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Noncalcemic actions of 1,25-dihydroxyvitamin D3 and clinical applications
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Noncalcemic Actions of 1,25-Dihydroxyvitamin Clinical Applications
D3
and
M. F. H O L I C K Vitamin D, Skin and Bone Research Laboratory, Endocrinology Section, Department of Medicine, Boston Universi~' Medical Center, Boston, MA, USA
establishing a calcified skeleton in vertebrates. Most vertebrates, including hhmans, obtain most of their vitamin D from exposure to sunlight. When sunlight strikes the skin, the high energy ultraviolet B radiation (290--315 nm) causes the photolysis of 7dehydrocholesterol to previtamin D 3. Since 7-dehydrocholesterol is sandwiched between the bilipid membrane, once it is photoisomerized to previtamin D 3 , the previtamin D 3 remains in its thermodynamically unstable s-cis, s-cis conformation to efficiently isomerize to vitamin D 3' 16 As it is formed, vitamin Da leaves the epidermal cell membrane propelled by its conformational change into the circulation. Vitamin D is biologically inert and requires two successive hydroxylations in the liver and kidney to form its biologically active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D]. 11.14.15 It is believed that the principal mechanism by which 1,25(OH)2D carries out its biologic activities in regulating calcium and bone metabolism is through its interaction with a specific high affinity, low capacity, nuclear receptor commonly known as the vitamin D receptor (VDR). The goal of this presentation is to provide an overview of the pleotrophic actions of 1,25(OH)2D 3 and the potential development of 1,25(OH)2D 3 analogs for the treatment of a wide variety of clinical disorders.
Vitamin D is absolutely essential for the maintenance of a healthy skeleton. Without vitamin D, children develop rickets and adults exacerbate their osteoporosis and develop osteomalacia. Casual exposure to sunlight is the major source of vitamin D for most people. During exposure to sunlight, ultraviolet B photons photolyze cutaneous stores of 7-dehydrocholesterol to previtamin D 3. Previtamin D 3 undergoes a thermal isomerization to form vitamin D 3. Increased skin pigmentation, changes in latitude, time of day, sunscreen use, and aging can have a marked influence on the cutaneous production of vitamin D 3. Once vitamin D 3 is formed in the skin or ingested in the diet, it must be hydroxylated in the liver and kidney to 1,25-dihydroxyvitamin D 3 [I,25(OH)2D3]. It is now recognized that a wide variety of tissues and cells, both related to calcium metabolism and unrelated to calcium m e t a b o l i s m , are target sites for 1,25(OH)2D 3. 1,25(OH)2D 3 stimulates intestinal calcium absorption and mobilizes stem cells to mobilize calcium stores from bone. Noncalcemic tissues that possess receptors for 1,25(OH)2D 3 respond to the hormone in a variety of ways. Of great interest is that 1,25(OH)2D 3 is a potent antiproliferative and prodifferentiation mediator. As a result, 1,25(OH)2D 3 and its analogs have wide clinical application in such diverse clinical disorders as rheumatoid and psoriatic arthritis; diabetes mellitus type I; hypertension; cardiac arrhythmias; seizure disorders; cancers of the breast, prostate, and colon; some leukemias and myeloproliferative disorders; chemotherapy-induced hair loss; and skin rejuvenation as well as skin diseases like psoriasis and ichthyosis. (Bone 17:
Calcium Regulating Activities of 1,25(OH)2D The major physiologic function of 1,25(OH)2D (D without a subscript represents either D 2 o r D3) is to maintain serum calcium levels in the normal range. It accomplishes this by stimulating the small intestine to increase its efficiency of absorbing calcium from the diet. When dietary calcium absorption is inadequate to satisfy the body's requirement, then 1,25(OH)2D stimulates monocytic cells to become mature osteoclasts which, in turn, mobilize calcium stores from bone to maintain the serum calcium in the normal range for the maintenance of neuromuscular activity. 15
107S-111S; 1995) Key Words: 1,25(OH)2D3; Vitamin D receptor; noncalcemic; Vitamin D; Psoriasis.
Introduction Noncalcemic Activities of 1,25(OH)2D
There is evidence that the photosynthesis of vitamin D has been occurring on earth for over 750 million years. J5 Although the biologic function of vitamin D in lower life forms is not well understood, it is accepted that vitamin D evolved into an essential hormone responsible for regulating calcium metabolism and
Identification of VDR in Noncalcemic Tissues Until 1979, it was generally accepted that the major if not sole biologic function of vitamin D was to regulate calcium metabolism. In 1979, Stumpf et al. 34 reported a most curious finding; autoradiography analysis of frozen sections of tissues from vitamin D-deficient rats that received an intravenous injection of 3H-I,25(OH)2D3 revealed nuclear localization of 3H1,25(OH)2D 3 in a wide variety of tissues not associated with
Address for correspondence and reprints: Dr. Michael F. Holick, Vita-
D, Skin and Bone Research Laboratory, Endocrinology Section, Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA. min
© 1995 by Elsevier Science Inc.
