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J. Biol. Chem., Vol. 279, Issue 8, 6959-6966, February 20, 2004

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Collagen Metabolism Is a Novel Target of the Neuropeptide -Melanocyte-stimulating Hormone^*

Markus Böhm, Michael Raghunath¶, Cord Sunderkötter||, Meinhard Schiller, Sonja Ständer, Thomas Brzoska, Thomas Cauvet**, Helgi B. Schiöth, Thomas Schwarz, and Thomas A. Luger

From the Department of Dermatology and the Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin and the Departments of ^||Experimental Dermatology and ^**Medicine, Haematology, and Oncology, University of Münster, 48149 Münster, Germany and the Department of Neuroscience, Uppsala University, 751 24 Uppsala, Sweden

Suppression of collagen synthesis is a major therapeutic goal in the treatment of fibrotic disorders. We show here that -melanocyte-stimulating hormone (-MSH), a neuropeptide well known for its pigment-inducing capacity, modulates collagen synthesis and deposition. -MSH in vitro suppresses the synthesis of collagen types I, III, and V and down-regulates the secretion of procollagen type I C-terminal peptide (PICP) in human dermal fibroblasts treated with the fibrogenic cytokine transforming growth factor-₁ (TGF-₁). -MSH did not interfere with TGF-₁ signaling, because TGF-₁-induced expression of collagen mRNA was not affected, implying a posttranscriptional mechanism. Human dermal fibroblasts in vitro express a high affinity binding site for MSH, which was identified by reverse transcription PCR and immunofluorescence analysis as the melanocortin-1 receptor (MC-1R). Immunohistochemical studies on normal adult human skin confirmed MC-1R expression in distinct dermal fibroblastic cells. The MC-1R on fibroblasts appears to be functionally relevant because -MSH increased the amount of intracellular cAMP, and coincubation with a synthetic peptide corresponding to the human Agouti signaling protein abrogated the inhibition of TGF-₁-induced PICP secretion by -MSH. To assess the in vivo relevance of these findings, a mouse model was used in which dermal fibrosis was induced by repetitive intracutaneous injections with TGF-₁. The inductive activity of TGF-₁ on collagen deposition and the number of dermal cells immunoreactive for vimentin and -smooth muscle actin was significantly suppressed by injection of -MSH. Melanocortins such as -MSH may therefore represent a novel class of modulators with potential usefulness for the treatment of fibrotic disorders.

Received for publication, November 17, 2003

^* This work was supported by Deutsche Forschungsgemeinschaft Grant 1075/5-1 (to M. B.) and a grant from the Deutsche Stiftung Sklerodermie to (M. R.). 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.

^¶ Present address: Division of Bioengineering and Dept. of Biochemistry, National University of Singapore, Singapore 119260.

Supported by the Swedish Research Council (Vetenskapsrådet; medicine) and Melacure Therapeutics AB, Uppsala, Sweden.

To whom correspondence should be addressed: Dept. of Dermatology, University of Münster, Von Esmarch-Str. 58, 48149 Münster, Germany. Tel.: 49-251-835-6496; Fax: 49-251-835-6522; E-mail: bohmm{at}uni-muenster.de.

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