A Nonsecosteroidal Vitamin D Receptor Modulator Ameliorates Experimental Autoimmune Encephalomyelitis without Causing Hypercalcemia

Abstract

Vitamin D receptor (VDR) agonists are currently the agents of choice for the treatment of psoriasis, a skin inflammatory indication that is believed to involve an autoimmune component. 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], the biologically active metabolite of vitamin D, has shown efficacy in animal autoimmune disease models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and type I diabetes. However, the side effect of 1,25-(OH)2D3 and its synthetic secosteroidal analogs is hypercalcemia, which is a major impediment in their clinical development for autoimmune diseases. Hypercalcemia develops as a result of the action of VDR agonists on the intestine. Here, we describe the identification of a VDR modulator (VDRM) compound A that was transcriptionally less active in intestinal cells and as a result exhibited less calcemic activity in vivo than 1,25-(OH)2D3. Cytokine analysis indicated that the VDRM not only modulated the T-helper cell balance from Th1 to Th2 effector function but also inhibited Th17 differentiation. Finally, we demonstrate that the oral administration of compound A inhibited the induction and progress of experimental autoimmune encephalomyelitis in mice without causing hypercalcemia.

Vitamin D and multiple sclerosis

“…[3] Recent investigations suggest that this effect requires a functional VDR on T-lymphocytes , [34] as previously observed, [35] and involves modulation of Th17 cell differentiation and IL-17a expression. [36] STAT6 also appears necessary for amelioration of EAE following 1,25(OH)2D3 treatment in ex vivo studies. [37] Calcitriol, however, can cause hypercalcemia, and its effect may in part be mediated by increased calcium levels.…”

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…More importantly, serum calcium levels were within the normal range after compound A treatment versus 1,25-(OH) 2 D 3 . Ex vivo stimulation of total splenocytes from diseased mice revealed that compound A inhibited both T H 1 and T H 17 cell differentiation (Na et al, 2011).…”

Vitamin D receptor as a therapeutic target for benign prostatic hyperplasia

“…[10] Since the supraphysiological doses of 1α,25(OH)2D3 required to demonstrate the stout anti- inflammatory effects also stimulate hypercalcemia, vitamin D analogs were synthesized in order to potentiate the anti- inflammatory properties of VDR agonists without inducing the hypercalcemic side effects. [11]…”