Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL, 60611, USA.
Curr Osteoporos Rep. 2021 Oct;19(5):500-509. doi: 10.1007/s11914-021-00697-5. Epub 2021 Jul 31.
Chronic kidney disease-mineral and bone disorder (CKD-MBD) has become a global health crisis with very limited therapeutic options. Dentin matrix protein 1 (DMP1) is a matrix extracellular protein secreted by osteocytes that has generated recent interest for its possible involvement in CKD-MBD pathogenesis. This is a review of DMP1 established regulation and function, and early studies implicating DMP1 in CKD-MBD.
Patients and mice with CKD show perturbations of DMP1 expression in bone, associated with impaired osteocyte maturation, mineralization, and increased fibroblast growth factor 23 (FGF23) production. In humans with CKD, low circulating DMP1 levels are independently associated with increased cardiovascular events. We recently showed that DMP1 supplementation lowers circulating FGF23 levels and improves bone mineralization and cardiac outcomes in mice with CKD. Mortality rates are extremely high among patients with CKD and have only marginally improved over decades. Bone disease and FGF23 excess contribute to mortality in CKD by increasing the risk of bone fractures and cardiovascular disease, respectively. Previous studies focused on DMP1 loss-of-function mutations have established its role in the regulation of FGF23 and bone mineralization. Recent studies show that DMP1 supplementation may fill a crucial therapeutic gap by improving bone and cardiac health in CKD.
慢性肾脏病-矿物质和骨异常（CKD-MBD）已成为全球性健康危机，治疗选择非常有限。牙本质基质蛋白 1（DMP1）是成骨细胞分泌的一种细胞外基质蛋白，因其可能参与 CKD-MBD 的发病机制而受到关注。本文综述了 DMP1 的表达调控和功能，以及早期研究中 DMP1 与 CKD-MBD 的关联。
CKD 患者和小鼠的骨组织中 DMP1 表达失调，与成骨细胞成熟、矿化受损以及成纤维细胞生长因子 23（FGF23）产生增加有关。在 CKD 患者中，循环 DMP1 水平降低与心血管事件增加独立相关。我们最近发现，DMP1 补充可降低 CKD 小鼠的循环 FGF23 水平，并改善骨矿化和心脏结局。CKD 患者的死亡率极高，几十年来仅略有改善。骨病和 FGF23 过度通过增加骨折和心血管疾病的风险分别导致 CKD 患者的死亡率增加。以前的研究集中在 DMP1 功能丧失突变上，已确定其在 FGF23 和骨矿化调节中的作用。最近的研究表明，DMP1 补充可能通过改善 CKD 患者的骨骼和心脏健康来填补关键的治疗空白。
