title: Calcipotriol counteracts betamethasone-induced decrease in extracellular matrix components related to skin atrophy.
abstract: The calcipotriol/betamethasone dipropionate fixed-combination gel is widely used for topical treatment of psoriasis vulgaris. It has been hypothesized that calcipotriol counteracts glucocorticoid-induced skin atrophy which is associated with changes in the extracellular matrix (ECM). To elucidate the combined effects of calcipotriol and betamethasone on key ECM components, a comparative study to the respective mono-treatments was carried out. The effect on collagen I synthesis, matrix metalloproteinase (MMP) secretion, and hyaluronic acid (HA) production was investigated in primary human fibroblast and keratinocyte cultures as well as in a human skin explant model. We show that calcipotriol counteracts betamethasone-induced suppression of collagen I synthesis. Similarly, calcipotriol and betamethasone have opposing effects on MMP expression in both fibroblasts and keratinocytes. Moreover, calcipotriol is able to restore betamethasone-impaired HA synthesis in keratinocytes and prevent betamethasone-induced epidermal thinning in minipigs upon treatment with the calcipotriol/betamethasone gel. In summary, our results show for the first time in primary human skin cultures that calcipotriol reduces early signs of betamethasone-induced skin atrophy by modulation of key ECM components. These results indicate that the calcipotriol component of the fixed-combination gel counteracts the atrophogenic effects of betamethasone on the skin.
authors.affiliation: Department of Molecular Biomedicine, LEO Pharma A/S, Industriparken 55, Ballerup, Denmark, hanne.norsgaard@leo-pharma.com.
authors.forename: Hanne
authors.initials: H
authors.lastname: Norsgaard
authors.forename: Sandrine
authors.initials: S
authors.lastname: Kurdykowski
authors.forename: Pascal
authors.initials: P
authors.lastname: Descargues
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gonzalez
authors.forename: Troels
authors.initials: T
authors.lastname: Marstrand
authors.forename: Georg
authors.initials: G
authors.lastname: Dünstl
authors.forename: Mads
authors.initials: M
authors.lastname: Røpke
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001284:Atrophy / Q000209:etiology / Q000517:prevention & control; D001623:Betamethasone / Q000008:administration & dosage / Q000009:adverse effects*; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002478:Cells, Cultured; D004338:Drug Combinations; D004347:Drug Interactions; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000473:pathology; D009924:Organ Culture Techniques; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D013552:Swine; D013556:Swine, Miniature
chemical_list: D000893:Anti-Inflammatory Agents; D004338:Drug Combinations; C055085:calcipotriene; D001623:Betamethasone; D002117:Calcitriol