Bleomycin-induced fibrosis in MC1 signalling-deficient C57BL/6J-Mc1r(e/e) mice further supports a modulating role for melanocortins in collagen synthesis of the skin.
The melanocortin-1 receptor (MC1 ) binds α-melanocyte-stimulating hormone (α-MSH) with high affinity and has a physiological role in cutaneous melanin pigmentation. Previously, we reported that human dermal fibroblasts also express functional MC1 . α-MSH suppressed transforming growth factor-β1 - and bleomycin (BLM)-induced collagen synthesis in vitro and in vivo. Using MC1 signalling-deficient C57BL/6J-Mc1r(e/e) mice, we tested as to whether MC1 has a regulatory role on dermal collagen synthesis in the BLM model of scleroderma. Notably, mice with a C57BL/6J genetic background were previously shown to be BLM-non-susceptible. Interestingly, treatment of C57BL/6J-Mc1r(e/e) but not of C57BL/6J-wild-type mice with BLM increased cutaneous collagen type I content at RNA and protein level along with development of skin fibrosis. Cutaneous levels of connective tissue growth factor and monocyte chemotactic protein-1 were also increased in BLM-treated C57BL/6J-Mc1r(e/e) mice. Primary dermal fibroblasts from C57BL/6J-wt mice further expressed MC1 , suggesting that these cells are directly targeted by melanocortins to affect collagen production of the skin. Our findings support the concept that MC1 has an endogenous regulatory function in collagen synthesis and controls the extent of fibrotic stress responses of the skin.
Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University of Münster, Münster, Germany.
Markus
M
Böhm
Agatha
A
Stegemann
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D018932:Chemokine CCL2 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics; D053486:Melanocortins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D044102:Receptor, Melanocortin, Type 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000378:metabolism / Q000473:pathology*
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053486:Melanocortins; D044102:Receptor, Melanocortin, Type 1; D001761:Bleomycin; D055513:Connective Tissue Growth Factor; D003094:Collagen
bleomycin; collagen; fibroblasts; fibrosis; neuropeptides