Collagen metabolism is a novel target of the neuropeptide alpha-melanocyte-stimulating hormone.
Suppression of collagen synthesis is a major therapeutic goal in the treatment of fibrotic disorders. We show here that alpha-melanocyte-stimulating hormone (alpha-MSH), a neuropeptide well known for its pigment-inducing capacity, modulates collagen synthesis and deposition. Alpha-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-beta1 (TGF-beta1). Alpha-MSH did not interfere with TGF-beta1 signaling, because TGF-beta1-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 alpha-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-beta1-induced PICP secretion by alpha-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-beta1. The inductive activity of TGF-beta1 on collagen deposition and the number of dermal cells immunoreactive for vimentin and alpha-smooth muscle actin was significantly suppressed by injection of alpha-MSH. Melanocortins such as alpha-MSH may therefore represent a novel class of modulators with potential usefulness for the treatment of fibrotic disorders.
Böhm
Markus
M
Department of Dermatology and the Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, University of Münster, 48149 Münster, Germany. bohmm@uni-muenster.de
Raghunath
Michael
M
Sunderkötter
Cord
C
Schiller
Meinhard
M
Ständer
Sonja
S
Brzoska
Thomas
T
Cauvet
Thomas
T
Schiöth
Helgi B
HB
Schwarz
Thomas
T
Luger
Thomas A
TA
D000199:Actins / Q000378:metabolism; D054366:Agouti Signaling Protein; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009130:Muscle, Smooth / Q000378:metabolism; D009479:Neuropeptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D044102:Receptor, Melanocortin, Type 1 / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D000521:alpha-MSH / Q000737:chemistry*
D000199:Actins; D054366:Agouti Signaling Protein; D036341:Intercellular Signaling Peptides and Proteins; D009479:Neuropeptides; D010455:Peptides; D044102:Receptor, Melanocortin, Type 1; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000521:alpha-MSH; D003094:Collagen; D000242:Cyclic AMP