Abstract
The pathophysiology of osteoarthritis (OA) involves dysregulation of anabolic and catabolic processes associated with a broad panel of proteins that ultimately lead to cartilage degradation. An increased understanding about these protein interactions with systematic in vitro analyses may give new ideas regarding candidates for treatment of OA related cartilage degradation. Therefore, an ex vivo tissue model of cartilage degradation was established by culturing tissue explants with bacterial collagenase II. Responses of healthy and degrading cartilage were analyzed through protein abundance in tissue supernatant with a 26-multiplex protein profiling assay, after exposing the samples to a panel of 55 protein stimulations present in synovial joints of OA patients. Multivariate data analysis including exhaustive pairwise variable subset selection identified the most outstanding changes in measured protein secretions. MMP9 response to stimulation was outstandingly low in degrading cartilage and there were several protein pairs like IFNG and MMP9 that can be used for successful discrimination between degrading and healthy samples. The discovered changes in protein responses seem promising for accurate detection of degrading cartilage. The ex vivo model seems interesting for drug discovery projects related to cartilage degradation, for example when trying to uncover the unknown interactions between secreted proteins in healthy and degrading tissues.
Highlights
Osteoarthritis (OA) is a progressive disease involving mechanical, biochemical and genetic factors that disturb associations between chondrocytes and extracellular matrix (ECM), alter cellular metabolic responses and result in degradation of articular cartilage1
The results of GAG release and collagen II content, mechanical tests and histology of cartilage discs treated for 24h with DMEM or collagenase II are presented
It can be observed that collagenase II treatment increases the GAG release into explant supernatant (p = 0.006) and decreases the collagen II content of the tissue (p = 0.009)
Summary
Osteoarthritis (OA) is a progressive disease involving mechanical, biochemical and genetic factors that disturb associations between chondrocytes and extracellular matrix (ECM), alter cellular metabolic responses and result in degradation of articular cartilage. Prominent proteins associated with the pathophysiology of OA are pro-inflammatory cytokines including the interleukins IL1a/b, IL6, IL8 and the tumor necrosis factor TNFa [1]. Aggrecanases and matrix metalloproteinases (MMPs) that degrade the ECM as well as growth factor families of bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs) and transforming growth factors (TGFs) are all present in synovial joints of OA patients [3,4]. The fact that proteins with opposing effects are found in OA joints simultaneously (e.g. pro-inflammatory and anti-inflammatory cytokines or matrix degrading enzymes and chondrogenic cytokines) suggests nontrivial inherent interactions between these proteins
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