Xie Wei, Wan Wen-Tao, Liu Shuai-Yi, Wang Jia-Qi, Chen Chao, Sun Xun, Liu Xin-Yu, Yang Qiang
Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin, China.
Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise & Health, Tianjin University of Sport, Tianjin, China.
Medicine (Baltimore). 2024 Dec 13;103(50):e40934. doi: 10.1097/MD.0000000000040934.
Epidemiological studies and a recent Mendelian randomization (MR) study have identified an association between low bone mass and an increased risk of scoliosis. Previous research suggests that bone loss in patients with scoliosis may be related to the RANK-RANKL-OPG system. This study is to investigate whether a causal relationship exists between the RANK-RANKL-OPG system and the development of scoliosis. Genome-wide association study (GWAS) data for RANK and RANKL were sourced from the UK Biobank's Pharmaceutical Proteomics Project, while OPG data were derived from 2 independent cohorts, and scoliosis data from the FinnGen R10 database. A bidirectional 2-sample MR framework was applied to investigate causal relationships between OPG, RANK, RANKL, and scoliosis, with inverse variance weighting (IVW) as the main analytical method. Meta-analysis was used to integrate findings across cohorts, and multiple sensitivity analyses were conducted to assess the robustness and reliability of the results. According to the IVW results, there was no significant causal relationship between RANK (OR = 0.973, 95% CI = 0.871-1.087, P = .626) and RANKL (OR = 1.048, 95% CI = 0.938-1.171, P = .411) and scoliosis. OPG is a potential protective factor for scoliosis (Folkersen 2020 OR = 0.739, 95% CI = 0.611-0.893, P = .002; Zhao 2023 OR = 0.833, 95% CI = 0.716-0.968, P = .017).The results of Meta-analysis also showed OPG (P = 1.428e-4) would reduce the risk of scoliosis. Inverse MR analysis showed no statistically significant causal relationship between scoliosis and RANK, RANKL and OPG levels (P > .05). Our study employing MR methodology provides robust evidence supporting a causal relationship between decreased osteoprotegerin (OPG) levels and increased susceptibility to scoliosis. However, no significant relationship was found between scoliosis with the RANK-RANKL-OPG system. This research establishes a basis for further exploration of the pathophysiological mechanisms and potential targeted treatments for scoliosis. Future studies are necessary to understand how OPG influences the development of scoliosis.
流行病学研究和最近的孟德尔随机化（MR）研究已经确定低骨量与脊柱侧弯风险增加之间存在关联。先前的研究表明，脊柱侧弯患者的骨质流失可能与RANK-RANKL-OPG系统有关。本研究旨在调查RANK-RANKL-OPG系统与脊柱侧弯发展之间是否存在因果关系。RANK和RANKL的全基因组关联研究（GWAS）数据来自英国生物银行的药物蛋白质组学项目，而OPG数据来自2个独立队列，脊柱侧弯数据来自芬兰基因研究R10数据库。应用双向双样本MR框架来研究OPG、RANK、RANKL和脊柱侧弯之间的因果关系，采用逆方差加权（IVW）作为主要分析方法。荟萃分析用于整合各队列的研究结果，并进行了多项敏感性分析以评估结果的稳健性和可靠性。根据IVW结果，RANK（OR = 0.973，95%CI = 0.871-1.087，P = 0.626）和RANKL（OR = 1.048，95%CI = 0.938-1.171，P = 0.411）与脊柱侧弯之间不存在显著因果关系。OPG是脊柱侧弯的一个潜在保护因素（福尔克森2020年OR = 0.739，95%CI = 0.611-0.893，P = 0.002；赵2023年OR = 0.833，95%CI = 0.716-0.968，P = 0.017）。荟萃分析结果还显示OPG（P = 1.428e-4）会降低脊柱侧弯风险。反向MR分析显示脊柱侧弯与RANK、RANKL和OPG水平之间无统计学显著因果关系（P > 0.05）。我们采用MR方法的研究提供了有力证据，支持骨保护素（OPG）水平降低与脊柱侧弯易感性增加之间的因果关系。然而，未发现脊柱侧弯与RANK-RANKL-OPG系统之间存在显著关系。本研究为进一步探索脊柱侧弯的病理生理机制和潜在靶向治疗奠定了基础。未来有必要开展研究以了解OPG如何影响脊柱侧弯的发展。
