Conclusions
The results of this study demonstrate that cartilaginous tissue
formation can be upregulated through the control of nutrient metabolism
and that the observed response is mediated through resultant changes in
HIF-1α signalling. By culturing in elevated volumes of media, glucose
uptake by chondrocytes is increased, leading to a change in metabolism
from primarily anaerobic to mixed aerobic-anaerobic (inverse
Crabtree effect ). When cultured at the transition between metabolic
states, a pseudo-hypoxic state is induced resulting in HIF-1α mediated
gene transcription and an associated increase in chondrogenesis. These
findings represent a novel, paradigm-shifting approach to develop
functional engineered cartilage implants that can be produced without
sophisticated stimulation methods. The developed methodology is highly
transferable and can be applied to any cartilage tissue engineering
approach. Such methods are attractive as they have fewer regulatory
barriers to aid commercialization efforts, thereby allowing for improved
clinical translation. Additionally, these newly identified metabolic
pathways could potentially provide insights into the mechanisms of
cartilage growth and development. Future avenues of research will
include metabolic modelling (e.g. 13C flux analyses)
to provide a framework to control chondrogenesis.