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Lack of MK2 Inhibits Myofibroblast Formation and Exacerbates Pulmonary Fibrosis

¹ Pulmonary and Critical Care Division, Department of Medicine/Tupper Research Institute, Tufts-New England Medical Center, and Tufts University School of Medicine, Boston, Massachusetts; and ² Institute of Biochemistry, Medical School Hannover, Hannover, Germany

Correspondence and requests for reprints should be addressed to Usamah S. Kayyali, Ph.D., Pulmonary & Critical Care Division, Tufts-New England Medical Center, 750 Washington Street # 257, Boston, MA 02111. E-mail: ukayyali{at}tufts-nemc.org

Fibroblasts play a major role in tissue repair and remodeling. Their differentiation into myofibroblasts, marked by increased expression of smooth muscle–specific -actin (-SMA), is believed to be important in wound healing and fibrosis. We have recently described a role for MK2 in this phenotypic differentiation in culture. In this article, we demonstrate that MK2 also regulates myofibroblasts in vivo. Disruption of MK2 in mice prevented myofibroblast formation in a model of pulmonary fibrosis. However, MK2 disruption and consequent lack of myofibroblast formation exacerbated fibrosis rather than ameliorated it as previously postulated. When mice lacking MK2 (MK2^–/–) were exposed to bleomycin, more collagen accumulated and more fibroblasts populated fibrotic regions in their lungs than in similarly treated wild-type mice. While there were many vimentin-positive cells in the bleomycin-treated MK2^–/– mouse lungs, few -SMA–positive cells were observed in these lungs compared with wild-type mouse lungs. siRNA against MK2 reduced -SMA expression in wild-type mouse embryonic fibroblasts (MEF), consistent with its suppression in MK2^–/– MEF. On the other hand expressing constitutively active MK2 in MK2^–/– MEF significantly increased -SMA expression. MK2^–/–MEF proliferated at a faster rate and produced more collagen; however, they migrated at a slower rate than wild-type MEF. Overexpressing phosphomimicking HSP27, a target of MK2, did not reverse the effect of MK2 disruption on fibroblast migration. MK2 disruption did not affect Smad2 activation by transforming growth factor-. Thus, MK2 appears to mediate myofibroblast differentiation, and inhibiting that differentiation might contribute to fibrosis rather than protect against it.

Key Words: actin • cytoskeleton • fibroblast • p38 • idiopathic pulmonary fibrosis

CLINICAL RELEVANCE Our findings implicate MK2 in the pathogenesis of pulmonary fibrosis. They further suggest that myofibroblasts might play a protective role in pulmonary fibrosis, in contrast to the commonly held view that they contribute to the pathogenesis of fibrosis.

 

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