Kotsifaki Amalia, Kalouda Georgia, Maroulaki Sousanna, Foukas Athanasios, Armakolas Athanasios
Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Third Department of Orthopaedic Surgery, "KAT" General Hospital of Athens, 2, Nikis Street, 14561 Kifissia, Greece.
Diseases. 2025 Mar 3;13(3):75. doi: 10.3390/diseases13030075.
Pseudoarthrosis-the failure of normal fracture healing-remains a significant orthopedic challenge affecting approximately 10-15% of long bone fractures, and is associated with significant pain, prolonged disability, and repeated surgical interventions. Despite extensive research into the pathophysiological mechanisms of bone healing, diagnostic approaches remain reliant on clinical findings and radiographic evaluations, with little innovation in tools to predict or diagnose non-union. The present review evaluates the current understanding of the genetic and biological basis of pseudoarthrosis and highlights future research directions. Recent studies have highlighted the potential of specific molecules and genetic markers to serve as predictors of unsuccessful fracture healing. Alterations in mesenchymal stromal cell (MSC) function, including diminished osteogenic potential and increased cellular senescence, are central to pseudoarthrosis pathogenesis. Molecular analyses reveal suppressed bone morphogenetic protein (BMP) signaling and elevated levels of its inhibitors, such as Noggin and Gremlin, which impair bone regeneration. Genetic studies have uncovered polymorphisms in BMP, matrix metalloproteinase (MMP), and Wnt signaling pathways, suggesting a genetic predisposition to non-union. Additionally, the biological differences between atrophic and hypertrophic pseudoarthrosis, including variations in vascularity and inflammatory responses, emphasize the need for targeted approaches to management. Emerging biomarkers, such as circulating microRNAs (miRNAs), cytokine profiles, blood-derived MSCs, and other markers (B7-1 and PlGF-1), have the potential to contribute to early detection of at-risk patients and personalized therapeutic approaches. Advancing our understanding of the genetic and biological underpinnings of pseudoarthrosis is essential for the development of innovative diagnostic tools and therapeutic strategies.
假关节——正常骨折愈合失败——仍然是一项重大的骨科挑战，影响着约10%至15%的长骨骨折，并且与严重疼痛、长期残疾及反复手术干预相关。尽管对骨愈合的病理生理机制进行了广泛研究，但诊断方法仍依赖于临床发现和影像学评估，预测或诊断骨不连的工具几乎没有创新。本综述评估了目前对假关节遗传和生物学基础的理解，并突出了未来的研究方向。最近的研究强调了特定分子和遗传标记作为骨折愈合失败预测指标的潜力。间充质基质细胞（MSC）功能的改变，包括成骨潜能降低和细胞衰老增加，是假关节发病机制的核心。分子分析显示骨形态发生蛋白（BMP）信号传导受到抑制，其抑制剂如Noggin和Gremlin的水平升高，这会损害骨再生。遗传学研究发现了BMP、基质金属蛋白酶（MMP）和Wnt信号通路中的多态性，提示存在骨不连的遗传易感性。此外，萎缩性和肥大性假关节之间的生物学差异，包括血管分布和炎症反应的差异，强调了需要有针对性的治疗方法。新兴的生物标志物，如循环微小RNA（miRNA）、细胞因子谱、血液来源的MSC和其他标志物（B7-1和PlGF-1），有可能有助于早期发现高危患者并制定个性化治疗方案。加深我们对假关节遗传和生物学基础的理解对于开发创新的诊断工具和治疗策略至关重要。
