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Smads in the Fibrotic Response: Findings in the Smad3 Knockout Mouse

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Transforming Growth Factor-β in Cancer Therapy, Volume I

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Transforming growth factor-β (TGF-β) mediates both physiological and pathological fibrotic responses by inducing influx and activation of inflammatory cells, epithelial to mesenchymal transdifferentiation of cells, and influx of fibroblasts and secretion of extracellular matrix. Activated TGF-β receptors phosphorylate signaling intermediates called Smad proteins which translocate to the nucleus and alter gene transcription. Mice in which the gene for Smad3, one of the TGF-β signaling proteins. has been deleted show more rapid healing of incisional and excisional wounds with less inflammation and matrix deposition. Smad3 null inflammatory cells and fibroblasts do not respond to the chemotactic effects of TGF-β and do not autoinduce TGF-β or respond to TGF-β-mediated induction of extracellular matrix proteins. Smad3 also appears to modulate pathologic fibrosis in that Smad3 null mice are resistant to fibrosis in a number of animal models including radiation-induced cutaneous fibrosis, bleomycin-induced pulmonary fibrosis, glomerulosclerosis resulting from unilateral ureter obstruction, and proliferative vitreoretinopathy. Agents that inhibit phosphorylation of Smad3 by affecting the TGF-β Type I receptor kinase reduce collagen synthesis of cells in vitro. Inducing expression of Smad7, an inhibitory Smad, inhibits unwanted matrix deposition in animal models of cutaneous, pulmonary, ocular, and renal fibrosis, suggesting that Smad3 inhibitors may have clinical potential in the treatment of pathological fibrotic diseases.

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  1. Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, The National Institute of Health, Bethesda, MD, USA

    Kathleen C. Flanders PhD

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Flanders, K.C. (2008). Smads in the Fibrotic Response: Findings in the Smad3 Knockout Mouse. In: Transforming Growth Factor-β in Cancer Therapy, Volume I. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-292-2_37

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  • DOI: https://doi.org/10.1007/978-1-59745-292-2_37

  • Publisher Name: Humana Press

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