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J. Biol. Chem., Vol. 281, Issue 51, 39471-39479, December 22, 2006

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Regulation of SOX9 mRNA in Human Articular Chondrocytes Involving p38 MAPK Activation and mRNA Stabilization^*

From the UK Centre for Tissue Engineering and Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom

Human articular chondrocytes rapidly lose their phenotype in monolayer culture. Recently we have shown that overexpression of the transcription factor SOX9 greatly enhanced re-expression of the phenotype in three-dimensional aggregate cultures. Here we show that endogenous SOX9 mRNA can be rapidly up-regulated in subcultured human articular chondrocytes if grown in alginate, in monolayer with cytochalasin D, or with specific inhibition of the RhoA effector kinases ROCK1 and -2, which all prevent actin stress fiber formation. Disruption of actin stress fibers using any of these redifferentiation stimuli also supported the superinduction of SOX9 by cycloheximide. The superinduction was blocked by inhibitors of the p38 MAPK signaling pathway and involved the stabilization of SOX9 mRNA. Furthermore stimulation of chondrocyte p38 MAPK activity with interleukin-1 resulted in increased levels of SOX9 mRNA, and this was again dependent on the absence of actin stress fibers in the cells. In this study of chondrocyte redifferentiation we have provided further evidence of the early involvement of SOX9 and have discovered a novel post-transcriptional regulatory mechanism activated by p38 MAPK, which stabilized SOX9 mRNA.

Received for publication, May 5, 2006 , and in revised form, September 27, 2006.

^* This work was funded by the United Kingdom research councils: Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council, and Medical 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.

¹ To whom correspondence should be addressed: UK Centre for Tissue Engineering, Faculty of Life Sciences, University of Manchester, Michael Smith Bldg., Oxford Rd., Manchester M13 9PT, UK. Tel.: 44-161-2755511; Fax: 44-161-2751505; E-mail: timothy.e.hardingham{at}manchester.ac.uk.

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