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

Abstract

The melanocortin-1 receptor (MC 1 ) binds a-melanocytestimulating hormone (a-MSH) with high affinity and has a physiological role in cutaneous melanin pigmentation. Previously, we reported that human dermal fibroblasts also express functional MC 1 . a-MSH suppressed transforming growth factor-b 1 -and bleomycin (BLM)-induced collagen synthesis in vitro and in vivo.e/e mice, we tested as to whether MC 1 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 BLMnon-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 MC 1 , suggesting that these cells are directly targeted by melanocortins to affect collagen production of the skin. Our findings support the concept that MC 1 has an endogenous regulatory function in collagen synthesis and controls the extent of fibrotic stress responses of the skin.

Deficiency in Melanocortin 1 Receptor Signaling Predisposes to Vascular Endothelial Dysfunction and Increased Arterial Stiffness in Mice and Humans

“…Treatment with α-MSH by activating MC1-R in fibroblasts suppressed collagen deposition in experimental models of skin fibrosis, 17 whereas MC1R e/e mice showed increased formation of cutaneous type I collagen compared with WT mice in similar models. 18 These observations lend support to the concept that MC1-R might have a regulatory role also in aortic collagen synthesis and deposition. Extending this further to physiological consequences, we noted that aortic compliance, as evidenced by increased mechanical stiffness and pulse pressure, was compromised in MC1R…”

Multiplex serum protein analysis reveals potential mechanisms and markers of response to hyperimmune caprine serum in systemic sclerosis

“…They also confirmed the presence of POMC and the MC1R in affected skin from patients with SSc and dermal fibroblasts strongly expressed both POMC and MC1R [31]. In a recent study MC1-signalling-deficient mice were susceptible to bleomycin-induced fibrosis, whereas wild-type animals were not [32]. …”

Antifibrotic effect of lysophosphatidic acid receptors LPA1 and LPA3 antagonist on experimental murine scleroderma induced by bleomycin

“…Bleomycin‐induced murine scleroderma is a powerful tool for the investigation of fibrosis. In addition, recent studies have suggested other possible mechanisms of accelerated fibrosis by inhibiting adipogenesis through TGF‐ β 1 as well as the role of melanocortins in collagen synthesis using this model. Therefore, other new mechanisms are highly involved in the induction of fibrosis, and further studies are necessary.…”