Foot and Ankle International - 2026-03-23 - Journal Article
The Synovial Fingerprint of Ankle Fractures: A Central Role for WNT Pathway Activation in Posttraumatic Ankle Osteoarthritis.
Matthias J, David MA, Buckley SE, Stark SD, Austin NA, Zona NE, Zuscik MJ, Hunt KJ
Topics
Key Takeaway
WNT7B is the most strongly upregulated gene in fracture and PTOA synovium, with WNT pathway activation significantly broader in PTOA than in nontraumatic OA, supporting a molecularly distinct PTOA subtype.
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Summary
This study used bulk RNA sequencing of synovial tissue from four groups—acute ankle fracture, end-stage PTOA, NTOA, and controls—to characterize transcriptional differences. Unsupervised k-means and hierarchical clustering identified distinct transcriptomic profiles separating PTOA from NTOA, with fracture and PTOA synovium sharing a unique overlapping signature. WNT7B demonstrated the strongest upregulation in fracture and PTOA groups, and logistic regression models classified synovial subtypes with high accuracy based on gene expression profiles.
Key Limitation
The sample size is unreported in the abstract, and without patient numbers per group, the validity of the machine learning classification models and differential expression findings cannot be critically evaluated.
Original Abstract
BACKGROUND
Osteoarthritis (OA) of the ankle is a disabling and understudied disease, most commonly emerging posttraumatically after ankle fractures (PTOA). Despite its prevalence, the molecular mechanisms linking joint trauma to ankle OA are not well defined, limiting opportunities for early intervention. This study characterized synovial transcriptional changes to identify early molecular drivers of disease onset in fracture-induced ankle PTOA.
METHODS
Synovium was collected under an institutional review board-approved protocol from patients undergoing ankle fracture fixation, and ankle arthroplasty for end-stage PTOA after a prior ankle fracture, or nontraumatic OA (NTOA). Synovium from patients with no or minimal OA served as controls. Bulk RNA sequencing was performed, followed by differential gene expression analysis and Gene Ontology (GO) enrichment. Machine learning clustering (k-means and hierarchical) and classification (logistic regression) models were employed to distinguish transcriptomic signatures of synovial subtypes.
RESULTS
RNA-seq and unsupervised clustering revealed distinct synovial transcriptional profiles separating NTOA and PTOA, with a uniquely shared signature between Fracture and PTOA synovium. WNT signaling was enriched across all groups compared to controls, with particularly broad activation in PTOA. WNT7B showed the strongest upregulation in Fracture and PTOA, with a smaller increase in NTOA. Logistic regression classified synovial subtypes based on gene expression profiles with high accuracy.
CONCLUSION
These findings support the hypothesis that ankle OA following fracture represents a molecularly distinct subtype. Although WNT pathway activation has been known in OA, its broader activation in PTOA suggests that joint trauma initiates a pathologic synovial cascade, with WNT pathway activation playing a central role. The clear timing of most ankle fractures offers a unique opportunity for early therapeutic intervention. Focused research on the synovial molecular link between ankle fractures and PTOA could underpin the development of targeted, disease-modifying strategies in the immediate postinjury period.