The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions
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 pathophysio...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-03-01
|
| Series: | Diseases |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-9721/13/3/75 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850205379079700480 |
|---|---|
| author | Amalia Kotsifaki Georgia Kalouda Sousanna Maroulaki Athanasios Foukas Athanasios Armakolas |
| author_facet | Amalia Kotsifaki Georgia Kalouda Sousanna Maroulaki Athanasios Foukas Athanasios Armakolas |
| author_sort | Amalia Kotsifaki |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-748db5a75abe4453a3c47a5bf3d83cbd |
| institution | OA Journals |
| issn | 2079-9721 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Diseases |
| spelling | doaj-art-748db5a75abe4453a3c47a5bf3d83cbd2025-08-20T02:11:05ZengMDPI AGDiseases2079-97212025-03-011337510.3390/diseases13030075The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future DirectionsAmalia Kotsifaki0Georgia Kalouda1Sousanna Maroulaki2Athanasios Foukas3Athanasios Armakolas4Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, GreecePhysiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, GreecePhysiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, GreeceThird Department of Orthopaedic Surgery, “KAT” General Hospital of Athens, 2, Nikis Street, 14561 Kifissia, GreecePhysiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, GreecePseudoarthrosis—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.https://www.mdpi.com/2079-9721/13/3/75pseudoarthrosisnon-union fracturesgenetic biomarkersbone healingbiological biomarkersmesenchymal stromal cells |
| spellingShingle | Amalia Kotsifaki Georgia Kalouda Sousanna Maroulaki Athanasios Foukas Athanasios Armakolas The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions Diseases pseudoarthrosis non-union fractures genetic biomarkers bone healing biological biomarkers mesenchymal stromal cells |
| title | The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions |
| title_full | The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions |
| title_fullStr | The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions |
| title_full_unstemmed | The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions |
| title_short | The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions |
| title_sort | genetic and biological basis of pseudoarthrosis in fractures current understanding and future directions |
| topic | pseudoarthrosis non-union fractures genetic biomarkers bone healing biological biomarkers mesenchymal stromal cells |
| url | https://www.mdpi.com/2079-9721/13/3/75 |
| work_keys_str_mv | AT amaliakotsifaki thegeneticandbiologicalbasisofpseudoarthrosisinfracturescurrentunderstandingandfuturedirections AT georgiakalouda thegeneticandbiologicalbasisofpseudoarthrosisinfracturescurrentunderstandingandfuturedirections AT sousannamaroulaki thegeneticandbiologicalbasisofpseudoarthrosisinfracturescurrentunderstandingandfuturedirections AT athanasiosfoukas thegeneticandbiologicalbasisofpseudoarthrosisinfracturescurrentunderstandingandfuturedirections AT athanasiosarmakolas thegeneticandbiologicalbasisofpseudoarthrosisinfracturescurrentunderstandingandfuturedirections AT amaliakotsifaki geneticandbiologicalbasisofpseudoarthrosisinfracturescurrentunderstandingandfuturedirections AT georgiakalouda geneticandbiologicalbasisofpseudoarthrosisinfracturescurrentunderstandingandfuturedirections AT sousannamaroulaki geneticandbiologicalbasisofpseudoarthrosisinfracturescurrentunderstandingandfuturedirections AT athanasiosfoukas geneticandbiologicalbasisofpseudoarthrosisinfracturescurrentunderstandingandfuturedirections AT athanasiosarmakolas geneticandbiologicalbasisofpseudoarthrosisinfracturescurrentunderstandingandfuturedirections |