Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan 410000, China.
National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha, Hunan 410000, China.
Chin Med J (Engl). 2023 Jun 20;136(12):1468-1477. doi: 10.1097/CM9.0000000000002690. Epub 2023 May 16.
Congenital scoliosis (CS) is a complex spinal malformation of unknown etiology with abnormal bone metabolism. Fibroblast growth factor 23 (FGF23), secreted by osteoblasts and osteocytes, can inhibit bone formation and mineralization. This research aims to investigate the relationship between CS and FGF23.
We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region. FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured. Receiver operator characteristic (ROC) curve analyses were conducted to evaluate the specificity and sensitivity of FGF23. The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3 (FGFr3)/tissue non-specific alkaline phosphatase (TNAP)/osteopontin (OPN) in primary osteoblasts from CS patients (CS-Ob) and controls (CT-Ob) were detected. In addition, the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined.
DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins, accompanied by increased mRNA levels. CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography (CT) values compared with controls. The FGF23 mRNA levels were negatively correlated with the CT value of the spine, and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS. Additionally, significantly increased levels of FGF23, FGFr3, OPN, impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob. Moreover, FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels, while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob. Mineralization of CS-Ob was rescued after FGF23 knockdown.
Our results suggested increased peripheral blood FGF23 levels, decreased bone mineral density in CS patients, and a good predictive ability of CS by peripheral blood FGF23 levels. FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP / OPN pathway.
先天性脊柱侧凸（CS）是一种病因不明的复杂脊柱畸形，伴有异常的骨代谢。成纤维细胞生长因子 23（FGF23）由成骨细胞和破骨细胞分泌，可抑制骨形成和矿化。本研究旨在探讨 CS 与 FGF23 的关系。
我们收集了两对同卵双胞胎的外周血进行靶向区域的甲基化测序。测量 CS 患者和年龄匹配对照者外周血中 FGF23 mRNA 水平。通过接收者操作特征（ROC）曲线分析评估 FGF23 的特异性和敏感性。检测 CS 患者（CS-Ob）和对照者（CT-Ob）原代成骨细胞中 FGF23 及其下游因子成纤维细胞生长因子受体 3（FGFr3）/组织非特异性碱性磷酸酶（TNAP）/骨桥蛋白（OPN）的表达水平。此外，还检测了 FGF23 敲低或过表达 Ob 的成骨能力。
与同卵双胞胎相比，CS 患者 FGF23 基因的 DNA 甲基化降低，mRNA 水平升高。与对照组相比，CS 患者外周血 FGF23 mRNA 水平升高，计算机断层扫描（CT）值降低。FGF23 mRNA 水平与脊柱 CT 值呈负相关，ROC 分析显示 FGF23 mRNA 水平对 CS 具有较高的灵敏度和特异性。此外，CS-Ob 中 FGF23、FGFr3、OPN 水平升高，成骨矿化受损，TNAP 水平降低。此外，CT-Ob 中 FGF23 的过表达增加了 FGFr3 和 OPN 水平，降低了 TNAP 水平，而 CS-Ob 中 FGF23 的敲低则诱导了 FGFr3 和 OPN 的下调和 TNAP 的上调。CS-Ob 的矿化在 FGF23 敲低后得到挽救。
我们的结果表明，CS 患者外周血 FGF23 水平升高，骨密度降低，外周血 FGF23 水平对 CS 具有良好的预测能力。FGF23 可能通过 FGFr3/TNAP/OPN 通路导致 CS 患者骨质疏松。