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Noncalcemic actions of 1,25-dihydroxyvitamin D3 calcium metabolism, including gonads, pituitary gland, thymus, pancreas, stomach, breast, and skin. They also reported nuclear localization of 3H-1,25(OH)2D 3 in tissues that regulate calcium metabolism including the small intestine, bone, and kidney. This seminal observation spawned great interest in identifying VDR in all of these tissues as well as in a variety of cell types. These efforts have resulted in the identification of VDR in all of the tissues that originally demonstrated nuclear localization for 3H- 1,25(OH)2D 3.11.15 In addition, cultured myocardial smooth muscle cells, skeletal myoblasts, and several tumor cell lines of breast, melanoma, and osteosarcoma as well as a variety of mononuclear cells, including circulating monocytes and activated T and B lymphocytes, all had VDR activity T M (Table 1). Recognition of VDR in Cancer Cells The next chapter in this exciting story began to unfold in 1981, when Abe et al. 1 reported that the mouse myeloid leukemic cell line (M-l) possessed VDR and, when they were exposed to 1,25(OH)2D 3, the cells were induced to differentiate into macrophages. Similar observations were made in the human promyelocytic leukemic cell line HL-60.15.35 1,25(OH)2D 3 was found to decrease cellular proliferative activity, reduce c-myc-mRNA, and induce the expression of monocyte-specific cell surface antigen 63D3. 35 At the same time, Eisman et al. '2 reported that 80% of 54 unselected breast cancers had VDR activity. Although these observations were of great curiosity, the demonstration that M-1 leukemic mice treated with 1,25(OH)2D 3 or lct-hydroxyvitamin D 3 had a substantially increased survival 17 suggested the possibility of using 1,25(OH)2D 3 and its analogs as an antiproliferative agent for the treatment of a variety of hyperproliferative malignant disorders. Immune Cells as a Target for 1,25(OH)2D 3 1,25(OH)2D 3 can induce phagocytic activity in a time- and dosedependent manner, expression of cell surface antigens including Fc and C-3 receptors, enhance lysosomal activity, increase OKII binding, and augment the production of interleukin-1. 4'5''5'35 R e s t i n g T l y m p h o c y t e s do not p o s s e s s r e c e p t o r s for 1,25(OH)2D 3. However, when they are activated with phytohemoglutinin, a VDR is induced which, in turn, permits these activated T lymphocytes to respond to 1,25(OH)2D 3 by decreasing IL-2 production. 1,25(OH)2D3 has also been shown to inhibit DNA synthesis and immunoglobulin production in stimulated B lymphocytes. 29 Table 1. Vitamin D activity in calcemic and noncalcemic tissues Vitamin D receptor activi~/ in calcemic tissues • Small intestine • Bone • Kidney Vitamin D receptor activi~ in noncalcemic tissues • Epidermis • Pituitary • Melanocytes • Prostate • Hair follicles • Gonads • Dermis • Thymus • Monocytes • Parathyroids • Lymphocytes • Pancreas • Myocytes • Breast • Cardiac muscle • Stomach • Placenta
Although the exact role of 1,25(OH)2D 3 on regulating the immune system is not well understood, there have been reports that patients with vitamin D-deficient rickets had recurrent infections mainly of the respiratory tract. 23 It is also known that lymphocytes isolated from the human thymus and tonsils have VDR activity and the number of cells in the G,a phase of the cell cycle correlated positively with the number of VDR present in the cell. 5 It has also been reported that vitamin D-deficient patients have both a depressed inflammatory and phagocytic response that is corrected by making the patients vitamin D sufficient. 23 In humans with a vitamin D receptor defect (vitamin D-dependent rickets type II [DDR II]), concavalin A-induced mononuclear cells demonstrated a marked decrease in their responsiveness to the antiproliferative activity of 1,25(OH)2D 3 compared to monocytes from normal patients. 2' It is, however, interesting to note that patients with DDR II are not overwhelmed by any type of infection; and therefore, it appears that there is at best a subtle effect of 1,25(OH)2D on the immune system. It is now recognized that activated macrophages and T lymphocytes also metabolize 25-hydroxyvitamin D 3 (25-OH-D) to 1,25(OH)2D3 .2'9 Thus, it appears that these ceils not only are induced to produce a VDR but they also are capable of making the VDR ligand. The overall importance of this on the biologic function of these cells is not well understood. There is now a major effort underway to develop analogs of 1,25(OH)2D 3 that have immunosuppressive and immunoenhanced activities. These analogs have great potential for the development of pharmaceuticals for the treatment of a variety of immunologic disorders including autoimmune diabetes, z6 rheumatoid arthritis, psoriatic arthritis, and psoriasis. 5 Effect of 1,25(OH)2D 3 Smooth Muscle
on
Skeletal and Myocardial
