146 JOURNAL OF COSMETIC SCIENCE CALCIOTROPIC HORMONES AND THE SKIN: A MILLENNIUM PERSPECTIVE Michael F. Holick, Ph.D. Boston University School of Medicine, Boston, MA It has been estimated, that within 50 years, that almost one million Americans will reach the age of 100 years. One of the major consequences of aging on the body is its effect on the skin. Retinoids have been found to be very effective in stimulating epidermal cell growth and rejuvenating the dermis to help relieve the ravages of aging on the skin. Retinoids can cause some side effects including skin irritation. There is a need to develop new safe effective approaches for maintaining skin and hair follicle health and rejuvenating skin health. It is well known that the most beneficial effect of exposure to sunlight on the skin is the production of vitamin D3. Vitamin D3 is equated with bone health. However, it is now appreciated that the skin is not only the organ responsible for making vitamin D3 but is a target tissue for activated vitamin D3. It is well established that once vitamin D• is made in the skin, it is converted in the liver to 25-hydroxyvitamin D3 and then in the kidney to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). 1,25(OH)2D3 is responsible for enhancing intestinal calcium absorption and mobilizing calcium stores from the bone to maintain physiologically acceptable blood levels of calcium for promoting metabolic functions and maximum bone health. It is now recognized that the skin also has the enzymatic machinery to make 1,25(OH)2D. 1,25(OH)2D is a potent inhibitor of proliferation and inducer of terminal differentiation of human epidermal cells One practical advantage of this unique biologic property is that activated vitamin D compounds are effective in treating the hyperproliferative skin disorder, psoriasis. It is remarkable that although 1,25(OH)2D3 is a potent inhibitor of epidermal proliferation, it does not have any adverse effects on the epidermis when topically applied for up to 10 years. It appears that this calciotropic hormone normalizes proliferative activity, and

2000 ANNUAL SCIENTIFIC MEETING 147 helps maintain both epidermal and dermal health. Development of vitamin D analogs for pharmaceutical and cosmetic applications for skin health holds great promise. The skin produces the calciotropic hormone parathyroid hormone related peptide (PTHrP). Immunohistochemical localization of PTHrP in the epidermis revealed that there was a gradient of its expression with none being expressed in the basal cells and increased expression in the upper layers of the epidermis. PTHrP receptor agonists including PTH(1-34) and PTHrP(1-34) inhibit proliferation and induce terminal differentiation of cultured human keratinocytes and inhibit DNA synthesis in the epidermis of mice in vivo. A practical application for PTHrP agonists is for the treatment of hyperproliferative skin disorders. PTH(1-34) was formulated in a liposomal based cream and found to be effective when topically applied to patients with psoriasis. It was reasoned that if PTHrP is the endogenous factor that down regulates epidermal proliferation, that it might be possible to block its action by using a PTHrP receptor antagonist. It is known that PTH(7-34) binds to the receptor but does not cause any biologic function thereby acting as a pure antagonist. When PTH(7-34) was co-incubated with PTH(1-34) in cultured human keratinocytes, it partially restored the normal proliferative activity of the cells. When PTH(7-34), in a liposomal cream, was topically applied to SKH-1 hairless mice, it markedly enhanced DNA synthesis in a dose dependent fashion and increased the thickness of the epidermis two to three fold. No untoward toxicity was observed in the animals that received a topical application of this antagonist for two months.