Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2016) 41 S25.2 | DOI: 10.1530/endoabs.41.S25.2

ECE2016 Symposia What's new and exciting in nuclear receptor action? (3 abstracts)

Ligand independent activities of vitamin D receptor

Gilles Laverny



The bioactive form of Vitamin D [1,25(OH)2D3] plays a major role in calcium homeostasis. Moreover, it has potent anti-inflammatory and anti-proliferative properties, and thus is a potential pharmacological agent to treat various refractory diseases. Nevertheless, the doses required to elicit such effects induce hypercalcemia. The activity of 1,25(OH)2D3 is mediated by the vitamin D receptor (VDR), a member of nuclear receptor superfamily. A number of patients with rickets carry mutations of VDR impairing either its DNA- or ligand- binding, but only mutations impairing DNA binding induce alopecia.

In order to dissociate the calcemic activities of 1,25(OH)2D3 from its anti-inflammatory and antiproliferative properties, more than 3000 analogs were synthesized. The resolution of the VDR ligand binding domain 3D structure facilitated the design of such analogs, but no potent agonists devoid of hypercalcemic activities have been obtained.

Based on VDR structural data, we generated mice expressing a point-mutated VDR (VDRgem), unresponsive to 1,25(OH)2D3, but the activity of which is induced by gemini ligands. We have shown that these mice present clinical signs of rickets that their mineral ion and bone homeostasis are more impaired than in VDR-null mice, and that unliganded VDR has repressive activities. As VDRgem mice have a normal hair cycle in contrast to VDR-null mice, these results indicate that skeletal defects might be more severe in patients expressing a ligand binding deficient VDR than in those with full receptor deficiency. Thus, these results might facilitate the stratification of patients with Vitamin-D dependent rickets.

In addition, we have shown that administration of gemini ligands to VDRgem mice normalizes their serum calcium levels, demonstrating that the activity of VDRgem can be induced in-vivo. Further analysis of VDRgem mice should help to unravel both liganded and unliganded VDR signaling.

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