Department of Biomedical and Molecular Sciences, Queen's University, 3048C Etherington Hall, Kingston, ON, K7L 3V6, Canada.
Department of Medicine, Queen's University, Kingston, ON, K7L 3V6, Canada.
Calcif Tissue Int. 2021 Mar;108(3):354-363. doi: 10.1007/s00223-020-00783-3. Epub 2021 Jan 22.
The 24 kD form of secreted phosphoprotein (SPP-24), a cytokine-binding bone matrix protein with various truncated C-terminal products, is primarily synthesized by the liver. SPP-24 shares homology with fetuin-A, a potent vascular and soft tissue calcification inhibitor and SPP-24 is one component of calciprotein particles (CPPs), a circulating fetuin-mineral complex. The limited molecular evidence to date suggests that SPP-24 may also function as an inhibitor of bone formation and ectopic vascular calcification, potentially through bone morphogenic protein 2 (BMP-2) and Wnt-signaling mediated actions. The C-terminal products of SPP-24 bind to BMP-2 and attenuate BMP-2-induced bone formation. The aim of this study was to assess circulating SPP-24 in relation to kidney function and in concert with markers of mineral metabolism in humans. SPP-24 was measured in the serum of total of 192 subjects using ELISA-based measurements. Subjects were participants of one of two cohorts: (1) mGFR Cohort (n = 80) was participants of a study of measured GFR (mGFR) using inulin urinary clearance, recruited mostly from a chronic kidney disease clinic with low-range kidney function (eGFR 38.7 ± 25.0 mL/min/1.73 m) and (2) CaMOS Cohort (n = 112) was a subset of randomly selected, community-dwelling participants of year 10 of the Canadian Multicentre Osteoporosis Study with eGFR in the normal range of 75.0 ± 15.9 mL/min/1.73 m. In the combined cohort, the mean SPP-24 was 167.7 ± 101.1 ng/mL (range 33.4-633.6 ng/mL). The mean age was 66.5 ± 11.3, 57.1% female and mean eGFR (CKD-EPI) was 59.9 ± 27.0 mL/min/1.73 m (range 8-122 mL/min/1.73 m). There was a strong inverse correlation between SPP-24 and eGFR (R = - 0.58, p < 0.001) that remained after adjustment for age. Following adjustment for age, eGFR, and sex, SPP-24 was significantly associated with phosphate (R = - 0.199), PTH (R = 0.298), and the Wnt-signaling inhibitor Dickkopf-related protein 1 (R = - 0.156). The results of this study indicate that SPP-24 is significantly altered by kidney function and is the first human data linking levels of SPP-24 to other biomarkers involved in mineral metabolism. Whether there is a role for circulating SPP-24 in bone formation and ectopic mineralization requires further study.
24kD 分泌型磷酸化蛋白（SPP-24）是一种细胞因子结合性骨基质蛋白，具有多种截短的 C 末端产物，主要由肝脏合成。SPP-24 与胎球蛋白-A 具有同源性，胎球蛋白-A 是一种有效的血管和软组织钙化抑制剂，而 SPP-24 是钙磷蛋白颗粒（CPPs）的一个组成部分，CPPs 是一种循环的胎球蛋白-矿物质复合物。目前有限的分子证据表明，SPP-24 也可能作为骨形成和异位血管钙化的抑制剂发挥作用，可能通过骨形态发生蛋白 2（BMP-2）和 Wnt 信号转导介导的作用。SPP-24 的 C 末端产物与 BMP-2 结合，并减弱 BMP-2 诱导的骨形成。本研究旨在评估与肾功能相关的循环 SPP-24，并与人类矿物质代谢标志物同时进行评估。使用基于 ELISA 的测量方法在总共 192 名受试者的血清中测量 SPP-24。受试者是两个队列的参与者：（1）mGFR 队列（n=80）是使用菊粉尿清除率测量肾小球滤过率（mGFR）研究的参与者，主要从低范围肾功能（eGFR 38.7±25.0 mL/min/1.73 m）的慢性肾脏病诊所招募；（2）CaMOS 队列（n=112）是加拿大多中心骨质疏松症研究第 10 年随机选择的、居住在社区的参与者的亚组，其 eGFR 在正常范围内为 75.0±15.9 mL/min/1.73 m。在联合队列中，SPP-24 的平均值为 167.7±101.1 ng/mL（范围 33.4-633.6 ng/mL）。平均年龄为 66.5±11.3，女性占 57.1%，平均 eGFR（CKD-EPI）为 59.9±27.0 mL/min/1.73 m（范围 8-122 mL/min/1.73 m）。SPP-24 与 eGFR 之间存在强烈的负相关关系（R=-0.58，p<0.001），这种相关性在调整年龄后仍然存在。在调整年龄、eGFR 和性别后，SPP-24 与磷酸盐（R=-0.199）、甲状旁腺激素（PTH）（R=0.298）和 Wnt 信号抑制剂 Dickkopf 相关蛋白 1（R=-0.156）显著相关。这项研究的结果表明，SPP-24 显著受肾功能影响，这是将 SPP-24 水平与其他参与矿物质代谢的生物标志物联系起来的第一组人类数据。循环 SPP-24 是否在骨形成和异位矿化中发挥作用还需要进一步研究。
