Abstract
Articular cartilage lacks an intrinsic repair capacity and due to the ability of mesenchymal stem cells (MSCs) to differentiate into chondrocytes, MSCs have been touted as a cellular source to regenerate damaged cartilage. However, a number of prevailing concerns for such a treatment remain. Generally, administration of MSCs into a cartilage defect results in poor regeneration of the damaged cartilage with the repaired cartilage consisting primarily of fibro-cartilage rather than hyaline cartilage. Methods that improve the chondrogenic potential of transplanted MSCs in vivo may be advantageous. In addition, the proclivity of MSC-derived cartilage to undergo hypertrophic differentiation or form bone in vivo also remains a clinical concern. If MSC-derived cartilage was to undergo hypertrophic differentiation in vivo, this would be deleterious in a clinical setting. This study focuses on establishing a mechanism of action by which hypoxia or low oxygen tension can be used to both enhance chondrogenesis and attenuate hypertrophic differentiation of both MSC and ATDC5 derived chondrocytes. Having elucidated a novel mechanism of action, the subsequent goals of this study were to develop an in vitro culture regime to mimic the beneficial effects of physiological low oxygen tension in a normoxic environment.
Highlights
To assess the effect of hypoxia upon mesenchymal stem cells (MSCs) chondrogenesis, pellets were differentiated for 28 days in normoxic (19% O2) or hypoxic (2% O2) conditions
We examined the effects of hypoxia on hypertrophy, as indicated by the decreased expression of RUNX2, Collagen X and Alkaline phosphatase (ALP) content
We observed a significant increase in ALP content in ATDC5 cells differentiated in hypoxia compared to vehicle controls
Summary
Hypoxia causes decreased expression of hypertrophic markers Collagen X and Runt-related Transcription Factor 2 (RUNX2) during chondrogenesis, the mechanism of action has yet to be fully elucidated[23,24,25]. We hypothesize that activation of hypoxia inducible pathways by physiological, genetic or pharmacological means can have beneficial effects on the development of cartilage formed It does so by attenuating hypertrophy and improving the phenotype of the de novo cartilage so it resembles native articular cartilage. We aim to demonstrate the development of an in vitro culture regime to mimic the beneficial effects of physiological low oxygen tension in a normoxic environment We propose that such a regime could be clinically translated to in vivo settings to promote the formation of de novo cartilage that closely resembles native articular cartilage
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