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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00403-014-1485-3) contains supplementary material, which is available to authorized users.

The Beneficial Regulation of Extracellular Matrix and Heat Shock Proteins, and the Inhibition of Cellular Oxidative Stress Effects and Inflammatory Cytokines by 1α, 25 dihydroxyvitaminD3 in Non-Irradiated and Ultraviolet Radiated Dermal Fibroblasts

“…Skin aging/photoaging is associated with the loss of structural collagen, co-regulated HSP-47, and solar elastosis from stimulation of elastin and elastases [1,3,12,14,16]. Vitamin D stimulates collagen expression and inhibits elastin expression in dermal fibroblasts [35][36][37]. We herein report that vitamin D stimulates the expression of type I collagen, transcriptionally, in non-irradiated and UVA-radiated fibroblasts, though not in UVB-radiated fibroblasts.…”

“…The UV radiation is the predominant environmental factor that accelerates skin aging. The regulatory properties of 1α, 25dihydroxyvitamin D3 (vitamin D) include endocrine, ECM regulation, cell differentiation, photoprotection, and anti-inflammation [34][35][36][37][38][39][40][41][42][43][44][45].…”

“…The ROS directly damage DNA to generate 8-oxo-7, 8-dihydro-2 -deoxyguanosine (8-oxo-dG) and pyrimidine dimmers, proteins to generate carbonyl amino acid derivatives, and lipids to generate lipid peroxides and lipid inflammatory mediators [4,5,[24][25][26][27]. Phenolic compounds have anti-oxidative and anti-inflammatory properties, and thereby anti-aging properties, because of their structure and the number and location of their hydroxyl groups [1][2][3][4][5][31][32][33].The structure of 1α, 25dihydroxyvitamin D3 (vitamin D) and its endocrine role in cellular homeostasis as well as its photoprotective and anti-inflammatory role makes it essential to skin health [34][35][36][37][38][39][40][41][42][43][44][45]. Vitamin D, or its analog, stimulates the expression of collagen and counteracts the glucocorticoid mediated inhibition of collagen synthesis in dermal fibroblasts [35,36].…”

“…The structure of 1α, 25dihydroxyvitamin D3 (vitamin D) and its endocrine role in cellular homeostasis as well as its photoprotective and anti-inflammatory role makes it essential to skin health [34][35][36][37][38][39][40][41][42][43][44][45]. Vitamin D, or its analog, stimulates the expression of collagen and counteracts the glucocorticoid mediated inhibition of collagen synthesis in dermal fibroblasts [35,36]. Vitamin D inhibits the expression of elastin in several cell types [37].…”

A novel vehicle for the treatment of psoriasis

“…It has also been observed that the combined pharmacological treatment improves the patients' adherence to therapy, since in a single application they can use both drugs, minimizing the side effects of cortisone (Patel, Felix, Reimer, & Feldman, ). It is in fact believed that calcipotriol is able to counteract the atrogenic effect of the corticosteroid through a mechanism of modulation of the extracellular matrix (Norsgaard et al, ). More and more recent studies are aimed at improving the penetration of the molecules contained in the foam, favoring effectiveness and reducing health care expense (Frieder, Kivelevitch, & Menter, ).…”