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J. Biol. Chem., Vol. 280, Issue 12, 11749-11758, March 25, 2005

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Selective Activation of the MEK-ERK Pathway Is Regulated by Mechanical Stimuli in Forming Joints and Promotes Pericellular Matrix Formation^*

Edward R. Bastow, Katherine J. Lamb, Jo C. Lewthwaite, Anne C. Osborne¶, Emma Kavanagh||, Caroline P. D. Wheeler-Jones, and Andrew A. Pitsillides**

From the Department of Veterinary Basic Sciences, Royal Veterinary College, Royal College St., London, NW1 0TU, United Kingdom

It is well established that local modification of extracellular matrix (ECM) hyaluronan composition is vital in the regulation of cell behavior. Indeed, the formation of articulating chick joint cavities, which requires mechanical stimuli derived from skeletal movement, is dependent upon the accumulation of an ECM rich in hyaluronan (HA). However, the mechanisms responsible for such precise mechano-dependent regulation of cell behavior and the formation of a HA-rich ECM remain undefined. Here we show that extracellular-regulated kinase 1/2 (ERK1/2) is selectively activated in cells at sites of cavity formation and activity diminished by in ovo immobilization that induces cartilaginous fusion across presumptive joint interzones. In vitro analyses offer mechanistic support for the role of mechanical stimuli in promoting a MEK-dependent activation of ERK1/2. In addition, our direct regulation of ERK1/2 phosphorylation status via modulation of its up-stream "classical cascade" activator either pharmacologically or by transfection with dominant negative or constitutively active Mek confirms the essential role for ERK1/2 activation in the elaboration of HA-rich pericellular matrices. Together, our findings demonstrate that the MEK-ERK pathway, regulated by mechanical stimuli, controls HA-rich matrix assembly. The precision of ERK1/2 activation selectively distinguishing cells at the joint line suggests that it directly contributes to the loss of tissue cohesion essential for generating HA-rich cavities between joint elements during their development.

Received for publication, December 23, 2004

^* This work was supported by The Wellcome Trust, The Arthritis Research Campaign, and the Biotechnology and Biological Sciences Research Council. 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.

These authors contributed equally to this work.

^¶ Current address: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.

^|| Current address: Dept. of Cell Biology, Institute of Ophthalmology, 11–43 Bath St., London, EC1V 9EL, UK.

^** To whom correspondence should be addressed: Veterinary Basic Sciences, Royal Veterinary College, Royal College St., London, NW1 0TU, UK. Tel.: 44-20-74685036; Fax: 44-20-74685204; E-mail: apitsill{at}rvc.ac.uk.

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