to the effects of Notch in vitro, Notch induced Ctgf in vivo, and calvariae and femurs from Rosa(Notch) mice mated with transgenics expressing the Cre recombinase in cells of the osteoblastic lineage exhibited increased expression of Ctgf. In conclusion, Ctgf is a target of Notch canonical signaling in osteoblasts, and may act in concert with Notch to regulate skeletal homeostasis.

SUBMITTER: Canalis E

PROVIDER: S-EPMC4069863 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Connective tissue growth factor is a target of notch signaling in cells of the osteoblastic lineage.

Canalis Ernesto E Zanotti Stefano S Smerdel-Ramoya Anna A

Bone 20140502

Connective tissue growth factor (Ctgf) or CCN2 is a protein synthesized by osteoblasts necessary for skeletal homeostasis, although its overexpression inhibits osteogenic signals and bone formation. Ctgf is induced by bone morphogenetic proteins, transforming growth factor β and Wnt; and in the present studies, we explored whether Notch regulated Ctgf expression in osteoblasts. We employed Rosa(Notch) mice, where the Notch intracellular domain (NICD) is expressed following the excision of a STOP ...[more]

PMID: 24792956

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Project description:BACKGROUND:Adenomyosis is a medical condition defined by the abnormal presence of endometrial tissue within the myometrium, in which fibrosis occurs with new collagen deposition and myofibroblast differentiation. In this study, the effect of several mediators and growth factors on collagen expression was investigated on human endometrial stromal cells (fibroblasts) derived from adenomyotic endometrium. EXPERIMENTAL APPROACH:RT-PCR, Western blot analysis, pharmacological interventions and siRNA interference were applied to primary cultured human endometrial stromal cells (fibroblasts). Immunohistochemistry was used to analyze protein expression in adenomyotic endometrium tissue specimens. RESULTS:Of the tested mediators, transforming growth factor ?1 (TGF?1) and its isoforms were effective to induce collagen and connective tissue growth factor (CTGF) expression. Collagen and CTGF induction by TGF?1 could be reduced by the inhibitors targeting DNA transcription, protein translation, and Smad2/3 signaling. Interestingly, TGF?1 induced Smad2/3 phosphorylation and CTGF mRNA expression, but not collagen mRNA expression, suggesting that TGF?1 mediates collagen expression through CTGF induction and Smad2/3 activation. In parallel, TGF?1 and CTGF also induced expression of heat shock protein (HSP) 47, a protein required for the synthesis of several types of collagens. However, only CTGF siRNA knockdown, could compromise TGF?1-induced collagen expression. Finally, the immunohistochemistry revealed vimentin- and ?-SMA-positive staining for (myo)fibroblasts, TGF?1, collagen, and CTGF in the subepithelial stroma region of human adenomyotic endometria. CONCLUSION AND IMPLICATIONS:We reveal here that TGF?1, collagen, and CTGF are expressed in the stroma of adenomyotic endometria and demonstrate that TGF?1 can induce collagen production in endometrium-derived fibroblasts through cellular Smad2/3-dependent signaling pathway and CTGF expression, suggesting that endometrial TGF? may take part in the pathogenesis of adenomyosis and ectopic endometrium may participate in uterine adenomyosis.

Dataset Information

Connective tissue growth factor is a target of notch signaling in cells of the osteoblastic lineage.

Publications

Connective tissue growth factor is a target of notch signaling in cells of the osteoblastic lineage.

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