CARD-024, a vitamin D analog, attenuates the pro-fibrotic response to substrate stiffness in colonic myofibroblasts

详细信息	查看全文 | 推荐本文 |

• 作者：Laura A. Johnson^a ; Kay L. Sauder^a ; Eva S. Rodansky^a ; Robert U. Simpson^b ; Peter D.R. Higgins^a ; ^{phiggins@med.umich.edu}
• 关键词：CD ; Crohn's disease ; ECM ; extracellular matrix ; TGF尾 ; transforming growth factor beta ; 伪SMA ; alpha-smooth muscle actin
• 刊名：Experimental and Molecular Pathology
• 出版年：2012
• 期刊代码：291_00144800
• 类别：med
• 出版时间：August, 2012
• 卷：93
• 期：1
• 页码：91-98
• 文件大小：986 K

摘要

Intestinal fibrosis is one of the major complications of Crohn's disease (CD) for which there are no effective pharmacological therapies. Vitamin D deficiency is common in CD, though it is not known whether this is a contributing factor to fibrosis, or simply a consequence of the disease itself. In CD, fibrosis is mediated mainly by activated intestinal myofibroblasts during remodeling of extracellular matrix in response to wound healing. We investigated the effects of CARD-024 (1-alpha-hydroxyvitamin D5), a vitamin D analog with minimal hypercalcemic effects, on the pro-fibrotic response of intestinal myofibroblasts to two fibrogenic stimuli: TGF尾 stimulation and culture on a physiologically stiff matrix.

TGF尾 stimulated a fibrogenic phenotype in Ccd-18co colonic myofibroblasts, characterized by an increase in actin stress fibers and mature focal adhesions, and increased 伪SMA protein expression, while CARD-024 repressed 伪SMA protein expression in a dose-dependent manner. Culture of colonic myofibroblasts on physiological high stiffness substrates induced morphological changes with increased actin stress fibers and focal adhesion staining, induction of 伪SMA protein expression, FAK phosphorylation, induction of fibrogenic genes, and repression of COX-2 and IL-1尾. CARD-024 treatment repressed the stiffness-induced morphological features including stellate cell morphology and the maturation of focal adhesions. CARD-024 repressed the stiffness-mediated induction of 伪SMA protein expression, FAK phosphorylation, and MLCK and ET-1 gene expression. In addition, CARD-024 partially stimulated members of the COX-2/IL-1尾 inflammatory pathway.

In summary, CARD-024 attenuated the pro-fibrotic response of colonic myofibroblasts to high matrix stiffness, suggesting that vitamin D analogs such as CARD-024 may ameliorate intestinal fibrosis.