Expression of thrombospondin-4 in the infrapatellar fat pad and synovial fluid – potential contribution to osteoarthritis pain

Abstract

Background: During osteoarthritis (OA) pathogenesis, the infrapatellar fat pad (IFP) undergoes fibrotic changes that might contribute to pain development. Recent studies have demonstrated that thrombospondin-4 (TSP-4), first detected in the extracellular matrix of cartilage and released during its degradation, has been implicated in the pathogenesis of pain. Therefore, we analyzed TSP-4 levels in the IFP and synovial fluid and correlated this data with IFP fibrosis and knee joint pain. Methods: IFP and synovial fluid were collected from patients undergoing total knee replacement surgery. Total WOMAC total and pain scores were determined preoperatively. IFP sections were stained using standard Masson trichrome and hematoxylin/eosin dyes to assess fibrotic changes, number of vessels and lymphocytic infiltration. TSP-4 expression in the IFP was detected immunohistochemically. TSP-4 in synovial fluid samples was quantified using ELISA. Results: TSP-4 was detectable in human IFP tissue at the protein level and its expression levels showed a positive correlation with the degree of tissue fibrosis. Regarding the degree of fibrosis and TSP-4-stained areas, four patient subgroups could be distinguished. Notably, moderate levels of TSP-4 expression were already detectable in samples exhibiting a low degree of fibrosis. There was no significant correlation between TSP-4 staining intensity in IFP and pain. There was no correlation between TSP-4 staining intensity and synovial fluid TSP-4 concentrations. A significant relationship between synovial fluid TSP-4 concentration and pain intensity was only found in female OA patients. Conclusions: TSP-4 has been detected in the IFP for the first time. The correlation between TSP-4 expression and fibrotic severity indicates a possible involvement of TSP-4 in the development of fibrosis. Although TSP-4 within the IFP may not directly mediate pain, its presence in synovial fluid could be of functional relevance in pain-related mechanisms. Further analysis of synovial fluid and even serum samples from larger patient populations will determine whether TSP-4 could serve as a biomarker for pain or potentially represent a novel target for analgesic therapies.