DR. MICHAEL HOLICK
Professor of Medicine, Physiology and Biophysics
Director of the General Clinical Research Center
Director of the Bone Health Care Clinic
BOSTON UNIVERSITY MEDICAL CENTER
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CONTRIBUTIONS TO ENDOCRINOLOGY
INSTITUTION AND LOCATION DEGREE (if applicable) YEAR(s) FIELD OF STUDY
Seton Hall, New Jersey BS 1968 Chemistry
University of Wisconsin, Madison MS 1970 Biochemistry
University of Wisconsin, Madison PhD 1971 Biochemistry
University of Wisconsin, Madison MD 1976
1971-75 Research Associate; Depart. of Biochemistry, University of Wisconsin, Madison, WI
1975-76 Research Associate, Endocrine Unit, Massachusetts General Hospital, Boston, MA
1976-78 Intern, Resident, and Clinical Fellow in Medicine, Massachusetts General Hospital, Boston, MA
1978-81 Assistant Professor of Medicine, Harvard Medical School; Assistant in Medicine, Massachusetts General Hospital
1981-85 Associate Professor of Medicine, Harvard Medical School
1981-85 Associate Professor of Nutritional Biochemistry, Massachusetts Institute of Technology, Cambridge, MA
1985-87 Professor of Physiology, Medicine, and Nutrition Tufts University; USDA/Nutrition Research Center on Aging
1986-93 Chief, Endocrine Unit; Boston City Hospital, Boston, MA
1986- Director, General Clinical Research Center and Director Osteoporosis Diagnostic Center, Boston University, School of Medicine, Boston, MA
1987-2004 Professor of Medicine, Physiology, and Dermatology, Boston University
School of Medicine
1993-2000 Chief, Section of Endocrinology, Nutrition and Diabetes, Boston
2004- Professor of Medicine, Physiology and Biophysics, Boston University School of Medicine
1972 Wilson S. Stone Memorial Award, M.D. Anderson Hospital, Houston, TX
1980 Fuller Albright Young Investigator Award
1981 Ten Outstanding Young Leders Award
1983 Mead Johnson Award, American Institute of Nutrition
1985 Pisa Medalion for Excellence in Science, Pisa, Italy
1986 Merit Award, National Institutes of Health
1986 Stanley S. Bergan Award for excellence in the medical field, Seton Hall University
1989 Arnold-Rickle-Prize for research in UV radiation and vitamin D metabolism
1989 Duhring Lecture in Dermatology
1991 Osborne and Mendel Award, American Institute of Nutrition
1994 E.V. McColIum Award, American Society for Clinical Nutrition
1995 Second Annual Beaudette-Thompson Lecture, Rutgers University
2000 American Skin Association's Psoriasis Research Achievement Award
2002 American College of Nutrition's ACN Award
2003 Robert H Herman Memorial Award in Clinical Nutrition, American Society for Clinical Nutrition
1 Holick MF, DeLuca HF. A new chromatographic system for vitamin D3 and its metabolites: Resolution of a new vitamin D-3 metabolite. J. Lipid Res. 1971; 12:460-465.
2 Holick MF, Schnoes HK, DeLuca HF. Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine. Proc Natl Acad Sci. USA. 1971; 68:803-804.
3 MacLaughlin JA, Gange W., Taylor D, Smith E, and Holick MF. Cultured psoriatic fibroblasts from involved and uninvolved sites have a partial but not absolute resistance to the proliferation-inhibition activity of 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci 1985; 82:5409-5412.
4 Holick, M.F., Ray, S., Chen, T., Tian, X., and Persons, K. Novel functions of a parathyroid hormone antagonist: stimulation of epidermal proliferation and hair growth in mice. Proc Natl Acad Sci 91:8014-8016, 1994.
5 Schilli, M.B. Ray, S., Paus, R., Obi-Tabot, E. and Holick, M.F. Control of hair growth with parathyroid hormone (7-34). J. Invest. Dermatol. 108:928-932, 1997.
6 Krause, R., Buhring, M. Hopfenmuller, W., Holick, M.F. and Sharma, A.M. Ultraviolet B and blood pressure. Lancet 352:709-710, 1998.
7 Perez, A., Chen, T.C., Turner, A., Raab, R., Bhawan, J., Poche, P., and Holick, M.F. Efficacy and safety topical calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis. Br. J. Dermatol. 134:238-246, 1996.
8 Schwartz, G.G., Whitlatch, L.W., Chen T.C., Lokeshwar, B.L., and Holick, M.F. Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Epidemiology, Biomarkers & Prevention 7:391-395, 1998.
