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Insulin-Like Growth Factor Binding Protein-5 Interacts with the Vitamin D Receptor and Modulates the Vitamin D Response in Osteoblasts

Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia

Address all correspondence and requests for reprints to: Dr. Lyn Schedlich, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. E-mail: lyns{at}med.usyd.edu.au.

The 1,25 dihydroxyvitamin D₃ [1,25(OH)₂D₃]-induced differentiation of osteoblasts comprises the sequential induction of cell cycle arrest at G₀/G₁ and the expression of bone matrix proteins. Reports differ on the effects of IGF binding protein (IGFBP)-5 on bone cell growth and osteoblastic function. IGFBP-5 can be growth stimulatory or inhibitory and can enhance or impair osteoblast function. In previous studies, we have shown that IGFBP-5 localizes to the nucleus and interacts with the retinoid receptors. We now show that IGFBP-5 interacts with nuclear vitamin D receptor (VDR) and blocks retinoid X receptor (RXR):VDR heterodimerization. VDR and IGFBP-5 were shown to colocalize to the nuclei of MG-63 and U2-OS cells and coimmunoprecipitate in nuclear extracts from these cells. Induction of osteocalcin promoter activity and alkaline phosphatase activity by 1,25(OH)₂D₃ were significantly enhanced when IGFBP-5 was down-regulated in U2-OS cells. Moreover, we found IGFBP-5 increased basal alkaline phosphatase activity and collagen 1 type 1 expression, and that 1,25(OH)₂D₃ was unable to further induce the expression of these bone differentiation markers in MG-63 cells. Expression of IGFBP-5 inhibited MG-63 cell growth and caused cell cycle arrest at G₀/G₁ and G₂/M. Furthermore, IGFBP-5 reduced the effects of 1,25(OH)₂D₃ in blocking cell cycle progression at G₀/G₁ and decreased the expression of cyclin D1. These results demonstrate that IGFBP-5 can interact with VDR to prevent RXR:VDR heterodimerization and suggest that IGFBP-5 may attenuate the 1,25(OH)₂D₃-induced expression of bone differentiation markers while having a modest effect on the 1,25(OH)₂D₃-mediated inhibition of cell cycle progression in bone cells.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR  |  RXRα

Ligands:   Calcitriol

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				A. Mukherjee and P. Rotwein Insulin-Like Growth Factor-Binding Protein-5 Inhibits Osteoblast Differentiation and Skeletal Growth by Blocking Insulin-Like Growth Factor Actions Mol. Endocrinol., May 1, 2008; 22(5): 1238 - 1250. [Abstract] [Full Text] [PDF]