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.

在慢性肾脏疾病（CKD）期间，骨骼和矿物质代谢的改变包括激素成纤维细胞生长因子23（FGF23）的产生增加，这可能会导致心血管疾病死亡。骨细胞蛋白牙本质基质蛋白1（DMP1）会降低FGF23并增强骨骼矿化作用，但其在CKD中的作用尚不清楚。我们检验了在CKD中补充DMP1可以改善骨骼健康，防止FGF23升高并最大程度减少随之而来的不良心血管结果的假设。我们调查了野生型（WT）小鼠和CKD的Col4a3 ^-/-小鼠模型中DMP1的调控和作用。Col4a3 ^-/-小鼠表现出肾功能受损，骨DMP1表达降低，骨量减少，骨细胞形态和连接性改变，骨细胞凋亡增加，血清FGF23升高，高磷酸盐血症，左心室肥大（LVH）和存活率降低。通过在Col4a3 ^-//小鼠中进行DMP1的遗传或药理补充，可以防止骨细胞凋亡，保留骨细胞网络，校正骨量，通过减弱NFAT诱导的FGF23转录来部分降低FGF23的水平，并进一步增加血清磷酸盐。尽管肾功能受损和高磷血症恶化，DMP1仍可阻止LVH的发展并改善Col4a3 ^-/-生存。我们的数据表明，CKD降低了DMP1的表达，而其恢复代表了降低FGF23并改善CKD骨骼和心脏健康的潜在治疗方法。