Matrix extracellular phosphoglycoprotein (MEPE) is a new bone renal hormone and vascularization modulator.
Increased matrix extracellular phosphoglycoprotein (MEPE) expression occurs in several phosphate and bone-mineral metabolic disorders. To resolve whether MEPE plays a role, we created a murine model overexpressing MEPE protein (MEPE tgn) in bone. MEPE tgn mice displayed a growth and mineralization defect with altered bone-renal vascularization that persisted to adulthood. The growth mineralization defect was due to a decrease in bone remodeling, and MEPE tgn mice were resistant to diet-induced renal calcification. MEPE protein-derived urinary ASARM peptides and reduced urinary Ca X PO4 product mediated the suppressed renal calcification. Osteoblastic cells displayed reduced activity but normal differentiation. Osteoclastic precursors were unable to differentiate in the presence of osteoblasts. In the kidney, NPT2a up-regulation induced an increase in phosphate renal reabsorption, leading to hyperphosphatemia. We conclude MEPE and MEPE-phosphate-regulating gene with homologies to endopeptidases on the X chromosome (MEPE-PHEX) interactions are components to an age-diet-dependent pathway that regulates bone turnover and mineralization and suppresses renal calcification. This novel pathway also modulates bone-renal vascularization and bone turnover.
David
Valentin
V
The Kidney Institute, Kansas University Medical Center, Kansas City, Kansas 66160, USA.
Martin
Aline
A
Hedge
Anne-Marie
AM
Rowe
Peter S N
PS
D000375:Aging; D000450:Aldosterone / Q000652:urine; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001846:Bone Development / Q000187:drug effects; D001842:Bone and Bones / Q000098:blood supply; D002117:Calcitriol / Q000097:blood; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D006023:Glycoproteins / Q000502:physiology*; D054559:Hyperphosphatemia / Q000503:physiopathology; D006996:Hypocalcemia / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics; D053495:Osteopontin / Q000378:metabolism; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000502:physiology; D010281:Parathyroid Hormone / Q000097:blood; D010750:Phosphoproteins / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C518716:Mepe protein, mouse; D010281:Parathyroid Hormone; D010750:Phosphoproteins; C506896:Spp1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D053495:Osteopontin; D000450:Aldosterone; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse; D002117:Calcitriol