9 Kong, X.F., Zhu, X.H., Pei, Y.L., Jackson, D.M., and Holick, M.F. Molecular cloning, characterization, and promoter analysis of the human 25-hydroxyvitamin D3-1- hydroxylase gene. Proc. Natl. Acad. Sci. USA 96:6988-6993, 1999.
10 Tian, X.Q., and Holick, M.F. a liposomal model that mimics the cutaneous production of vitamin D3. J Biol Chem 274:4174-4179, 1999.
11 Tangpricha, V., Flanagan, J.N., Whitlatch, L.W., Tseng, C.C., Chen, T.C., Holt, P.R., Lipkin, M.S., and Holick. 25-Hydroxyvitamin D-1α-hydroxylase in normal and malignant colon tissue. Lancet 357:1673-1674, May 26, 2001.
12 Flanagan, J.N., Whitlatch, L.W., Chen, T.C., Zhu, X.H., Holick, M.T., Kong, X., and Holick, M.F. Enhancing 1,-hydroxylase activity with the 25-hydroxyvitamin D-1-hydroxylase gene in cultured human keratinocytes and mouse skin. J. Invest. Dermatol. 116:910-914,2001.
13 Peters, Eva, M.J., Foitzik, K., Paus, R., Ray, S., and Holick, M.F. A new strategy for modulating chemotherapy-induced alopecia, using PTH/PTHrP receptor agonist and antagonist. J. Invest. Dermatol. 117:173-178,2001.
14 Whitlatch, L.W., Young, M.V., Schwartz, G., Flanagan, J., Burnstein, K., Lokeshwar, Bal L., Rich, E., Holick, M.F., and Chen, T.C. 25-Hydroxyvitamin D-1-hydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer. Steroid Biochem & Molecul Biol 81:135-140, 2002.
15 Tangpricha, V., Koutkia, P., Rieke, S.M., Chen, T.C., Perez, A., and Holick, M.F. Fortification of orange juice with vitamin D: A novel approach to enhance vitamin D nutritional health. Am J Clin Nutr , 77:1478-83, 2003.
16 Holick, M.F., Chimeh, F.N., and Ray, S. Topical PTH (1-34) is a novel, safe and effective treatment for psoriasis. Br J Dermatol 149:370-376, 2003.
17 Holick, M.F., Chimeh, F.N., and Ray, S. Topical PTH (1-34) in a novel, safe and effective treatment for psoriasis. Br Jl Dermatol 149:370-376, 2003.
18 Moore, C., Murphy, M.M., Keast, D.R., and Holick, M.F. Vitamin D intake in the United States. J Am Diet Assoc 104:980-983, 2004.
19 Durakovic, C., Ray, S., and Holick, M.F. Topical paricalcitol (19-nor-1α,25-dihydroxyvitamin D2) is a novel, safe and effective treatment for plaque psoriasis: a pilot study. Brit J Dermatol 151:190-195, 2004.
20 Tangpricha, V. Turner, A., Spina, C., Decastro, S., Chen, T., and Holick, M.F. Tanning is associated with optimal vitamin D status (serum 25-hydroxyvitamin D concentration) and higher bone mineral density. Am J Clin Nutr 80:1645-1649, 2004.
21 Holick, MF and Jenkins, M. The UV Advantage, iBooks:New York, 2004.
22 Sweeney, A., Tangpricha, V., Weinberg, J., Malbanan, A., Chimeh, F., and Holick, M.F. Comparison of the effects of a novel conjugated oral estrogen, estradiol-3β-glucoside, with oral micronized 17β-estradiol in postmenopausal women. Menopause (Submitted).
23 Spina, C., Tangpricha, V., Min, Y., Zhou, W., Wolfe, M., Maehr, H., Uskokovic, M., Adorini, L., and Holick, M.F. Colon cancer and ultraviolet B radiation and prevention and treatment of colon cancer in mice with vitamin D and its Gemini analogues. J Steroid Biochem Molecular Biol. (Submitted)
CONTRIBUTIONS IN ENDOCRINOLOGY
1. Vitamin D3 Metabolism
Dr. Holick's first contributions in the field of vitamin D nutrition occurred while he was a graduate student with Dr. Hector DeLuca at the University of Wisconsin. Dr. Holick isolated and identified 25-hydroxyvitamin D3 from human blood and was the first to isolate and identify the biologically active form of vitamin D3 as 1,25-dihydroxyvitamin D3. For his creative work, he received several awards outlined in the Biography and his achievement was considered as one of the Landmarks in research and featured in the Journal of National Institutes of Health Research in 1992.He played a key role in the first chemical synthesis of 1,25-dihydroxyvitamin D3 and its 25-deoxy analog 1α-hydroxyvitamin D3 that are used to treat renal osteodystrophy and vitamin D dependent rickets type I. He carried out the seminal investigations on the regulation of the renal synthesis of 1,25-dihydroxyvitamin D3 by parathyroid hormone, calcium, and phosphorus. He also helped pioneer the development of the 25(OH)D and 1,25(OH)2D assays for clinical use.
