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J. Biol. Chem., Vol. 279, Issue 40, 41453-41460, October 1, 2004

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Myofibroblastic Differentiation Leads to Hyaluronan Accumulation through Reduced Hyaluronan Turnover^*

Robert H. Jenkins, Gareth J. Thomas, John D. Williams, and Robert Steadman

From the Institute of Nephrology, University of Wales College of Medicine, and Cardiff Institute of Tissue Engineering and Repair, Heath Park, Cardiff CF14 4XN, Wales, United Kingdom

During the initiation and progression of fibrosis there is extensive differentiation of cells to a myofibroblastic phenotype. Because the synthesis of hyaluronan (HA) was recently linked to oncogenic epithelial-mesenchymal transformation, the present study investigated whether increased HA synthesis was also associated with myofibroblastic differentiation. HA synthesis and size were measured by incorporation of [³H]glucosamine, ion exchange, and size exclusion chromatography. Hyaluronan synthase (HAS) or hyaluronidase (HYAL) mRNA levels were assessed by reverse transcription-PCR. HYAL was detected by immunoblotting and the degradation of [³H]HA. Between 2- and 3-fold more HA appeared in the conditioned medium and became associated with the cells upon myofibroblastic differentiation. Inhibition of HAS and examination of HAS mRNA expression demonstrated that this was not the result of increased synthesis of HA or the induction of HAS 2. After differentiation, however, myofibroblasts metabolized exogenously supplied [³H]HA at a slower rate than fibroblasts and expressed lower levels of both HYAL 1 and HYAL 2 mRNA. Immunoblotting revealed more HYAL 1 and 2 in the myofibroblast conditioned medium. After acidification, however, there was no difference in HA degradation. This suggests that much of the released HYAL is inactive and that the observed differences in HA degradation are caused by cell-associated rather than secreted activity. This was confirmed by immunohistochemical staining for HYAL 1 and HYAL 2. This finding indicates the potential importance of the HYAL enzymes in controlling fibrotic progression and contrasts HA synthesis as a mediator of oncogenic transformation with that of HA degradation controlling fibrogenic differentiation.

Received for publication, February 16, 2004 , and in revised form, July 7, 2004.

^* 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 correspondence should be addressed. Tel.: 44-292-074-8389; Fax: 44-292-074-8470; E-mail: steadmanr{at}cf.ac.uk.

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