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Departments of Medicine (D.M., X.B., D.P., A.C.K., D.G.), Dentistry, and Anatomy and Cell Biology (M.D.M.), McGill University, Montréal, Québec, Canada H3A 1A1
Address all correspondence and requests for reprints to: Dr. David Goltzman, Calcium Research Laboratory, Department of Medicine, Room H4.67, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1.
To explore how the loss of Phex function contributes to the pathogenesis of osteomalacia, we examined the abnormalities of mineralization, Phex, and bone matrix protein expression occurring in Hyp mice in vivo and in ex vivo bone marrow cell cultures. The results in vivo show that mineralization was decreased significantly in Hyp mouse bone. Phex protein was identifiable in osteoblasts and osteocytes in wild-type mice, but not in Hyp mice. In Hyp mice, osteocalcin, bone sialoprotein, and vitronectin expression were down-regulated, whereas biglycan and fibrillin-1 expression were up-regulated in osteocytes and bone matrix relative to those in their wild-type counterparts. Parallel studies ex vivo demonstrated that cells derived from 18-day Hyp mouse bone marrow cell cultures had a 3'-Phex deletion, no Phex protein expression, decreased alkaline phosphatase activity, collagen deposition, and calcium accumulation, and reduced osteocalcin, bone sialoprotein, and vitronectin at both the protein and messenger RNA levels. Furthermore conditioned medium from Hyp mouse bone marrow cultures could induce analogous defects in bone marrow cell cultures of wild-type cells. These novel findings indicate that there is an intrinsic osteogenic cell differentiation defect in addition to the known hypomineralization of bone in Hyp mice, which may be inducible by an autocrine/paracrine secreted factor. These results suggest that alterations in the Phex gene may control bone matrix mineralization indirectly by regulating the synthesis and deposition of bone matrix proteins.
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X.-Y. Bai, D. Miao, D. Goltzman, and A. C. Karaplis The Autosomal Dominant Hypophosphatemic Rickets R176Q Mutation in Fibroblast Growth Factor 23 Resists Proteolytic Cleavage and Enhances in Vivo Biological Potency J. Biol. Chem., March 7, 2003; 278(11): 9843 - 9849. [Abstract] [Full Text] [PDF]
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H. Pizzi, J. Gladu, L. Carpio, D. Miao, D. Goltzman, and S. A. Rabbani Androgen Regulation of Parathyroid Hormone-Related Peptide Production in Human Prostate Cancer Cells Endocrinology, March 1, 2003; 144(3): 858 - 867. [Abstract] [Full Text] [PDF]
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 X. Bai, D. Miao, D. Panda, S. Grady, M. D. McKee, D. Goltzman, and A. C. Karaplis Partial Rescue of the Hyp Phenotype by Osteoblast-Targeted PHEX (Phosphate-Regulating Gene with Homologies to Endopeptidases on the X Chromosome) Expression Mol. Endocrinol., December 1, 2002; 16(12): 2913 - 2925. [Abstract] [Full Text] [PDF]
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E. R. Hines, J. F. Collins, M. D. Jones, S. H. Serey, and F. K. Ghishan Glucocorticoid regulation of the murine PHEX gene Am J Physiol Renal Physiol, August 1, 2002; 283(2): F356 - F363. [Abstract] [Full Text] [PDF]
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S. M. Jan De Beur and M. A. Levine Molecular Pathogenesis of Hypophosphatemic Rickets J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2467 - 2473. [Full Text] [PDF]
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S. Liu, R. Guo, Q. Tu, and L. D. Quarles Overexpression of Phex in Osteoblasts Fails to Rescue the Hyp Mouse Phenotype J. Biol. Chem., January 25, 2002; 277(5): 3686 - 3697. [Abstract] [Full Text] [PDF]
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D. Miao, X.-K. Tong, G. K. Chan, D. Panda, P. S. McPherson, and D. Goltzman Parathyroid Hormone-related Peptide Stimulates Osteogenic Cell Proliferation through Protein Kinase C Activation of the Ras/Mitogen-activated Protein Kinase Signaling Pathway J. Biol. Chem., August 17, 2001; 276(34): 32204 - 32213. [Abstract] [Full Text] [PDF]
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