Children with rickets often had severe muscle weakness that was not fully accounted for by either the hypocalcemia or hypophosphatemia associated with vitamin D deficiency. The first suggestion that skeletal muscle may be a target tissue for vitamin D was the observation that vitamin D repletion of vitamin D-deficient rats increased protein synthesis in diaphragm muscle. 6 A decade later, Boland et al. 7 reported 1,25(OH)ED 3 receptor binding activity in myoblasts released from chick embryo skeletal muscle. When cultured VDR + myoblast cells (G-8 and H9c2) were incubated with 1,25(OH)2D 3, there was a dose-dependent decrease in cell proliferation and induction to terminal differentiation. Furthermore, when the cells became fused microtubules, the VDR activity decreased. 3° 1,25(OH)2D 3 receptors are also present in rodent heart tissue and, when cardiac muscle cells are exposed to 1,25(OH)zD 3, the hormone increased calcium uptake in a time- and dose-dependent fashion. 36 Although these in vivo and in vitro observations are interesting, Grady et al. ,3 reported that, when 1,25(OH)2D 3 was given to elderly patients, there was no demonstrable increase in muscular strength of the legs. Patients with vitamin D deficiency or DDR II show no major cardiovascular or hemodynamic abnormalities implying, therefore, that the role of 1,25(OH)zD 3 on skeletal muscle and myocardial smooth muscle may be subtle in its effect. Regulation of Parathyroid Hormone Secretion by 1,25(OH )eD3 The parathyroid glands possess a VDR. i,25(OH)zD 3 is able to suppress preproparathyroid hormone mRNA levels in cultured
Bone Vol. 17, No. 2, Supplement August 1995:107S- I 11S bovine parathyroid cells. 8'~5 Based on these observations, it has been suggested that 1,25(OH)2D 3 may play a physiologic role in regulating PTH production. This has clinical application for the intravenous use of 1,25(OH)ED 3 in patients with chronic renal failure. The high blood levels of 1,25(OH)zD 3 may help suppress the secondary hyperparathyroidism that is associated with this disease. ~5 Analogs of 1,25(OH)2D 3 that have little or no calcemic activity (such as 22-oxacalcitriol) that suppress PTH production may be useful for treating secondary hyperparathyroidism associated with renal failure 8 and possibly even primary hyperparathyroidism in patients who are poor surgical candidates.
Effect of 1,25(OH)zD 3 in the Skin In 1979, Stumpf et al. 34 reported 3H-I,25(OH)2D3 localization in the nuclei of cells in the outer root sheath of hair and in the stratum granulosum, stratum spinosum, and stratum basale of the epidermis. There is now ample evidence that the VDR exits in these cell types. When cultured human and murine keratinocytes are incubated with 1,25(OH)2D3, this hormone inhibited their proliferation and induced them to terminally differentiate. 14.15 Human skin fibroblasts also have a VDR and respond to the hormone in a similar manner. However, when f i b r o b l a s t s f r o m D D R 11 p a t i e n t s were i n c u b a t e d with 1,25(OH)2D3, there is a marked decrease in the antiproliferative activity of 1,25(OH)2D 3.15,21
M.F. Holick Noncalcemic actions of 1,25-dihydroxyvitamin D 3
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Cultured melanoma cells that have VDR are responsive to 1,25(OH)2D3's antiproliferative and prodifferentiating activities. 18 However, when normal human melanocytes were isolated from neonatal foreskins and incubated with 1,25(OH)2D3, there was no effect on either their proliferation or melanogenesis. 25 Despite the lack of VDR and 1,25(OH)2D 3 activity in normal cultured melanocytes, immunocytochemical localization studies suggest that melanocytes are indeed a target for 1,25(OH)2D3 .27
Actions of 1,25(OH)2D 3 on Prostate and Testes It has been shown that both the ovaries and testes have VDR activity. In cultures Sertoli cells, 1,25(OH)2D 3 enhanced rapid uptake of 45Ca2 ÷ .3 Recently, it has been found that primary cultured prostate cells derived from normal, benign prostatic hyperplasia and prostate cancer tissues possess VDR. 32 When prostate cancer cell lines and primary cultures of stromal and epithelial cells derived from normal and malignant prostate tissues were incubated with 1,25(OH)2D 3, it was demonstrated that this hormone elicited antiproliferative and differentiation actions. 32
Potential Clinical Uses for the Nonealcemic Activities of 1,25(OIt)zD a
Treatment of Some Cancers It is of great interest that 1,25(OH)2D 3 is a potent inhibitor of proliferation and induces differentiation in a wide variety
Figure 1. Photo at left shows a patient with psoriasis before treatment, and photo at right shows the same patient following treatment with oral 1,25(OH)2D 3 (2 i~g per night). (Reproduced with permission, Smith, E. L., Pincus, S. H., Donovan, L., and Holick, M. F. A novel approach for the evaluation and treatment of psoriasis: Oral or topical use of 1,25-dihydroxyvitamin D~ can be a safe and effect therapy for psoriasis. J Am Acad Dermatol 19:516; 1988.)
