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Diverse signaling pathways regulate fibroblast differentiation and transformation through Rho kinase activation.
J Cell Physiol. 2007 May; 211(2):353-63.JC

Abstract

This study examined the role of agonist-induced Rho kinase (ROCK) involvement in the morphological outcome of pulmonary-derived fibroblasts. Normal human lung fibroblasts (NHLF) spontaneously differentiate into network-like structures in a two-dimensional growth factor reduced Matrigel matrix-based assay. Sphingosine 1-phosphate (SPP), a bioactive phospholipid that regulates angiogenesis, inhibited fibroblast morphogenesis in a dose-dependent manner, virtually eliminating the presence of multi-cellular structures at 500 nM. Pretreatment with the Rho kinase-specific inhibitor, H1152, eradicated the high dose SPP-induced inhibition. Similarly, NHLFs transfected with Rho kinase siRNA prevented SPP-induced inhibition of the fibroblast morphogenesis. Alternatively, transforming growth factor-beta1 (TGF-beta1), a cytokine recognized as a key mediator of wound healing, terminally differentiates NHLF into myofibroblasts as evidenced by the expression of the smooth muscle cell isoform of alpha-actin (alpha-SMA). H1152 suppressed TGF-beta1-induced alpha-SMA expression in a dose-dependent manner. Similarly, treatment with Rho kinase siRNA reduced alpha-SMA expression by greater than 50%. SPP treatment had no effect on TGF-beta1-induced transformation into myofibroblasts, and TGF-beta1 treatment did not alter fibroblast morphogenesis. This study suggests a dual regulatory role for Rho kinase in cellular regulation of fibroblasts in which SPP-induced Rho kinase activation via a G-protein coupled receptor suppresses fibroblast morphogenesis while TGF-beta1-induced Rho kinase activation through a serine/threonine kinase receptor culminates in transformation into myofibroblasts.

Authors+Show Affiliations

Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Indianapolis, Indiana, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17167780

Citation

Harvey, Kevin A., et al. "Diverse Signaling Pathways Regulate Fibroblast Differentiation and Transformation Through Rho Kinase Activation." Journal of Cellular Physiology, vol. 211, no. 2, 2007, pp. 353-63.
Harvey KA, Paranavitana CN, Zaloga GP, et al. Diverse signaling pathways regulate fibroblast differentiation and transformation through Rho kinase activation. J Cell Physiol. 2007;211(2):353-63.
Harvey, K. A., Paranavitana, C. N., Zaloga, G. P., & Siddiqui, R. A. (2007). Diverse signaling pathways regulate fibroblast differentiation and transformation through Rho kinase activation. Journal of Cellular Physiology, 211(2), 353-63.
Harvey KA, et al. Diverse Signaling Pathways Regulate Fibroblast Differentiation and Transformation Through Rho Kinase Activation. J Cell Physiol. 2007;211(2):353-63. PubMed PMID: 17167780.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diverse signaling pathways regulate fibroblast differentiation and transformation through Rho kinase activation. AU - Harvey,Kevin A, AU - Paranavitana,Corine Nivanka, AU - Zaloga,Gary P, AU - Siddiqui,Rafat A, PY - 2006/12/15/pubmed PY - 2007/5/16/medline PY - 2006/12/15/entrez SP - 353 EP - 63 JF - Journal of cellular physiology JO - J Cell Physiol VL - 211 IS - 2 N2 - This study examined the role of agonist-induced Rho kinase (ROCK) involvement in the morphological outcome of pulmonary-derived fibroblasts. Normal human lung fibroblasts (NHLF) spontaneously differentiate into network-like structures in a two-dimensional growth factor reduced Matrigel matrix-based assay. Sphingosine 1-phosphate (SPP), a bioactive phospholipid that regulates angiogenesis, inhibited fibroblast morphogenesis in a dose-dependent manner, virtually eliminating the presence of multi-cellular structures at 500 nM. Pretreatment with the Rho kinase-specific inhibitor, H1152, eradicated the high dose SPP-induced inhibition. Similarly, NHLFs transfected with Rho kinase siRNA prevented SPP-induced inhibition of the fibroblast morphogenesis. Alternatively, transforming growth factor-beta1 (TGF-beta1), a cytokine recognized as a key mediator of wound healing, terminally differentiates NHLF into myofibroblasts as evidenced by the expression of the smooth muscle cell isoform of alpha-actin (alpha-SMA). H1152 suppressed TGF-beta1-induced alpha-SMA expression in a dose-dependent manner. Similarly, treatment with Rho kinase siRNA reduced alpha-SMA expression by greater than 50%. SPP treatment had no effect on TGF-beta1-induced transformation into myofibroblasts, and TGF-beta1 treatment did not alter fibroblast morphogenesis. This study suggests a dual regulatory role for Rho kinase in cellular regulation of fibroblasts in which SPP-induced Rho kinase activation via a G-protein coupled receptor suppresses fibroblast morphogenesis while TGF-beta1-induced Rho kinase activation through a serine/threonine kinase receptor culminates in transformation into myofibroblasts. SN - 0021-9541 UR - https://www.unboundmedicine.com/medline/citation/17167780/Diverse_signaling_pathways_regulate_fibroblast_differentiation_and_transformation_through_Rho_kinase_activation_ L2 - https://doi.org/10.1002/jcp.20939 DB - PRIME DP - Unbound Medicine ER -