Wednesday, April 2, 2025
4/2/2025
Mechanism of action and function of novel secosteroid 20(OH)D3 in the skin - Ultraviolet B both damages the skin and is required for photochemical transformation of 7-dehydrocholesterol to vitamin D3 (D3). Sequential hydroxylation of D3 at C25 and C1α generates biologically active 1,25(OH)2D3 that displays a variety of pleiotropic activities. It was believed that all these effects are mediated by a single molecule, 1,25(OH)2D3, and a single receptor, VDR. Discovery of alternative pathways, in which CYP11A1 oxidizes the side chain of D3 generating 20(OH)D3 that is further metabolized to other downstream metabolites, (OH)nD3, challenged this dogma. 20(OH)D3, which is detectable in human epidermis at a concentration higher than 25(OH)D3, and in human serum at ~3nM. 20(OH)D3, can act as an endogenous regulator of epidermal barrier, while its presence in circulation indicates hormonal functions. 20(OH)D3 is noncalcemic at pharmacological doses (30-60 µg/kg). Our ongoing studies have demonstrated that its metabolites have anti-proliferative, pro-differentiation, anti-inflammatory, anti-oxidative, radioprotective, and anti-cancer effects on skin cells both under in vitro and in vivo conditions, being even more potent than its precursor. (OH)nD3 without OH at C1α are noncalcemic and non-toxic at supra-pharmacological doses. Furthermore, they act on alternative nuclear receptors (NRs), such as agonists on aryl hydrocarbon receptor (AhR) and liver X receptors (LXR)α and β, and as inverse agonists on RORα and γ. The latter is coupled to their anti-inflammatory effects. The focus of this competitive renewal is on skin and photobiology. We will determine the preclinical efficacy of selected (OH)nD3 metabolites, including 20,23(OH)2D3 and 20,25(OH)2D3 in comparison to their C1α(OH) derivatives, against UVB-induced damage and photocarcinogenesis, and investigate the hypothesis that their protective and reparative functions are mediated through interactions with distinct NRs. The hypothesis will be tested as follows: Aim 1. To define selected CYP11A1-derived (OH)nD3 as efficient protective agents against UVB-induced skin pathology in vivo. Subaim 1: In vivo testing of preventive and reparative properties of (OH)nD3. Their effects against UVB-induced epidermal damage will be tested in SKH-1 mice and human skin ex vivo. Subaim 2: Testing selected (OH)nD3 against UVB-induced cancer in the mouse models of photocarcinogenesis. The preventive or inhibitory activity of selected (OH)nD3 against UVB- induced carcinogenesis will be tested in animal models to assess development and progression of SCC and BCC. Aim 2. To define the mechanism of action (MOA) of selected (OH)nD3 compounds in protection against UVB damage in the skin. First, we will evaluate the relative involvement of AhR and/or LXRs in comparison to VDR in keratinocyte differentiation and photoprotection induced by (OH)nD3 compounds using skin from mice in which the NR of interest is knocked out vs wild type mice. These studies will include transcriptomics, proteomics, Chip-seq, and bioinformatics. The results will be validated in human skin cells with silenced genes of interest vs controls. Alternative master regulators will also be considered, if experimentally indicated.
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