Wound healing is essential for survival. This is a multistep processes involving a number of different cell types. In the skin wounding is followed initially by inflammation, with the innate immune response contributing both to protection against invasive organisms and to triggering the inflammatory response. This is followed by proliferation and migration of dermal and epidermal cells to close the wound. Finally remodeling and differentiation restore the skin to normal, reestablishing the permeability barrier. Vitamin D and calcium signaling most likely play a role in these processes, although this has received little study in wound healing. Stem cells in the bulge of the hair follicle provide keratinocytes not only for hair follicle formation but also for the reepithelialization of the epidermis following wounding. The function of these bulge stem cells is regulated by VDR. Vitamin D signaling is necessary for a normal innate immune response in the epidermis. Mice lacking the vitamin D receptor (VDR) or lacking the enzyme (CYP27B1) critical for producing the key ligand for VDR, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3), fail to activate their innate immune response following wounding. Vitamin D signaling is also critical for regulation of keratinocyte proliferation and differentiation, eventuating in the reformation of the permeability barrier. Mice lacking the VDR show decreased expression of differentiation markers and a retarded barrier recovery after wounding (tape stripping). Calcium is a critical participant in the mechanism by which vitamin D signaling regulates these processes in keratinocytes. Calcium like vitamin D induces the genes responsible for differentiation, and limits proliferation. Reestablishment of the calcium gradient parallels the restoration of the permeability barrier after wounding (tape stripping). The calcium sensing receptor (CaR) is critical here, and its expression is stimulated by 1,25(OH)2D3. Mice lacking the CaR have a defective innate immune response, decreased expression of differentiation markers, and delayed recovery of the barrier after wounding (tape stripping). These observations have led us to the following hypothesis. Vitamin D signaling regulates wound healing by enabling the initial inflammatory response of the epidermis to wounding, by controlling the proliferation and migration of keratinocytes to close the wound, and by stimulating the differentiation of the keratinocytes to reform the permeability barrier through mechanisms requiring the CaR. We will test this hypothesis by achieving the following aims. 1. Determine the requirement for VDR in the wound healing process by assessing the innate immune response, the rate of reepithelialization, and the rate of differentiation in mice lacking VDR in their keratinocytes. 2. Determine the requirement for VDR in the migratory response of keratinocytes to wounding. 3. Determine the requirement for CaR in the wound healing response. We anticipate that our findings will lead to new therapies by which the wounding process can be accelerated, a process of great importance for our Military and Veteran populations.

Public Health Relevance

The skin provides the major barrier to the life threatening forces in the environment. Disrupting this barrier leads to loss of bodily fluids and provides a portal for infectious organisms. Failure to heal skin wounds can lead to death. Therefore, it is essential that wound healing be efficient and at the same time protect the body from both losses of essential fluids and infection during the healing process. The normal skin does this quite well. Although all creatures require efficient wound healing for health, Veterans are more likely to have medical conditions that compromise this process, whether it be burns, old trauma, or medical diseases such as diabetes mellitus. Among the important regulators of these functions in skin is vitamin D. Vitamin D facilitates the formation of the permeability barrier, protecting against losses of fluids, and the innate immune response, protecting against infection. This project will evaluate the impact of loss of vitamin D signaling on events that contribute to the wound healing process.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Surgery (SURG)
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Veterans Affairs Medical Center San Francisco
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Bikle, Daniel D; Malmstroem, Sofie; Schwartz, Janice (2017) Current Controversies: Are Free Vitamin Metabolite Levels a More Accurate Assessment of Vitamin D Status than Total Levels? Endocrinol Metab Clin North Am 46:901-918
Bikle, Daniel D (2016) Extraskeletal actions of vitamin D. Ann N Y Acad Sci 1376:29-52
Oda, Yuko; Tu, Chia-Ling; Menendez, Alicia et al. (2016) Vitamin D and calcium regulation of epidermal wound healing. J Steroid Biochem Mol Biol 164:379-385
Bikle, Daniel D; Jiang, Yan; Nguyen, Thai et al. (2016) Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer. Front Physiol 7:296
Jiang, Yan J; Bikle, Daniel D (2014) LncRNA profiling reveals new mechanism for VDR protection against skin cancer formation. J Steroid Biochem Mol Biol 144 Pt A:87-90
Bikle, Daniel D; Mauro, Theodora M (2014) Calcium, Orai1, and epidermal proliferation. J Invest Dermatol 134:1506-1508
Jiang, Yan J; Bikle, Daniel D (2014) LncRNA: a new player in 1?, 25(OH)(2) vitamin D(3) /VDR protection against skin cancer formation. Exp Dermatol 23:147-50
Christakos, Sylvia; Hewison, Martin; Gardner, David G et al. (2013) Vitamin D: beyond bone. Ann N Y Acad Sci 1287:45-58
Mamillapalli, Ramanaiah; VanHouten, Joshua; Dann, Pamela et al. (2013) Mammary-specific ablation of the calcium-sensing receptor during lactation alters maternal calcium metabolism, milk calcium transport, and neonatal calcium accrual. Endocrinology 154:3031-42
Bikle, Daniel D; Elalieh, Hashem; Welsh, Joellen et al. (2013) Protective role of vitamin D signaling in skin cancer formation. J Steroid Biochem Mol Biol 136:271-9

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