Using genetic and pharmacologic approaches to increase DMP1 concentrations in bone of WT and Col4a3−/− mice with CKD, we also show that restoration of DMP1 in bone prevents CKD-associated bone disease by reducing osteocyte apoptosis, lowers FGF23 production via an NFAT signaling pathway, attenuates LVH, and prolongs survival despite unchanged severity of kidney disease and worsened hyperphosphatemia. The gene discussed is COL4A3; the disease is hyperphosphatemia.