IlOS
M . F . Holick Noncalcemic actions of 1,25-dihydroxyvitamin D 3
Table 2. Clinical uses of 1,25(OH)2D
3
and analogs
Established clinical utility • • • • • • •
Renal osteodystrophy Hypoparathyroidism Osteoporosis Vitamin D-dependent rickets types I and II X-linked hypophosphatemic rickets Psoriasis Ichthyosis
Potential clinical utility • Cancer--breast, colon, prostate, leukemia
• • • • • • • • •
Autoimmune diseases---rheumatoid arthritis, psoriatic arthritis Autoimmune diabetes mellitus type I Hair growth disturbances Seizure disorders Hypertension Cardiac arrhythmias Hyperparathyroidism 1 and 2 Wound healing Rejuvenate aged skin
Bone Vol. 17, No. 2, Supplement August 1995:107S-111S nant hyperproliferative disorders such as the skin disease psoriasis. Psoriasis afflicts approximately 5% o f the w o r l d ' s population. Although its cause is u n k n o w n , it is manifested by a marked increase in the proliferative activity o f the basal cells in the epidermis and is characterized by an infiltration o f monocytic and granulocytic cells in the dermis and epidermis.t4"28 There are now numerous reports that topical and oral 1,25(OH)2D 3 ( F i g u r e 1) as well as t o p i c a l a p p l i c a t i o n o f a n a l o g s o f 1,25(OH)2D 3 including 1,24-dihydroxyvitamin D 3 and calcipotriene are safe and effective for the treatment o f psoriasis. 22"28 Analogs o f 1,25(OH)2D 3 may also be useful for treating other hyperproliferative skin disorders such as congenital ichthyosis. 24 It was recognized by Stumpf et al. 33 that 3H-I,25(OH)2D3 has localized in the nuclei o f hair follicles. The V D R activity is increased in the nuclei o f the outer root sheath, keratinocytes, and dermal papilla cells when the hair follicle is entering the maturation stage (anagen I V - V I and catagen) o f the hair cycle. Although the exact function o f 1,25(OH)2D 3 on hair growth is not well understood, one practical application is the use o f 1,25(OH)2D 3 in preventing chemotherapy-induced alopecia, t9 Conclusion
o f cell types as well as in a multitude o f different cancer cell lines. O n e o f the m a j o r c o n c e r n s , h o w e v e r , in using 1,25(OH)2D 3 for treating a variety o f cancers, such as leukemia, is that the h o r m o n e has a strong propensity to cause hypercalcemia and hypercalciuria. W h e n 18 patients with m y e l o d y s p l a s i a (preleukemia) received up to 2 i~g o f 1,25(OH)2D 3 for 12 weeks, it was found that a majority o f the patients initially had a significant increase in their granulocyte, monocyte, and platelet counts. However, concomitant with this increase was a rise in serum calcium up to 17 m g % . After 12 w e e k s o f the study, there was no significant difference in the blood count for granulocytes, monocytes, and platelets c o m p a r e d to baseline and most o f the patients progressed to acute myelocytic leukemia. 2° It has also been reported that three patients with myelofibrosis, w h o received 1,25(OH)2D 3 (0.5 p,g dally), had some improvement in their blood count indexes after therapy. C l e a r l y , o n e o f t h e m o s t l i m i t i n g f a c t o r s in u s i n g 1,25(OH)2D 3 for the treatment o f hyperproliferative diseases such as cancer is that its major side effect is hypercalcemia. H o w e v e r , with the multitude o f analogs o f 1,25(OH)2D 3 that are now available that have been demonstrated to have little calcemic activity while maintaining potent antiproliferative activity, it is likely that analogs can be developed to o v e r c o m e this major s i d e e f f e c t , s ' l ° H o w e v e r , it r e m a i n s u n c l e a r w h e t h e r 1,25(OH)2D 3 analogs will have any significant impact for use in the treatment o f a variety o f cancers. The likely reason that these drugs will not be the first line o f defense is that the cancer cells can mutate to either decrease or produce a defective V D R which, thereby, makes the mutant cancer cell resistant to the antiproliferative activity o f the vitamin D analog. H o w e v e r , a potent antiproliferative 1,25(OH)2D3 analog could be developed as an adjunctive therapy for s o m e cancers such as breast, prostate, colon and some leukemias.
Treatment of Psoriasis and Other Skin Disorders The potent antiproliferative activity and prodifferentiation activity o f 1,25(OH)2D 3 and its analogs has great use for nonmalig-
Autoradiographic and immunocytochemical localization studies have provided evidence that a wide diversity o f tissues from the brain to the gonads are potential target tissues for 1,25(OH)2D 3. The development o f analogs o f 1,25(OH)2D 3 that have targeted responses in selective tissues offers great promise for the development o f new therapeutic modalities for the treatment o f such diverse diseases as cancer, rheumatoid and psoriatic arthritis, autoimmune disorders, psoriasis, ichthyosis, seizure disorders, hypertension, cardiac arrhythmias, and hair loss; it may also help to rejuvenate aged photodamaged skin and enhance w o u n d healing (Table 2).
Acknowledgments: This work was supported in part by Grants M0100533, AR 36963, and DK 43690.
