成骨不全症的发病机制与精准管理：从遗传机制到新型疗法

文献信息

中文摘要

背景： 成骨不全症（OI）是一种临床和遗传异质性的骨骼发育不良，以全身性骨脆性为特征。除骨骼表现外，OI是一种多系统疾病，涉及牙本质发育不全、听力损失、关节过度松弛和心肺并发症。OI的诊断范式已发生革命性转变，从传统的临床表型分析转向基于分子病因的框架。在高通量测序进展的推动下，20多个相关基因的突变已将当前的OI疾病分类扩展至至少23种不同类型。
数据来源： 本叙述性综述通过检索PubMed/MEDLINE中的论文进行。使用单一和/或组合关键词识别相关出版物，包括：成骨不全症、基因（如COL1A1和COL1A2）、动物模型、表型（如骨质减少和股骨弯曲）、药物治疗（如双膦酸盐和地诺单抗）、间充质干细胞、基因治疗和多能干细胞。
结果： 本综述系统阐述了OI的分子发病机制，将缺陷归类为胶原生物合成破坏、翻译后修饰受损、前胶原转运异常以及成骨细胞分化或矿化通路功能障碍。值得注意的是，我们强调了亚洲人群中OI独特的遗传背景和临床特征。此外，我们评估了向精准管理的转变。OI的手术管理已通过 telescopic rodding 和多学科方法得到优化。双膦酸盐仍是药物治疗的基石，尽管反应因OI基因型而异。新兴的靶向生物制剂包括地诺单抗、罗莫索单抗、setrusumab和fresolimumab。最后，我们讨论了基于细胞的疗法，特别是间充质干细胞的变革潜力。精准基因编辑技术，如CRISPR-Cas9，为解决OI的根本遗传原因提供了一种策略。
结论： 将分子诊断与稳健的基因型-表型关联相结合对于推进个性化医疗至关重要。未来的突破将依赖于基因和细胞疗法的转化，最终改善OI患者的长期临床结局。

英文摘要

BACKGROUND: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous skeletal dysplasia characterized by systemic bone fragility. Beyond skeletal manifestations, OI is a multisystem condition involving dentinogenesis imperfecta, hearing loss, joint hyperlaxity, and cardiopulmonary complications. The diagnostic paradigm for OI has undergone a revolutionary shift from traditional clinical phenotyping to a molecular etiology-based framework. Driven by advancements in high-throughput sequencing, mutations in over 20 implicated genes have expanded the current OI nosology to at least 23 distinct types.
DATA SOURCES: This narrative review was conducted by searching for papers using PubMed/MEDLINE. Relevant publications were identified using single and/or combined keywords including: osteogenesis imperfecta, genes (such as COL1A1 and COL1A2), animal models, phenotypes (such as osteopenia and femoral bowing), and drug therapies (such as bisphosphonate and denosumab), mesenchymal stem cells, gene therapy, and pluripotent stem cells.
RESULTS: This review systematically delineates the molecular pathogenesis of OI, categorizing defects into disrupted collagen biosynthesis, impaired post-translational modification, aberrant procollagen trafficking, and dysfunctional osteoblast differentiation or mineralization pathways. Of note, we highlight the unique genetic landscape and clinical characterization of OI within Asian populations. Furthermore, we evaluate the transition towards precision management. Surgical management of OI has been optimized by telescopic rodding and a multidisplinary approach. Bisphosphonates remain a cornerstone of medical therapy, though responses vary with OI genotypes. Emerging targeted biologics include denosumab, romosozumab, setrusumab, and fresolimumab. Finally, we discuss the transformative potential of cell-based therapies, particularly mesenchymal stem cells. Precision gene editing technologies, such as CRISPR-Cas9, offer a strategy in addressing the root genetic causes of OI.
CONCLUSIONS: Integrating molecular diagnostics with robust genotype-phenotype correlations is essential for advancing personalized care. Future breakthroughs will rely on the translation of gene and cell therapies to ultimately improve the long-term clinical outcomes for patients with OI.