Targeting Expression of the Human Vitamin D Receptor to the Keratinocytes of Vitamin D Receptor Null Mice Prevents Alopecia

Abstract

Vitamin D receptor (VDR) null mice develop hypocalcemia, hyperparathyroidism, rickets, osteomalacia and alopecia. Normalization of mineral ion homeostasis prevents all of these abnormalities except alopecia. Hair reconstitution assays, performed in athymic nude mice, demonstrate that the lack of VDR in keratinocytes leads to a defect in anagen initiation, similar to that observed in VDR null mice. Although these studies demonstrate that expression of the VDR in keratinocytes is necessary, they do not prove that it is sufficient for maintenance of the normal hair cycle. To address this hypothesis, we generated transgenic mice expressing the human VDR under the control of the keratin 14 (K14) promoter. Two highly expressing transgenic lines were mated with VDR null mice to obtain VDR null mice expressing the human VDR transgene (hVDR+/mVDR-). Expression of the transgene in the VDR null mice prevented alopecia. Furthermore, when subjected to anagen initiation, the hair follicle keratinocytes of the hVDR+/mVDR- mice demonstrated an enhanced proliferative response compared to those of control littermates. Restoration of VDR expression in the keratinocytes of VDR null mice, prevents the hair cycle defect that leads to the development of alopecia.

A unique insertion/duplication in the VDR gene that truncates the VDR causing hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia

“…Chen et al [20] and Kong et al [21] have shown that specific expression of WT VDR in keratinocytes of VDR knockout mice can restore hair growth. Skorija et al [22] have recently shown that keratinocyte-targeted expression of either a mutant VDR (L233S) that does not bind ligand or a mutant VDR (L417S) that is defective in binding coactivators can restore hair growth in VDR knockout mice.…”

“…VDR knockout mice, generated by disrupting exon 2 [18] or exon 3 [19] that constitute the DBD, also exhibit alopecia. Hair growth can be restored by specific expression of WT VDR in keratinocytes of VDR knockout mice [20,21]. Importantly, keratinocyte-targeted expression of transactivation defective mutant VDRs with mutations that affect ligand binding or that prevent coactivator binding also restored hair growth [22].…”

Vitamin D Receptor: Key Roles in Bone Mineral Pathophysiology, Molecular Mechanism of Action, and Novel Nutritional Ligands

“…For example, hair cycling is greatly affected in VDR knockout animals (14,15) and in many patients with hereditary hypocalcemic vitamin D-resistant rickets type II (HVDRR-II), (16) although this process is not compromised in vitamin D deficiency. In addition, the secondary bile acid, lithocholate, has been recently recognized as a bona fide VDR ligand in the colon, capable of activating VDR to induce detoxifying, cytochrome P450-containing enzymes.…”

“…(17) The VDR is also absolutely required for a functional hair cycle as exemplified by the known phenotype of alopecia in HVDDR-II patients (16) and in VDR knockout mice. (14,15) Furthermore, essential polyunsaturated fatty acid (PUFA) deficiency has adverse effects on skin, including impaired hair growth and dermatitis. (55)(56)(57)(58) Administration of PUFAs such as linoleic acid has been shown to reverse these symptoms.…”

Vitamin D Status and the Effect of Oral Vitamin D Treatment in Children with Alopecia Areata

“…It has been reported that vitamin D plays an important role in cutaneous immune modulation [7][8][9]. The active form of vitamin D (1,25-dihydroxyvitamin D) acts as an immunomodulator targeting various immune cells such as macrophages, monocytes, dendritic cells as well as T lymphocytes and B lymphocytes [9][10][11].…”