DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease

Abstract

During chronic kidney disease (CKD), alterations in bone and mineral metabolism include increased production of the hormone fibroblast growth factor 23 (FGF23) that may contribute to cardiovascular mortality. The osteocyte protein dentin matrix protein 1 (DMP1) reduces FGF23 and enhances bone mineralization, but its effects in CKD are unknown. We tested the hypothesis that DMP1 supplementation in CKD would improve bone health, prevent FGF23 elevations and minimize consequent adverse cardiovascular outcomes. We investigated DMP1 regulation and effects in wild-type (WT) mice and the Col4a3 ^−/− mouse model of CKD. Col4a3 ^−/− mice demonstrated impaired kidney function, reduced bone DMP1 expression, reduced bone mass, altered osteocyte morphology and connectivity, increased osteocyte apoptosis, increased serum FGF23, hyperphosphatemia, left ventricular hypertrophy (LVH), and reduced survival. Genetic or pharmacological supplementation of DMP1 in Col4a3 ^−/− mice prevented osteocyte apoptosis, preserved osteocyte networks, corrected bone mass, partially lowered FGF23 levels by attenuating NFAT-induced FGF23 transcription, and further increased serum phosphate. Despite impaired kidney function and worsened hyperphosphatemia, DMP1 prevented development of LVH and improved Col4a3 ^−/− survival. Our data suggest that CKD reduces DMP1 expression, whereas its restoration represents a potential therapeutic approach to lower FGF23 and improve bone and cardiac health in CKD.

Chronic kidney disease: Bone protein protects the heart

Therapies based on a bone growth protein could prevent heart failure in chronic kidney disease (CKD) patients, say researchers in the USA. CKD often causes reduced bone mass and leads to left ventricular hypertrophy, a dangerous thickening of heart muscle related to over-production of the FGF23 hormone. In contrast, the dentin matrix protein DMP1, produced by bone cells, is known to reduce FGF23 levels and enhance bone growth. Aline Martin at Northwestern University in Chicago and co-workers increased the DMP1 levels in CKD mouse models through genetic modification and drugs, and found that this treatment restored regular bone mass, lowered FGF23 levels, reduced the occurrence of heart problems and led to longer lives. The findings suggest that therapies that restore DMP1 have the potential to improve both bone and heart health in CKD patients.