Increased MEPE expression occurs in several phosphate and bone-mineral metabolic disorders. To resolve whether MEPE plays a role we created a murine model over-expressing 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-PHEX interactions are component to an age-diet dependent pathway that regulates bone turnover, mineralization and suppresses renal calcification. This novel pathway also modulates bone-renal vascularization and bone turnover.