References
1. Abe, E.. Miyaura, C., Sakagami, H., et al. Differentiation of rat myc leukemia ceils induced by 1,25-dihydroxyvitaminD 3. Proc Acad Sci USA 78:49904994; 1981. 2. Adams, J. S., Gacad, M. A., Diz, M. M., and Nadler, J. L. A role for endogenousarchidonate metabolites in regulated expression of the 25-hydroxyvitamin D-l-hydroxylation reaction in cultured alveolar macrophages from patients with sarcoidosis. J Clin Endocrinol Metab 70:595-600; 1990. 3. Akerstrom, V. L. and Waiters, M. Physiological effects of 1,25-dihydroxyvitamin D 3 in TM4 sertoli cell line. Am J Physiol 262:E884-E890; 1992. 4. Bar-Shavit, Z., Noff, D., Edelstein, S., Meyer, M., Shibolet, S., and Goldman, R. 1,25-DihydroxyvitaminD 3 and the regulation of macrophage function. Calcif Tissue lnt 33:673-676: 1981. 5. Binderup, L. Immunological properties of vitamin D analogues and metabolites. Biocbem Pharm 43:1885-1892: 1992. 6. Birge, S. J. and Haddad, J. G. 25-Hydroxycholecalciferolstimulation of muscle metabolism. J Clin Invest 56:1100-1107: 1975. 7. Boland, R., Norman, A., Ritz. E.. and Hausselbach, W. Presence of 1,25d i h y d r o x y v i t a m i n D 3 receptor in chick skeletal muscle myoblasts. Biochem Biophys Res Commun 128:30:~311 ; 1985. 8. Brown, A. J.. Ritter, C. R., Finch, J. L., Morrissey, I., Martin, K. J., Murayama. E., et al. The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppressesparathyroid hormone synthesis and secretion. J Clin Invest 84:728732; 1989. 9. Cadranel, J.. Garabedian, M., Milleron, B., Guillozo, H.. Akoun, G., and Hance, A. J. 1.25(OH)2D3 production by T lymphocytes and alveolar macro-
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ELSEVIER
Noncalcemic Actions of 1,25-Dihydroxyvitamin Clinical Applications
D3
and
M. F. H O L I C K Vitamin D, Skin and Bone Research Laboratory, Endocrinology Section, Department of Medicine, Boston Universi~' Medical Center, Boston, MA, USA
establishing a calcified skeleton in vertebrates. Most vertebrates, including hhmans, obtain most of their vitamin D from exposure to sunlight. When sunlight strikes the skin, the high energy ultraviolet B radiation (290--315 nm) causes the photolysis of 7dehydrocholesterol to previtamin D 3. Since 7-dehydrocholesterol is sandwiched between the bilipid membrane, once it is photoisomerized to previtamin D 3 , the previtamin D 3 remains in its thermodynamically unstable s-cis, s-cis conformation to efficiently isomerize to vitamin D 3' 16 As it is formed, vitamin Da leaves the epidermal cell membrane propelled by its conformational change into the circulation. Vitamin D is biologically inert and requires two successive hydroxylations in the liver and kidney to form its biologically active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D]. 11.14.15 It is believed that the principal mechanism by which 1,25(OH)2D carries out its biologic activities in regulating calcium and bone metabolism is through its interaction with a specific high affinity, low capacity, nuclear receptor commonly known as the vitamin D receptor (VDR). The goal of this presentation is to provide an overview of the pleotrophic actions of 1,25(OH)2D 3 and the potential development of 1,25(OH)2D 3 analogs for the treatment of a wide variety of clinical disorders.
Vitamin D is absolutely essential for the maintenance of a healthy skeleton. Without vitamin D, children develop rickets and adults exacerbate their osteoporosis and develop osteomalacia. Casual exposure to sunlight is the major source of vitamin D for most people. During exposure to sunlight, ultraviolet B photons photolyze cutaneous stores of 7-dehydrocholesterol to previtamin D 3. Previtamin D 3 undergoes a thermal isomerization to form vitamin D 3. Increased skin pigmentation, changes in latitude, time of day, sunscreen use, and aging can have a marked influence on the cutaneous production of vitamin D 3. Once vitamin D 3 is formed in the skin or ingested in the diet, it must be hydroxylated in the liver and kidney to 1,25-dihydroxyvitamin D 3 [I,25(OH)2D3]. It is now recognized that a wide variety of tissues and cells, both related to calcium metabolism and unrelated to calcium m e t a b o l i s m , are target sites for 1,25(OH)2D 3. 1,25(OH)2D 3 stimulates intestinal calcium absorption and mobilizes stem cells to mobilize calcium stores from bone. Noncalcemic tissues that possess receptors for 1,25(OH)2D 3 respond to the hormone in a variety of ways. Of great interest is that 1,25(OH)2D 3 is a potent antiproliferative and prodifferentiation mediator. As a result, 1,25(OH)2D 3 and its analogs have wide clinical application in such diverse clinical disorders as rheumatoid and psoriatic arthritis; diabetes mellitus type I; hypertension; cardiac arrhythmias; seizure disorders; cancers of the breast, prostate, and colon; some leukemias and myeloproliferative disorders; chemotherapy-induced hair loss; and skin rejuvenation as well as skin diseases like psoriasis and ichthyosis. (Bone 17:
Calcium Regulating Activities of 1,25(OH)2D The major physiologic function of 1,25(OH)2D (D without a subscript represents either D 2 o r D3) is to maintain serum calcium levels in the normal range. It accomplishes this by stimulating the small intestine to increase its efficiency of absorbing calcium from the diet. When dietary calcium absorption is inadequate to satisfy the body's requirement, then 1,25(OH)2D stimulates monocytic cells to become mature osteoclasts which, in turn, mobilize calcium stores from bone to maintain the serum calcium in the normal range for the maintenance of neuromuscular activity. 15
107S-111S; 1995) Key Words: 1,25(OH)2D3; Vitamin D receptor; noncalcemic; Vitamin D; Psoriasis.
