The investigations in this proposal are focused on identifying the molecularbasis for the direct and indirect consequences ofVitamin D Receptor (VDR) ablation. VDRknockoutmice develophypocalcemia and secondary hyperparathyroidism which, in turn, leads to hypophosphatemia. They also develop rickets and osteomalacia. However,when placed on a special diet that maintains normal mineral ion levels, the VDR null mice have histologically, histomorphometrically and biomechanicallynormal long bones, thus the skeletal effects of VDR ablation are indirect and are a consequence of impaired VDRaction in the intestine which results in abnormal mineral ion homeostasis. This observation led us to focus our investigations on the pathophysiological basis for the development of rickets, which is an indirect consequence ofVDR ablation. We demonstrated that the growth plate abnormalities in the VDRnull mice are a consequenceof hypophosphatemia, which leads to expansion ofthe late hypertrophic chondrocyte layer due to impaired apoptosis ofthese cells. Since hypophosphatemia leads to impaired terminal chondrocytedifferentiation during postnatal life, studies are proposed to address the hypothesis that phosphate restriction also impairs chondrocyte differentiation during endochondral skeletal development and skeletal repair. Investigations will be performed using the ex vivo mouse metatarsal culture system and the in vivo femoral fracture repair models. These studies will identify developmental pathways that are interrupted byhypophosphatemia, an indirect consequence ofVDR ablation. Analogous to humans with VDRmutations, VDRnull mice have hair perinatally,but develop alopecia. Hair reconstitution assays and studies in transgenic mice demonstrate that VDRexpression in keratinocytes is both necessary and sufficient for the prevention of alopecia,thus the effects of the VDRin this cell are direct. We have also demonstrated that the actions ofthe VDRrequired to prevent alopecia are ligand- independent, thus reflect novel molecular actions of this nuclear receptor. Investigations in this proposal will address the hypothesis that the VDRis a key regulator ofthe canonical Wnt signalingpathway in keratinocyte stem cells and that these ligand-independent actions ofthe VDRare required for cutaneous homeostasis. The goal of these studies is not to study keratinocytebiologyper se, but rather to use this model system to characterize the molecularpathway and molecular partners involved in mediating these unique actions ofthe unliganded VDR. Thus, using the keratinocyte as a model,these studies will identify the novel molecular actions of the VDRwhich prevent the development of alopecia, a direct consequence ofVDR ablation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046974-17
Application #
7778233
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
1993-08-01
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
17
Fiscal Year
2010
Total Cost
$291,923
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Papaioannou, Garyfallia; Petit, Elizabeth T; Liu, Eva S et al. (2017) Raf Kinases Are Essential for Phosphate Induction of ERK1/2 Phosphorylation in Hypertrophic Chondrocytes and Normal Endochondral Bone Development. J Biol Chem 292:3164-3171
Saini, Vaibhav; Zhao, Hengguang; Petit, Elizabeth T et al. (2017) Absence of vitamin D receptor (VDR)-mediated PPAR? suppression causes alopecia in VDR-null mice. FASEB J 31:1059-1066
Christakos, Sylvia; White, John H; Hewison, Martin et al. (2017) Highlights from the 19th Workshop on Vitamin D in Boston, March 29-31, 2016. J Steroid Biochem Mol Biol 173:1-4
Song, Lige; Papaioannou, Garyfallia; Zhao, Hengguang et al. (2016) The Vitamin D Receptor Regulates Tissue Resident Macrophage Response to Injury. Endocrinology 157:4066-4075
Lisse, Thomas S; Saini, Vaibhav; Zhao, Hengguang et al. (2014) The vitamin D receptor is required for activation of cWnt and hedgehog signaling in keratinocytes. Mol Endocrinol 28:1698-706
Demay, Marie B (2013) Physiological insights from the vitamin D receptor knockout mouse. Calcif Tissue Int 92:99-105
Luderer, Hilary F; Nazarian, Rosalynn M; Zhu, Eric D et al. (2013) Ligand-dependent actions of the vitamin D receptor are required for activation of TGF-? signaling during the inflammatory response to cutaneous injury. Endocrinology 154:16-24
Rosen, Clifford J; Adams, John S; Bikle, Daniel D et al. (2012) The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev 33:456-92
Demay, Marie B (2012) The hair cycle and Vitamin D receptor. Arch Biochem Biophys 523:19-21
Luderer, Hilary F; Gori, Francesca; Demay, Marie B (2011) Lymphoid enhancer-binding factor-1 (LEF1) interacts with the DNA-binding domain of the vitamin D receptor. J Biol Chem 286:18444-51

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