The physiological VDR
ligand,
1 alpha,25-dihydroxyvitamin D3, acts upon a wide variety of tissues and cells, both related to and unrelated to
calcium and
phosphate homeostasis. The noncalcemic actions of natural and synthetic VDR
ligands are exemplified by their potent anti-proliferative, prodifferentiative and immunomodulatory activities. As a result, a VDR
ligand is an approved
drug for the topical treatment of
psoriasis. A plethora of actions of
1 alpha,25-dihydroxyvitamin D3 in various systems have suggested wide clinical applications of VDR
ligands in such diverse disease states as
inflammation (
rheumatoid arthritis,
psoriatic arthritis), dermatological indications (
psoriasis, photoaging and skin
rejuvenation),
osteoporosis,
cancers (breast, prostate, colon,
leukemia and
myelodysplastic syndrome) and
autoimmune diseases (
multiple sclerosis, type I diabetes and
systemic lupus erythematosus). VDR
ligands have shown therapeutic potential in limited human clinical trials as well as in animal models of these diseases. Some of the VDR
ligands have shown not only potent preventive but also therapeutic anabolic activities in animal models of
osteoporosis. However, the use of VDR in above mentioned indications as well as in oral
therapy for
psoriasis and even topical
therapy for severe
psoriasis is hampered by its associated toxicity, namely
hypercalcemia. New VDR
ligands have been synthesized which exhibit greater specificity by retaining desirable properties, but with reduced calcemic potential. The discovery of novel
vitamin D3 analogs along with an increased understanding of the
biological functions and mechanisms of action of VDR are likely to result in improved treatments for responsive indications.