Introduction Noncalcemic Activities of 1,25(OH)2D
There is evidence that the photosynthesis of vitamin D has been occurring on earth for over 750 million years. J5 Although the biologic function of vitamin D in lower life forms is not well understood, it is accepted that vitamin D evolved into an essential hormone responsible for regulating calcium metabolism and
Identification of VDR in Noncalcemic Tissues Until 1979, it was generally accepted that the major if not sole biologic function of vitamin D was to regulate calcium metabolism. In 1979, Stumpf et al. 34 reported a most curious finding; autoradiography analysis of frozen sections of tissues from vitamin D-deficient rats that received an intravenous injection of 3H-I,25(OH)2D3 revealed nuclear localization of 3H1,25(OH)2D 3 in a wide variety of tissues not associated with
Address for correspondence and reprints: Dr. Michael F. Holick, Vita-
D, Skin and Bone Research Laboratory, Endocrinology Section, Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA. min
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Noncalcemic actions of 1,25-dihydroxyvitamin D3 calcium metabolism, including gonads, pituitary gland, thymus, pancreas, stomach, breast, and skin. They also reported nuclear localization of 3H-1,25(OH)2D 3 in tissues that regulate calcium metabolism including the small intestine, bone, and kidney. This seminal observation spawned great interest in identifying VDR in all of these tissues as well as in a variety of cell types. These efforts have resulted in the identification of VDR in all of the tissues that originally demonstrated nuclear localization for 3H- 1,25(OH)2D 3.11.15 In addition, cultured myocardial smooth muscle cells, skeletal myoblasts, and several tumor cell lines of breast, melanoma, and osteosarcoma as well as a variety of mononuclear cells, including circulating monocytes and activated T and B lymphocytes, all had VDR activity T M (Table 1). Recognition of VDR in Cancer Cells The next chapter in this exciting story began to unfold in 1981, when Abe et al. 1 reported that the mouse myeloid leukemic cell line (M-l) possessed VDR and, when they were exposed to 1,25(OH)2D 3, the cells were induced to differentiate into macrophages. Similar observations were made in the human promyelocytic leukemic cell line HL-60.15.35 1,25(OH)2D 3 was found to decrease cellular proliferative activity, reduce c-myc-mRNA, and induce the expression of monocyte-specific cell surface antigen 63D3. 35 At the same time, Eisman et al. '2 reported that 80% of 54 unselected breast cancers had VDR activity. Although these observations were of great curiosity, the demonstration that M-1 leukemic mice treated with 1,25(OH)2D 3 or lct-hydroxyvitamin D 3 had a substantially increased survival 17 suggested the possibility of using 1,25(OH)2D 3 and its analogs as an antiproliferative agent for the treatment of a variety of hyperproliferative malignant disorders. Immune Cells as a Target for 1,25(OH)2D 3 1,25(OH)2D 3 can induce phagocytic activity in a time- and dosedependent manner, expression of cell surface antigens including Fc and C-3 receptors, enhance lysosomal activity, increase OKII binding, and augment the production of interleukin-1. 4'5''5'35 R e s t i n g T l y m p h o c y t e s do not p o s s e s s r e c e p t o r s for 1,25(OH)2D 3. However, when they are activated with phytohemoglutinin, a VDR is induced which, in turn, permits these activated T lymphocytes to respond to 1,25(OH)2D 3 by decreasing IL-2 production. 1,25(OH)2D3 has also been shown to inhibit DNA synthesis and immunoglobulin production in stimulated B lymphocytes. 29 Table 1. Vitamin D activity in calcemic and noncalcemic tissues Vitamin D receptor activi~/ in calcemic tissues • Small intestine • Bone • Kidney Vitamin D receptor activi~ in noncalcemic tissues • Epidermis • Pituitary • Melanocytes • Prostate • Hair follicles • Gonads • Dermis • Thymus • Monocytes • Parathyroids • Lymphocytes • Pancreas • Myocytes • Breast • Cardiac muscle • Stomach • Placenta
Although the exact role of 1,25(OH)2D 3 on regulating the immune system is not well understood, there have been reports that patients with vitamin D-deficient rickets had recurrent infections mainly of the respiratory tract. 23 It is also known that lymphocytes isolated from the human thymus and tonsils have VDR activity and the number of cells in the G,a phase of the cell cycle correlated positively with the number of VDR present in the cell. 5 It has also been reported that vitamin D-deficient patients have both a depressed inflammatory and phagocytic response that is corrected by making the patients vitamin D sufficient. 23 In humans with a vitamin D receptor defect (vitamin D-dependent rickets type II [DDR II]), concavalin A-induced mononuclear cells demonstrated a marked decrease in their responsiveness to the antiproliferative activity of 1,25(OH)2D 3 compared to monocytes from normal patients. 2' It is, however, interesting to note that patients with DDR II are not overwhelmed by any type of infection; and therefore, it appears that there is at best a subtle effect of 1,25(OH)2D on the immune system. It is now recognized that activated macrophages and T lymphocytes also metabolize 25-hydroxyvitamin D 3 (25-OH-D) to 1,25(OH)2D3 .2'9 Thus, it appears that these ceils not only are induced to produce a VDR but they also are capable of making the VDR ligand. The overall importance of this on the biologic function of these cells is not well understood. There is now a major effort underway to develop analogs of 1,25(OH)2D 3 that have immunosuppressive and immunoenhanced activities. These analogs have great potential for the development of pharmaceuticals for the treatment of a variety of immunologic disorders including autoimmune diabetes, z6 rheumatoid arthritis, psoriatic arthritis, and psoriasis. 5 Effect of 1,25(OH)2D 3 Smooth Muscle
