The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions

Abstract

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.

Keywords: MSCs; biological biomarkers; bone healing; genetic biomarkers; mesenchymal stromal cells; non-union fractures; pseudoarthrosis; regenerative medicine.

Figure 1

“Key biological factors and Wnt/β-actin molecular pathway in pseudoarthrosis in fractures”: This figure illustrates the most crucial biological and molecular elements involved in pseudoarthrosis, highlighting their roles in non-union fracture. It depicts the interplay between BMPs, MMPs, macrophages, blood factors, and vascularization factors—such as VEGF, TGF-β, and IGF-1—as well as osteoprogenitor cells. Additionally, the figure emphasizes the Wnt pathway’s role in promoting RUNX2 expression in MSCs and pre-osteoblastic cells, ultimately influencing osteoblast function. Understanding these interactions provides insights into potential therapeutic targets for improving bone healing and fracture repair.