2. Photobiology of Vitamin D
He established how sunlight produces vitamin D3 in human skin and how it is photodegraded thereby preventing vitamin D intoxication due to prolonged excessive exposure to sunlight. He established that aging, sunscreens, skin pigmentation decrease the capacity of human skin to produce vitamin D. He designed a clever model system to evaluate the effect of latitude, season, and time of day on the cutaneous production of vitamin D3 and found that latitude, season, and time of day all dramatically influenced the cutaneous production of vitamin D3. He observed for the first time that exposure to sunlight in the winter at latitudes above and below 40º north and south, respectively, did not result in any production of vitamin D3. This provided important information for dietary intake requirements for vitamin D in the winter especially for children and adults who are prone to developing vitamin D deficiency.
3. Effect of body fat composition and vitamin D
It is well known that obesity is associated with vitamin D deficiency. He speculated that vitamin D either coming from the skin or the diet would be so efficiently stored in the body fat that it would be less bioavailable in obese people. To test this hypothesis he recruited obese and normal weighted adults and exposed them to the same amount of simulated sunlight or gave them an oral dose of 50,000IU of vitamin D. He observed a marked reduction in the peak blood levels of vitamin D and 25(OH)D in the obese subjects that were exposed to simulated sunlight or took an oral dose of vitamin D2 when compared to normal weighted controls. These results provide strong evidence that obese individuals require a higher vitamin D intake in order to satisfy their body's vitamin D requirement, because their large body fat stores most of the cutaneously produced and orally ingested vitamin D.
4. Role of 1,25-Dihydroxyvitamin D3 in Human Skin
In the early 1980s, Dr. Holick observed that human skin possessed the receptor for 1,25-dihydroxyvitamin D3. In pioneering studies, he showed that 1,25-dihydroxyvitamin D3 inhibited proliferation and induced terminal differentiation of cultured human keratinocytes. He introduced the concept that activated vitamin D compounds could be used for the treatment of the hyperproliferative skin disorder psoriasis. He initiated one of the first clinical trials to demonstrate the therapeutic efficacy and safety of topically administered 1,25-dihydroxyvitamin D3 for the treatment of psoriasis. These observations have led to the worldwide use of 1,25-dihydroxyvitamin D3 and its analogs for treating this stubborn skin disease.
5. Redefining Vitamin D Insufficiency
It has been long suspected that the normal range for the 25 (OH) D assays, which is the gold standard for determining vitamin D status of patients, was inadequate to identify patients at risk for vitamin D deficiency. Dr. Holick initiated a study whereby he took healthy adults who had serum 25(OH)D that was considered to be in the low normal range (normal range for 25(OH)D is 10 to 55 ng/ml) from 11 ng/ml to 25 ng/ml and gave then 50,000 IU of vitamin D once a week for eight weeks. He measured their serum 25(OH)D and PTH values. He reasoned that if the PTH values declined in response to the vitamin D therapy, this would be an excellent indicator that the subject was not vitamin D sufficient. After treatment, the 25(OH)D levels increased by 109% and PTH levels decreased by 22%. When stratified to pretreatment 25(OH)D levels, PTH decreased by 35% for subjects with 25(OH)D between 11 and 15 ng/ml (55% of these healthy adults were found to have elevated PTH levels) and 26% for adults with 25(OH)D between 16-20 ng/ml (35% had secondary hyperparathyroidism). Adults who had 25(OH)D levels between 21 -25 ng/ml had no significant change in their PTH levels even though their 25(OH)D increased by 66%. These results provide strong evidence that serum 25(OH)D levels need to be at least 21 ng/ml for the body to be vitamin D sufficient.