on
Skeletal and Myocardial
Children with rickets often had severe muscle weakness that was not fully accounted for by either the hypocalcemia or hypophosphatemia associated with vitamin D deficiency. The first suggestion that skeletal muscle may be a target tissue for vitamin D was the observation that vitamin D repletion of vitamin D-deficient rats increased protein synthesis in diaphragm muscle. 6 A decade later, Boland et al. 7 reported 1,25(OH)ED 3 receptor binding activity in myoblasts released from chick embryo skeletal muscle. When cultured VDR + myoblast cells (G-8 and H9c2) were incubated with 1,25(OH)2D 3, there was a dose-dependent decrease in cell proliferation and induction to terminal differentiation. Furthermore, when the cells became fused microtubules, the VDR activity decreased. 3° 1,25(OH)2D 3 receptors are also present in rodent heart tissue and, when cardiac muscle cells are exposed to 1,25(OH)zD 3, the hormone increased calcium uptake in a time- and dose-dependent fashion. 36 Although these in vivo and in vitro observations are interesting, Grady et al. ,3 reported that, when 1,25(OH)2D 3 was given to elderly patients, there was no demonstrable increase in muscular strength of the legs. Patients with vitamin D deficiency or DDR II show no major cardiovascular or hemodynamic abnormalities implying, therefore, that the role of 1,25(OH)zD 3 on skeletal muscle and myocardial smooth muscle may be subtle in its effect. Regulation of Parathyroid Hormone Secretion by 1,25(OH )eD3 The parathyroid glands possess a VDR. i,25(OH)zD 3 is able to suppress preproparathyroid hormone mRNA levels in cultured
Bone Vol. 17, No. 2, Supplement August 1995:107S- I 11S bovine parathyroid cells. 8'~5 Based on these observations, it has been suggested that 1,25(OH)2D 3 may play a physiologic role in regulating PTH production. This has clinical application for the intravenous use of 1,25(OH)ED 3 in patients with chronic renal failure. The high blood levels of 1,25(OH)zD 3 may help suppress the secondary hyperparathyroidism that is associated with this disease. ~5 Analogs of 1,25(OH)2D 3 that have little or no calcemic activity (such as 22-oxacalcitriol) that suppress PTH production may be useful for treating secondary hyperparathyroidism associated with renal failure 8 and possibly even primary hyperparathyroidism in patients who are poor surgical candidates.
Effect of 1,25(OH)zD 3 in the Skin In 1979, Stumpf et al. 34 reported 3H-I,25(OH)2D3 localization in the nuclei of cells in the outer root sheath of hair and in the stratum granulosum, stratum spinosum, and stratum basale of the epidermis. There is now ample evidence that the VDR exits in these cell types. When cultured human and murine keratinocytes are incubated with 1,25(OH)2D3, this hormone inhibited their proliferation and induced them to terminally differentiate. 14.15 Human skin fibroblasts also have a VDR and respond to the hormone in a similar manner. However, when f i b r o b l a s t s f r o m D D R 11 p a t i e n t s were i n c u b a t e d with 1,25(OH)2D3, there is a marked decrease in the antiproliferative activity of 1,25(OH)2D 3.15,21
M.F. Holick Noncalcemic actions of 1,25-dihydroxyvitamin D 3
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Cultured melanoma cells that have VDR are responsive to 1,25(OH)2D3's antiproliferative and prodifferentiating activities. 18 However, when normal human melanocytes were isolated from neonatal foreskins and incubated with 1,25(OH)2D3, there was no effect on either their proliferation or melanogenesis. 25 Despite the lack of VDR and 1,25(OH)2D 3 activity in normal cultured melanocytes, immunocytochemical localization studies suggest that melanocytes are indeed a target for 1,25(OH)2D3 .27
Actions of 1,25(OH)2D 3 on Prostate and Testes It has been shown that both the ovaries and testes have VDR activity. In cultures Sertoli cells, 1,25(OH)2D 3 enhanced rapid uptake of 45Ca2 ÷ .3 Recently, it has been found that primary cultured prostate cells derived from normal, benign prostatic hyperplasia and prostate cancer tissues possess VDR. 32 When prostate cancer cell lines and primary cultures of stromal and epithelial cells derived from normal and malignant prostate tissues were incubated with 1,25(OH)2D 3, it was demonstrated that this hormone elicited antiproliferative and differentiation actions. 32
Potential Clinical Uses for the Nonealcemic Activities of 1,25(OIt)zD a
Treatment of Some Cancers It is of great interest that 1,25(OH)2D 3 is a potent inhibitor of proliferation and induces differentiation in a wide variety
Figure 1. Photo at left shows a patient with psoriasis before treatment, and photo at right shows the same patient following treatment with oral 1,25(OH)2D 3 (2 i~g per night). (Reproduced with permission, Smith, E. L., Pincus, S. H., Donovan, L., and Holick, M. F. A novel approach for the evaluation and treatment of psoriasis: Oral or topical use of 1,25-dihydroxyvitamin D~ can be a safe and effect therapy for psoriasis. J Am Acad Dermatol 19:516; 1988.)
