Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 14, Issue 3, 2014

Wound healing is essential for survival. This is a multistep process involving a number of different cell types. In the skin wounding triggers an acute inflammatory response, with the innate immune system contributing both to protection against invasive organisms and to triggering the invasion of inflammatory cells into the wounded area. These cells release a variety of cytokines and growth factors that stimulate the proliferation and migration of dermal and epidermal cells to close the wound. In particular, wounding activates stem cells in the interfollicular epidermis (IFE) and hair follicles (HF) to proliferate and send their progeny to re-epithelialize the wound. Failure to close wounds leads to medical costs estimated in the US at over $25 billion and affecting 6.5 million people. Our previous studies have shown that vitamin D and calcium signaling play important roles in these events. Vitamin D and calcium signaling are necessary for a normal innate immune and inflammatory response to wounding in the epidermis. Moreover, VDR is required for maintenance of hair follicle (HF) stem cells known to contribute to wound closure of the IFE. Mice lacking the calcium sensing receptor (CaSR) or the VDR when placed on a low calcium diet have delayed wound healing. This is associated with a reduction in the number of cells in the stem cell niches in both HF and IFE and reduced proliferation and migration in the cells at the leading edge of the epithelium after wounding. We hypothesize that at least part of this delay in wound closure is due to a reduction of stem cell activation and number in cells lacking the VDR and/or their failure of activation by calcium in cells lacking the CaSR, and are currently investigating this concept.

Sunlight has the potential to induce DNA damage in the skin. If these photolesions are left unrepaired, they can greatly increase the risk of skin cancer. This process is facilitated by another UV-induced insult, photoimmune suppression. Vitamin D metabolites have demonstrated a marked ability to mitigate these negative effects. The photoprotective pathway still remains elusive. Recent research, however, points to the important role of the vitamin D receptor and the endoplasmic reticulum protein ERp57 in mediating the actions of vitamin D compounds. Determining the functional relationship between vitamin D metabolites, the VDR/ERp57 complex, and downstream DNA repair mechanisms will contribute to the greater understanding of this photoprotective system. Furthermore, in light of evidence suggesting that CYP27B1 is not necessary for photoprotection, strong emphasis must now be placed on examining other vitamin D metabolic pathways and the actions of new metabolites in photoprotection. Recent literature points to 20(OH)D3 as a possible alternative to 1,25(OH)2D3. However, further work must be conducted to determine the photoprotective pathway of this vitamin D derivative.

The prevalence of vitamin D insufficiency in athletes is concerning due to the potential negative effects on physical performance. The concept that vitamin D status positively correlates with measures of muscular strength and cardiorespiratory fitness is receiving increased interest among a wide range of athletes. We reviewed published studies that examined the association of vitamin D status with, and the effect of vitamin D supplementation on measures of athletic performance. An increased vitamin D status was associated with improved athletic performance in only one observational study. Several intervention studies demonstrated that the improvement in muscular strength occurs when athletes with low vitamin D status are restored to vitamin D sufficient status. Further research in various athletic populations is needed to establish the role of vitamin D in athletic performance and optimal vitamin D status in athletes.

Femarelle (F) activates human derived cultured female bone cells (hObs) and human bone cell line (SaOS2), which express receptors for estradiol-17β (E2; ERα and ERβ) and vitamin D (VDR). Vitamin D metabolites and analogs regulate cell proliferation (DNA) and the specific activity of creatine kinase (CK). Pretreatment with vitamin D less-calcemic analog: JKF 1624F2-2 (JKF) up-regulated responsiveness to estrogens via modulation of ERs mRNA expression. The estrogens in turn induce VDR and 25- hydroxy vitamin D3 1-α hydroxylase (1OHase) expression and 1,25(OH)2D3 (1,25D) synthesis. We compared the effects of F to those of its precourser daidzein (D) and E2 on DNA and CK, and effect of JKF pretreatment. We found: 1. F, D and E2 stimulated DNA and CK. 2. JKF increased ERα and decreased ERβ mRNA expression, up-regulated DNA and CK response to E2 and D but not to F. 3. JKF increased only E2 intracellular competitive binding. 4. F, D and E2 increased VDR and 1OHase mRNA expression and its activity measured by 1,25D production. In conclusion, F, D and E2 increases DNA and CK, as well as 1,25D production and VDR and 1OHase mRNA expression. Pre- treatment with JKF modulates the effect of E2 and D but not of F while all estrogens modulate VDR expression and both mRNA expression and activity of 1OHase in the cells. These finding that F effects are not affected by the vitamin D levels in female-derived osteoblasts may contribute to its beneficial role in treatment of post-menopausal bone loss.

The 1,25D3-MARRS receptor is bioidentical with protein disulfide isomerase A3, and has been demonstrated to be required for the rapid, pregenomic actions of the steroid hormone 1,25D3 on calcium and phosphate uptake in a number of tissues. In this review we discuss the role of this receptor as it relates to the recent advances in calcium and phosphate transport along with its role in select disease states. We also review that another metabolite, 24,25D3, also has biological activity.