Molecular-biomechanical phenotyping of ankle osteoarthritis: from synovial biomarkers to weight-bearing digital signatures.

Ankle osteoarthritis (OA) is commonly staged by pain, deformity, and radiographic joint-space loss, but this morphology-first view leaves much of its clinical heterogeneity unexplained. An ankle-specific precision framework is biologically and technically plausible because ankle OA is strongly enriched for post-traumatic mechanisms, has cartilage and synovial biology that differs from knee OA, and can be measured with weight-bearing structural and digital functional tools. Comparative cartilage studies show joint-dependent differences in catabolic susceptibility, matrix synthesis, transport, cell-matrix organization, and injury response. Human synovial-fluid and synovial-transcriptomic studies identify local inflammatory, remodeling, and WNT-related signals, while weight-bearing computed tomography (WBCT), automated three-dimensional alignment metrics, distance maps, gait analysis, plantar pressure, center of pressure (COP), and ankle-specific activity monitoring quantify structural and functional load signatures. This Mini Review integrates these data into four provisional, non-mutually-exclusive baseline research phenotypes: inflammatory-dominant, malalignment-dominant, post-traumatic or instability-dominant, and end-stage structural collapse. Post-surgical recovery is treated separately as a longitudinal response trajectory rather than a fifth baseline phenotype. The evidence is comparatively mature for ankle-knee cartilage differences, promising but preliminary for synovial, three-dimensional structural, and laboratory functional signatures, and exploratory for center-of-pressure recovery and wearable trajectories. A validation-ready pathway is proposed around a defined minimum same-patient dataset, serial measurement, a 24-month ankle-specific patient-reported outcome, explicit minimal-important-difference rules, trajectory modeling, calibrated prediction, and external evaluation. The framework is intended to organize prospective cohorts and treatment-response questions; it is not a validated clinical classification or automated treatment selector.