IlOS
M . F . Holick Noncalcemic actions of 1,25-dihydroxyvitamin D 3
Table 2. Clinical uses of 1,25(OH)2D
3
and analogs
Established clinical utility • • • • • • •
Renal osteodystrophy Hypoparathyroidism Osteoporosis Vitamin D-dependent rickets types I and II X-linked hypophosphatemic rickets Psoriasis Ichthyosis
Potential clinical utility • Cancer--breast, colon, prostate, leukemia
• • • • • • • • •
Autoimmune diseases---rheumatoid arthritis, psoriatic arthritis Autoimmune diabetes mellitus type I Hair growth disturbances Seizure disorders Hypertension Cardiac arrhythmias Hyperparathyroidism 1 and 2 Wound healing Rejuvenate aged skin
Bone Vol. 17, No. 2, Supplement August 1995:107S-111S nant hyperproliferative disorders such as the skin disease psoriasis. Psoriasis afflicts approximately 5% o f the w o r l d ' s population. Although its cause is u n k n o w n , it is manifested by a marked increase in the proliferative activity o f the basal cells in the epidermis and is characterized by an infiltration o f monocytic and granulocytic cells in the dermis and epidermis.t4"28 There are now numerous reports that topical and oral 1,25(OH)2D 3 ( F i g u r e 1) as well as t o p i c a l a p p l i c a t i o n o f a n a l o g s o f 1,25(OH)2D 3 including 1,24-dihydroxyvitamin D 3 and calcipotriene are safe and effective for the treatment o f psoriasis. 22"28 Analogs o f 1,25(OH)2D 3 may also be useful for treating other hyperproliferative skin disorders such as congenital ichthyosis. 24 It was recognized by Stumpf et al. 33 that 3H-I,25(OH)2D3 has localized in the nuclei o f hair follicles. The V D R activity is increased in the nuclei o f the outer root sheath, keratinocytes, and dermal papilla cells when the hair follicle is entering the maturation stage (anagen I V - V I and catagen) o f the hair cycle. Although the exact function o f 1,25(OH)2D 3 on hair growth is not well understood, one practical application is the use o f 1,25(OH)2D 3 in preventing chemotherapy-induced alopecia, t9 Conclusion
o f cell types as well as in a multitude o f different cancer cell lines. O n e o f the m a j o r c o n c e r n s , h o w e v e r , in using 1,25(OH)2D 3 for treating a variety o f cancers, such as leukemia, is that the h o r m o n e has a strong propensity to cause hypercalcemia and hypercalciuria. W h e n 18 patients with m y e l o d y s p l a s i a (preleukemia) received up to 2 i~g o f 1,25(OH)2D 3 for 12 weeks, it was found that a majority o f the patients initially had a significant increase in their granulocyte, monocyte, and platelet counts. However, concomitant with this increase was a rise in serum calcium up to 17 m g % . After 12 w e e k s o f the study, there was no significant difference in the blood count for granulocytes, monocytes, and platelets c o m p a r e d to baseline and most o f the patients progressed to acute myelocytic leukemia. 2° It has also been reported that three patients with myelofibrosis, w h o received 1,25(OH)2D 3 (0.5 p,g dally), had some improvement in their blood count indexes after therapy. C l e a r l y , o n e o f t h e m o s t l i m i t i n g f a c t o r s in u s i n g 1,25(OH)2D 3 for the treatment o f hyperproliferative diseases such as cancer is that its major side effect is hypercalcemia. H o w e v e r , with the multitude o f analogs o f 1,25(OH)2D 3 that are now available that have been demonstrated to have little calcemic activity while maintaining potent antiproliferative activity, it is likely that analogs can be developed to o v e r c o m e this major s i d e e f f e c t , s ' l ° H o w e v e r , it r e m a i n s u n c l e a r w h e t h e r 1,25(OH)2D 3 analogs will have any significant impact for use in the treatment o f a variety o f cancers. The likely reason that these drugs will not be the first line o f defense is that the cancer cells can mutate to either decrease or produce a defective V D R which, thereby, makes the mutant cancer cell resistant to the antiproliferative activity o f the vitamin D analog. H o w e v e r , a potent antiproliferative 1,25(OH)2D3 analog could be developed as an adjunctive therapy for s o m e cancers such as breast, prostate, colon and some leukemias.
Treatment of Psoriasis and Other Skin Disorders The potent antiproliferative activity and prodifferentiation activity o f 1,25(OH)2D 3 and its analogs has great use for nonmalig-
Autoradiographic and immunocytochemical localization studies have provided evidence that a wide diversity o f tissues from the brain to the gonads are potential target tissues for 1,25(OH)2D 3. The development o f analogs o f 1,25(OH)2D 3 that have targeted responses in selective tissues offers great promise for the development o f new therapeutic modalities for the treatment o f such diverse diseases as cancer, rheumatoid and psoriatic arthritis, autoimmune disorders, psoriasis, ichthyosis, seizure disorders, hypertension, cardiac arrhythmias, and hair loss; it may also help to rejuvenate aged photodamaged skin and enhance w o u n d healing (Table 2).
Acknowledgments: This work was supported in part by Grants M0100533, AR 36963, and DK 43690.
References
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