6. Adequacy of Vitamin D Fortification of Milk
In the early 1990s, Dr. Holick was asked to evaluate an elderly patient with hypercalcemia and vitamin D intoxication. A thorough evaluation did not reveal a medicinal source for the vitamin D intoxication. Two weeks later he was asked to evaluate the cause of vitamin D intoxication in a young child at the Boston Children's Hospital. Once again, no obvious cause was apparent. However, these two apparently unrelated outbreaks of vitamin D intoxication prompted Dr. Holick to investigate the cause of the vitamin D intoxication. A survey was developed and circulated to physicians throughout the Boston area. He and his colleagues identified eight additional cases of vitamin D intoxication. The common denominator amongst all of the affected individuals was that they drank milk from the same local dairy. Using the vitamin D assay that he had developed, he purchased milk from the dairy and brought it back to his laboratory for an analysis of vitamin D. He found that the milk had in excess of 600 times more vitamin D than stated on the label. He informed the Department of Public Health about these findings and only after his repeated warnings did the DPH act and investigated the dairy. At the same time, he decided to evaluate the vitamin D content in milk produced by milk processors throughout the US and western Canada. He found that no more than 20% of milk samples produced by most of the major milk processors contained within 20% of the 400 IU that was suppose to be in the milk. He also observed that between 15 and 20% of skim milk samples contained no detectable vitamin D. Thus, he and his colleagues showed that milk cannot be depended on as a sole source of vitamin D to satisfy the body's requirement.
7. Novel Fortification of Orange Juice with Vitamin D
Since many adults do not drink milk and therefore do not avail themselves of the vitamin D nutritional content of this fortified product, there continues to be a need to find alternative foods that can be safely and effectively fortified with vitamin D. Dr. Holick's laboratory evaluated the effect of the fat content in milk on vitamin D bioavailability. They observed that vitamin D absorption from milk was equally effective whether it was present in whole milk or skim milk Since orange juice is now routinely fortified with calcium, vitamin E and C, he considered the possibility of fortifying orange juice with vitamin .He conducted a study and observed in healthy young and middle-aged adults that vitamin D was highly bioavailable and raised blood levels of 25-hydroxyvitamin D more than two-fold, compared to adults who drank the same orange juice that was not fortified with vitamin D. These observations have provided the impetus for the food industry to consider fortifying orange juice with vitamin D. This new fortification process will have important health implications for vitamin D nutrition for the general population.
8. Function of Vitamin D in Regulating Cell Growth
It is well documented that there is a latitudinal effect on the incidence of colon, breast, ovarian, and prostate cancer. It had been speculated that this latitudinal effect was due in part to sunlight mediated vitamin D synthesis. However, it was difficult to fully understand how an increase in vitamin D3 synthesis in the skin could relate to cell proliferation and prevention of these cancers. The reason for this skepticism was that the production of 1,25-dihydroxyvitamin D3 by the kidney was tightly regulated; and therefore, an increase in the cutaneous production of vitamin D3 would not increase the renal production of 1,25-dihydroxyvitamin D3, a known inhibitor of proliferation of various cancer cell lines. Dr. Holick and his colleagues reasoned that maybe colon, breast, and prostate cells could metabolize 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 and that this hormone, in turn, would act in an autocrine/paracrine function to regulate cell growth. Dr. Holick and his colleagues incubated normal human prostate cells, benign prostatic hypertrophy cells, and three separate prostate cancer cell lines with 3H-25-hydroxyvitamin D3. They observed for the first time that normal human prostate cells and human prostate cancer cells had the synthetic machinery to convert 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3. This observation provides the basis for a new concept for the function of vitamin D in tissues not related to calcium metabolism.
9. Cloning of the Human 25-Hydroxyvitamin D-1α-Hydroxylase and a Novel Use for Gene Therapy
Dr. Holick and his colleagues cloned the human vitamin D-1α-hydroxylase with its entire promoter region. Transfection of this construct into prostate cancer cells resulted in the expression of the enzyme in the mitochondria of the prostate cell. Dr. Holick considered another use for his 1α-OHase construct. He reasoned he could topically apply it to the skin and enhance the production of 1,25(OH)2D3. This could be a unique way to treat psoriasis by gene therapy with 1α-OHase. He topically applied the naked plasmid in water to the skin of mice and found that there was increased expression of the 1α-OHase throughout the entire epidermis. This offers a new avenue for using the vitamin D system for health and disease of the skin.
10. Parathyroid Hormone Related Peptide and the Skin
His laboratory recognized the important role that parathyroid hormone related peptide (PTHrP) played in regulating skin and hair cell growth. He developed a formulation for the topical application of peptides that had agonistic or antagonistic activity of the PTHrP. In a novel group of studies, he demonstrated that the topical application of a PTHrP agonist markedly inhibited skin cell growth and the antagonist markedly stimulated skin and hair growth in mice. He recently completed a study demonstrating the topical application of PTH (1-34) is safe and efficient for treating psoriasis. He also found that PTHrP receptor antangonist PTH(7-34) was effective in stimulating hair growth and preventing chemotherapy induced alopecia. These observations offer a novel approach for treating hirsutism and male and female pattern baldness.