Anatomy changes, signalling pathways, and clinical treatment after ankle sprain

Area of Science:

• Orthopedics and Sports Medicine
• Molecular Biology
• Biochemistry

Background:

• Ankle sprain (AS) is a common sports injury that can lead to chronic ankle instability (CAI) and post-traumatic arthritis.
• The molecular mechanisms underlying poor rehabilitation outcomes in AS remain poorly understood.
• Existing knowledge focuses on clinical manifestations rather than underlying molecular pathology.

Purpose of the Study:

• To review pathological changes in anatomical structures and signaling pathways in ankle sprains.
• To explore therapeutic strategies targeting these molecular mechanisms.
• To elucidate the molecular basis of chronic ankle instability following ankle sprains.

Main Methods:

• Comprehensive literature search across PubMed, Embase, Web of Science, and OVID MEDICINE (Jan 2000 - Aug 2025).
• Inclusion of English-language articles with experimental or clinical evidence.
• Exclusion of irrelevant studies, case reports, and non-original research.

Main Results:

• Transforming growth factor beta-1 promotes fibrosis and ligament stiffness via Smad-dependent collagen production.
• Piezo2 dysfunction contributes to proprioceptive deficits in CAI by impairing mechanosensation.
• Nuclear factor kappa B activation leads to inflammation and extracellular matrix degradation; dysregulated apoptosis affects tissue integrity.

Conclusions:

• Integrating biomechanical and molecular insights is crucial for optimizing ankle sprain management.
• Pathway-targeted therapies show promise but require further validation.
• Future research should focus on mechanoimmunomodulatory therapies to address instability and degeneration cycles.