Ligand-Dependent Actions of the Vitamin D Receptor Are Required for Activation of TGF-β Signaling during the Inflammatory Response to Cutaneous Injury

Abstract

The vitamin D receptor (VDR) has both 1,25-dihydroxyvitamin D-dependent and -independent actions in the epidermis. Ligand-dependent actions of the VDR have been shown to promote keratinocyte differentiation and to regulate formation of the epidermal barrier. In contrast, the actions of the VDR that regulate postmorphogenic hair cycling do not require 1,25-dihydroxyvitamin D. The VDR also has immunomodulatory actions that are dependent on its ligand, 1,25-dihydroxyvitamin D. To determine whether the ligand-dependent or -independent actions of the VDR regulate the inflammatory response to cutaneous injury, studies were performed in control, VDR knockout, and vitamin D-deficient mice. These investigations demonstrate that absence of receptor or ligand impairs the dermal response to cutaneous injury. Although neutrophil recruitment is not affected, the absence of VDR signaling leads to defects in macrophage recruitment and granulation tissue formation. Studies performed to identify the molecular basis for this phenotype demonstrate that absence of the VDR, or its ligand, impairs TGF-β signaling in the dermis, characterized by decreased expression of monocyte chemotactic protein-1 and reduced phosphorylation of phosphorylated Smad-3 as well as attenuated phosphorylated Smad-3 phosphorylation in response to TGF-β in primary dermal fibroblasts lacking the VDR. Thus, these data demonstrate that the liganded VDR interacts with the TGF-β signaling pathway to promote the normal inflammatory response to cutaneous injury.

Vitamin D and calcium regulation of epidermal wound healing

“…Tian et al (20) observed that topical 1,25(OH 2 D enhanced wound healing. Luderer et al (21) observed that in the global VDR knockout mouse, there was a reduction in TGFβ signaling in the dermis, although re-epithelialization was not impaired. Although our initial studies with epi VDRKO mice did not show a significant delay in re-epithelialization, comparable to the results obtained by Luderer et al (21) in their global VDRKO mouse, we have observed that re-epithelialization is impaired when the deletion of VDR is accompanied by a low calcium diet.…”

“…Luderer et al (21) observed that in the global VDR knockout mouse, there was a reduction in TGFβ signaling in the dermis, although re-epithelialization was not impaired. Although our initial studies with epi VDRKO mice did not show a significant delay in re-epithelialization, comparable to the results obtained by Luderer et al (21) in their global VDRKO mouse, we have observed that re-epithelialization is impaired when the deletion of VDR is accompanied by a low calcium diet. The low calcium diet by itself did not produce this delay suggesting that calcium signaling can compensate for defective vitamin D signaling, and vice versa, but disrupting both produces the phenotype.…”

47effects of Ageing and Vitamin D Deficiency on Vitamin D Receptor (Vdr) Expression in Human Skeletal Muscle

“…Myostatin, a growth differentiation factor of the transforming growth factor beta (TGF β) family, is found in skeletal muscle and is recognised to has been studied and shown in other organs such as how the skin reacts to injury [Luderer 2013] and inhibiting liver fibrosis [Ding 2013] supporting this pathway in skeletal muscles too. metabolism of the skeletal muscle cell that cannot be explained by a slow genetic pathway suggesting a non-genomic pathway that vitamin D and VDR influences skeletal muscles [Janssen 2002].…”

DNA Damage-Inducible Transcript 4 Is an Innate Surveillant of Hair Follicular Stress in Vitamin D Receptor Knockout Mice and a Regulator of Wound Re-Epithelialization

“…The importance of the cutaneous VDR is demonstrated in certain human patients with hereditary vitamin D-resistant rickets and mice that harbor loss-of-function mutations in the VDR and eventually develop hair loss (alopecia totalis [1]), as well as impaired skin wound repair [2,3]. In utero, the epithelium and underlying mesenchyme interact to form hair follicles during morphogenesis, which ends during the second week of life in mice.…”

“…In contrast to VDR −/− mice, mice lacking the enzyme that catalyzes synthesis of 1,25D 3 (cytochrome p450 27B1; CYP27B1 −/− ) have normal hair, but altered epidermal differentiation signatures, impaired permeability barrier and wound healing responses, suggesting that 1,25D 3 is crucial for epidermal integrity [22,23]. The cutaneous wound healing defects in global VDR −/− animals have been characterized by scarcity of infiltrating macrophages in the early inflammatory phase and disrupted vascular invasion of granulation tissue, yet re-epithelialization was reported to be unaffected [2]. In contrast, epithelial-specific deletion of the VDR in mice results in impaired re-epithelialization of wounds [3].…”