Abstract
Proteolytic fragments of fibronectin can have catabolic effects on cartilage, menisci, and synovium. Previous studies have reported that Toll-like receptor (TLR) signaling pathways might be associated with joint inflammation and joint destruction. Platelet-rich plasma (PRP) is increasingly being used to treat a range of joint conditions; however, it has yet to be determined whether PRP influences fibronectin fragment (FN-f) procatabolic activity and TLRs. In this study, human primary culture cells were treated with 30 kDa FN-f with/without PRP co-incubation, and then analyzed using real-time PCR to determine gene expression levels in articular chondrocytes, meniscal fibrochondrocytes, and synovial fibroblasts. Protein levels were evaluated by Western immunoblotting. This study observed an increase in the protein expression of matrix metalloproteinases (MMPs), Toll-like receptor 2 (TLR2), nitric oxide synthase 2 (NOS2), prostaglandin-endoperoxide synthase (PTGS2), and cyclooxygenase 2 (COX2) in articular chondrocytes, meniscal fibrochondrocytes, and synovial fibroblasts following insult with 30 kDa FN-f. Upregulation of these genes was significantly attenuated by PRP treatment. TLR2 and matrix metalloproteinase 13 (MMP-13) were also significantly attenuated by cotreatment with 30 kDa FN-f + PRP + TLR2 inhibitor. PRP treatment was shown to attenuate the 30 kDa FN-f-induced MMP-13 expression associated with the decreased expression of TLR2 in osteoarthritic chondrocytes and synovial fibroblasts. PRP treatment was also shown to attenuate procatabolic activity associated with MMP-13 expression via the TLR2 signaling pathway.
Highlights
Osteoarthritis (OA) is the most common form of arthritis among the elderly
In experiments involving cotreatment with Platelet-rich plasma (PRP), we again observed the attenuation of changes in protein expression in articular chondrocytes, meniscal fibrochondrocytes, and synovial fibroblasts, as follows: matrix metalloproteinases (MMPs)-1 (p = 0.0350, p = 0.046, and p = 0.027, respectively), matrix metalloproteinase-3 (MMP-3) (p = 0.043, p = 0.029, and p = 0.013, respectively), matrix metalloproteinase 13 (MMP-13) (p = 0.044, p = 0.0043, and p = 0.0013, respectively) (Figure 3B)
Our observation of Matrix metalloproteinase-1 (MMP-1), MMP-3, and MMP-13 gene expression in meniscal fibrochondrocytes as well as chondrocytes and synovial fibroblasts upon exposure to proinflammatory 30 kDa fibronectin fragment (FN-f), is a novel finding. These results suggest that PRP treatment could reduce FN-f-induced MMP-1, MMP-3, and MMP-13 protein-expression levels in meniscal fibrochondrocytes, articular chondrocytes, and synovial fibroblasts
Summary
Osteoarthritis (OA) is the most common form of arthritis among the elderly. The onset of cartilage degeneration (the hallmark of OA) can be traced to trauma caused by incorrect biomechanical loading of the joint and consequent biological responses. Mature chondrocytes express Toll-like receptor 1 (TLR1) and Toll-like receptor 2 (TLR2) and may react to cartilage matrix/chondrocyte-derived danger signals or degradation products. This leads to the synthesis of proinflammatory cytokines, which further stimulate TLR and cytokine expression, thereby establishing a vicious cycle, eventually leading to OA [2]. Previous studies have demonstrated that the expression of TLR2 in human articular cartilage can be upregulated using proarthritic agents, including interleukin 1 beta (IL-1β) and fibronectin fragment (FN-f) [3]. Signaling through TLR in human articular chondrocytes revealed a novel proinflammatory mechanism associated with OA, indicating that the targeting of these signaling pathways might be of value in the treatment of degenerative joint disease
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