Malavašič Petra, Lojk Jasna, Lovšin Marija Nika, Marc Janja
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Department for Laboratory Diagnostics, General Hospital Novo mesto, Šmihelska cesta 1, 8000 Novo Mesto, Slovenia.
Int J Mol Sci. 2025 Jul 26;26(15):7237. doi: 10.3390/ijms26157237.
Osteoporosis is a multifactorial, polygenic disease characterized by reduced bone mineral density (BMD) and increased fracture risk. Genome-wide association studies (GWASs) have identified numerous loci associated with BMD and/or bone fractures, but functional characterization of these target genes is essential to understand the biological mechanisms underlying osteoporosis. This review focuses on current methodologies and key examples of successful functional studies aimed at evaluating gene function in osteoporosis research. Functional evaluation typically follows a multi-step approach. In silico analyses using omics datasets expression quantitative trait loci (eQTLs), protein quantitative trait loci (pQTLs), and DNA methylation quantitative trait loci (mQTLs) help prioritize candidate genes and predict relevant biological pathways. In vitro models, including immortalized bone-derived cell lines and primary mesenchymal stem cells (MSCs), are used to explore gene function in osteogenesis. Advanced three-dimensional culture systems provide additional physiological relevance for studying bone-related cellular processes. In situ analyses of patient-derived bone and muscle tissues offer validation in a disease-relevant context, while in vivo studies using mouse and zebrafish models enable comprehensive assessment of gene function in skeletal development and maintenance. Integration of these complementary methodologies helps translate GWAS findings into biological insights and supports the identification of novel therapeutic targets for osteoporosis.
骨质疏松症是一种多因素、多基因疾病，其特征是骨矿物质密度（BMD）降低和骨折风险增加。全基因组关联研究（GWAS）已经确定了许多与BMD和/或骨折相关的基因座，但对这些靶基因进行功能表征对于理解骨质疏松症的生物学机制至关重要。本综述重点关注当前用于评估骨质疏松症研究中基因功能的方法以及成功进行功能研究的关键实例。功能评估通常采用多步骤方法。使用组学数据集进行的生物信息学分析，包括表达定量性状基因座（eQTL）、蛋白质定量性状基因座（pQTL）和DNA甲基化定量性状基因座（mQTL），有助于确定候选基因的优先级并预测相关的生物学途径。体外模型，包括永生化骨源细胞系和原代间充质干细胞（MSC），用于探索基因在骨生成中的功能。先进的三维培养系统为研究与骨相关的细胞过程提供了额外的生理相关性。对患者来源的骨和肌肉组织进行原位分析可在疾病相关背景下进行验证，而使用小鼠和斑马鱼模型进行的体内研究能够全面评估基因在骨骼发育和维持中的功能。整合这些互补方法有助于将GWAS研究结果转化为生物学见解，并支持识别骨质疏松症的新型治疗靶点。
