Abstract
Osteoarthritis (OA) is a progressive joint disease characterized by a continuous degradation of the cartilage extracellular matrix (ECM). The expression of the extracellular glycoprotein thrombospondin-4 (TSP-4) is known to be increased in injured tissues and involved in matrix remodeling, but its role in articular cartilage and, in particular, in OA remains elusive. In the present study, we analyzed the expression and localization of TSP-4 in healthy and OA knee cartilage by reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and immunoblot. We found that TSP-4 protein expression is increased in OA and that expression levels correlate with OA severity. TSP-4 was not regulated at the transcriptional level but we detected changes in the anchorage of TSP-4 in the altered ECM using sequential protein extraction. We were also able to detect pentameric and fragmented TSP-4 in the serum of both healthy controls and OA patients. Here, the total protein amount was not significantly different but we identified specific degradation products that were more abundant in sera of OA patients. Future studies will reveal if these fragments have the potential to serve as OA-specific biomarkers.
Highlights
The articular cartilage degeneration in osteoarthritis (OA) is slowly progressing and further hallmarks are the remodeling of the subchondral bone and formation of osteophytes, meaning new bone formation, leading to stiffness and pain [1,2]
The morphological appearance of the cartilage was graded visually based on the scoring system of the Osteoarthritis Research Society International (OARSI) (Figure 1a)
The surface of the knee condyle was observed and intact cartilage with a smooth surface and no fissures was scored as grade 1 (G1)
Summary
The articular cartilage degeneration in osteoarthritis (OA) is slowly progressing and further hallmarks are the remodeling of the subchondral bone and formation of osteophytes, meaning new bone formation, leading to stiffness and pain [1,2]. The two main suprastructures [6], the collagen network and the aggrecan gel, are degraded and minor components, like glycoproteins [7,8] and small proteoglycans [9] that bind to and interconnect these structures. Proteolytic cartilage matrix degradation releases fragments from the tissue into the synovial fluid that can be detected eventually in the blood circulation. Several proteins and fragments thereof can be used as biomarkers indicating ongoing cartilage degeneration. The appearance of distinct fragments and their potential as predictive and/or diagnostic biomarkers depend on the tissue-specific presence of both the substrate as well as the proteolytic enzymes generating unique degradation products
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