Abstract
Osteoarthritis (OA) is a degenerative condition that involves the production of inflammatory cytokines (e.g., interleukin-1β (IL-1β), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)) that stimulate degradative enzymes, matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS) resulting in articular cartilage breakdown. The presence of interleukin-1β (IL-1β) is one reason for poor clinical outcomes in current cell-based tissue engineering strategies for treating focal early osteoarthritic defects. Mesenchymal stem cells (MSCs) are a potential cell source for articular cartilage regeneration, although IL-1β has been shown to inhibit in vitro chondrogenesis. In vivo, articular chondrocytes reside under a low oxygen environment between 2–5% oxygen (physioxia) and have been shown to enhance in vitro MSC chondrogenic matrix content with reduced hypertrophic marker expression under these conditions. The present investigation sought to understand the effect of physioxia on IL-1β inhibited MSC chondrogenesis. MSCs expanded under physioxic (2% oxygen) and hyperoxic (20%) conditions, then chondrogenically differentiated as pellets in the presence of TGF-β1 and either 0.1 or 0.5 ng/mL IL-1β. Results showed that there were donor variations in response to physioxic culture based on intrinsic GAG content under hyperoxia. In physioxia responsive donors, MSC chondrogenesis significantly increased GAG and collagen II content, whilst hypertrophic markers were reduced compared with hyperoxia. In the presence of IL-1β, these donors showed a significant increase in cartilage matrix gene expression and GAG content relative to hyperoxic conditions. In contrast, a set of MSC donors were unresponsive to physioxia and showed no significant increase in matrix production independent of IL-1β presence. Thus, physioxia has a beneficial effect on MSC cartilage matrix production in responsive donors with or without IL-1β application. The mechanisms controlling the MSC chondrogenic response in both physioxia responsive and unresponsive donors are to be elucidated in future investigations.
Highlights
Osteoarthritis (OA) is a degenerative condition involving changes in articular cartilage matrix resulting from the stimulation of matrix metalloproteinases (MMPs) and aggrecanases [1,2]
To understand the effect and choose appropriate conditions for examination under physioxia, IL-1β concentrations ranging from 0.1–10 ng/mL were applied to chondrogenic Mesenchymal stem cells (MSCs) under hyperoxia
It was found that under both control and in the presence of IL-1β, responsive donors demonstrated a significant increase in wet weight and GAG content that corresponded to an upregulation in cartilage transcription factors and matrix genes under physioxic conditions (Figures 4 and 5)
Summary
Osteoarthritis (OA) is a degenerative condition involving changes in articular cartilage matrix resulting from the stimulation of matrix metalloproteinases (MMPs) and aggrecanases (a disintegrin and metalloproteinase with thrombospondin motifs, ADAMTS) [1,2]. In vitro studies examining methods to reduce the detrimental response have used anti-arthritic neutraceuticals (e.g., curcumin, reservatrol, mangiferin), adenoviruses (e.g., lL-1 receptor antagonist) or mechanical stimulation (e.g., ultrasound) [16,17,18,19,20,21,22,23]. The latter stimuli show that the negative effects of IL-1β on MSC chondrogenesis can be reduced via environmental stimuli.
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