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J. Biol. Chem., Vol. 279, Issue 6, 4588-4595, February 6, 2004

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The MEK-ERK Signaling Pathway Is a Negative Regulator of Cartilage-specific Gene Expression in Embryonic Limb Mesenchyme^*

Brent E. Bobick and William M. Kulyk

From the Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada

The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathway, also known as the MEK-ERK kinase cascade, has recently been implicated in the regulation of embryonic cartilage differentiation. However, its precise role in this complex process remains controversial. To more thoroughly examine the role of the MEK-ERK kinase cascade in chondrogenesis, we analyzed the effects of two structurally different pharmacological inhibitors of MEK, the upstream kinase activator of ERK, on chondrocyte differentiation in micromass cultures of embryonic chick limb mesenchyme cells. We found that the MEK inhibitors, U0126 and PD98059, promote increased accumulation of cartilage-characteristic mRNA transcripts for type II collagen, aggrecan, and the transcription factor, Sox9. PD98059 treatment stimulated increased deposition of sulfated glycosaminoglycan into both Alcian blue-stainable cartilage matrix and the surrounding culture medium, whereas U0126 elevated glycosaminoglycan secretion into the medium fraction alone. Both MEK inhibitors increased total type II collagen protein accumulation in micromass culture and elevated the activity of a transfected type II collagen enhancer-luciferase reporter gene. Thus, pharmacological MEK inhibition induced increased expression of multiple chondrocyte differentiation markers. Conversely, transfection of limb mesenchyme cells with a constitutively active MEK1 plasmid resulted in a prominent decrease in the activity of a co-transfected type II collagen enhancer-luciferase reporter gene. Collectively, these findings support the hypothesis that signaling through the MEK-ERK kinase cascade may function as an important inhibitory regulator of embryonic cartilage differentiation.

Received for publication, September 4, 2003 , and in revised form, November 13, 2003.

^* This investigation was supported by Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant 121407-00 (to W. M. K.) and by an NSERC postgraduate scholarship award (to B. E. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom all correspondence should be addressed: Dept. of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, 107 Wiggins Rd., Saskatoon, Saskatchewan S7N 5E5, Canada. Tel.: 306-966-4078; Fax: 306-966-4298; E-mail: kulykw{at}duke.usask.ca.

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