Thrombospondin-4 correlates with MRI measures of structural damage and pain sensitisation: a new biomarker in knee osteoarthritis

Abstract

Background We hypothesised thrombospondin-4 (TSP-4), a molecule mediating pain sensitisation in peripheral nerve injury, is associated with pain sensitisation in OA. Methods A cross-sectional study of clinical, imaging and fluid biomarkers from knee OA participants was conducted. TSP-4 was assessed by immunohistochemistry (IHC) for OA tissue samples and by ELISA in serum samples. Type II collagen degradation products (CTX-II), linked to OA structural damage, was determined from urine samples. A general linear model (GLM) was used to: a) investigate how patient-reported WOMAC (Western Ontario and McMaster Universities OsteoArthritis Index) pain/stiffness subscales and pain sensitisation measured by painDETECT, related to the Hospital Anxiety and Depression Scale (HADS), structural damage quantified from MRI and X-rays, CTX-II and TSP-4; b) how TSP-4 related to structural damage. We used linear discriminant analysis (LDA) to determine a classifier for pain-sensitisation from clinical and wet-biomarkers. Results TSP-4 was expressed in cartilage, bone marrow lesion (BML) and synovial tissue from OA samples. Upregulated TSP-4 protein was observed in cartilage, synovial tissue and BMLs in a perivascular distribution and in fibrotic tissue. Serum TSP-4 was significantly higher (p = 0.001) in those with pain sensitisation (painDETECT level ≥19) compared with non-sensitised participants. Serum TSP-4 was significantly increased with Hoffa’s synovitis (p < 0.001) and number of BMLs (p < 0.001 to p < 0.05). LDA provided classification accuracy of 80 % for pain sensitisation using TSP-4, CTX-II and HADS, supporting the biopsychosocial model of pain in OA. Conclusion Our data suggests TSP-4 is associated with pain sensitisation in OA and is a biomarker stratifying for pain sensitisation