Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, and Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan.
Medical Affairs Department, Kyowa Kirin Co., Ltd., Tokyo, Japan.
Endocrinology. 2023 Feb 11;164(4). doi: 10.1210/endocr/bqad022.
To elucidate the effect of evocalcet, a new oral calcimimetic to bone of secondary hyperparathyroidism (SHPT) with chronic kidney disease (CKD), the rats were 5/6 nephrectomized and fed on a high-phosphate diet. The treated rats were then divided into vehicle groups and evocalcet administered groups. The rats in the vehicle groups exhibited increased levels of serum PTH and inorganic phosphate (Pi) levels, high bone turnover, and severe cortical porosity, mimicking SHPT (CKD-SHPT rats). The cortical bone of the CKD-SHPT rats showed broad demineralization around the osteocytes, suppression of Phex/small integrin-binding ligand N-linked glycoprotein-mediated mineralization in the periphery of the osteocytic lacunae, and increased levels of osteocytic cell death, all of which were considered as the first steps of cortical porosity. In contrast, evocalcet ameliorated the increased serum PTH levels, the enlarged osteocytic lacunae, and the cortical porosity of the CKD-SHPT rats. Osteocytes of CKD-SHPT rats strongly expressed PTH receptor and Pit1/Pit2, which sense extracellular Pi, indicating that PTH and Pi affected these osteocytes. Cell death of cultured osteocytes increased in a Pi concentration-dependent manner, and PTH administration rapidly elevated Pit1 expression and enhanced osteocytic death, indicating the possibility that the highly concentrated serum PTH and Pi cause severe perilacunar osteolysis and osteocytic cell death. It is likely therefore that evocalcet not only decreases serum PTH but also reduces the exacerbation combined with PTH and Pi to the demineralization of osteocytic lacunae and osteocytic cell death, thereby protecting cortical porosity in CKD-SHPT rats.
为了阐明新型口服拟钙剂依卡路特（evocalcet）对慢性肾脏病（CKD）继发甲状旁腺功能亢进症（SHPT）骨的作用，将大鼠进行 5/6 肾切除术并给予高磷饮食。然后将治疗后的大鼠分为载体组和依卡路特给药组。载体组大鼠的血清甲状旁腺激素（PTH）和无机磷（Pi）水平升高，骨转换率高，皮质骨严重疏松，模拟 SHPT（CKD-SHPT 大鼠）。CKD-SHPT 大鼠的皮质骨中，在骨细胞周围出现广泛脱矿质，在骨细胞腔周围的 Phex/小整合素结合配体 N-连接糖蛋白介导的矿化受到抑制，并且骨细胞死亡增加，所有这些都被认为是皮质疏松的第一步。相比之下，依卡路特改善了 CKD-SHPT 大鼠血清 PTH 水平升高、骨细胞腔增大和皮质疏松。CKD-SHPT 大鼠的骨细胞强烈表达 PTH 受体和 Pit1/Pit2，它们可以感知细胞外 Pi，表明 PTH 和 Pi 影响了这些骨细胞。培养的骨细胞的死亡以 Pi 浓度依赖性方式增加，而 PTH 给药可迅速升高 Pit1 表达并增强骨细胞死亡，表明高浓度的血清 PTH 和 Pi 可能导致严重的骨陷窝周围骨溶解和骨细胞死亡。因此，依卡路特不仅降低血清 PTH，还减轻与 PTH 和 Pi 结合的加剧作用对骨细胞腔脱矿质和骨细胞死亡的影响，从而保护 CKD-SHPT 大鼠的皮质疏松。
