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Effect of Nutrient Metabolism on Cartilaginous Tissue Formation
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  • Roberto Tarantino,
  • Loraine Chiu,
  • Joanna Weber,
  • Yat Tse,
  • Davide Bardana,
  • Stephen Pang,
  • Stephen Waldman
Roberto Tarantino
Ryerson University

Corresponding Author:[email protected]

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Loraine Chiu
Ryerson University
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Joanna Weber
St Michael's Hospital Li Ka Shing Knowledge Institute
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Yat Tse
Queen's University
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Davide Bardana
Queen's University
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Stephen Pang
Queen's University
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Stephen Waldman
Ryerson University
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Despite the potential of tissue engineering approaches for cartilage repair, a major shortcoming is the low biosynthetic response of chondrocytes. While different strategies have been investigated to upregulate tissue formation, a novel approach may be to control nutrient metabolism. Although known for their anaerobic metabolism of glucose, chondrocytes are more synthetically active when cultured under conditions that elicit mixed aerobic-anaerobic metabolism. Here, we postulate this metabolic switch induces hypoxia inducible factor 1α (HIF-1α) signaling leading to improved tissue growth. Transition to different metabolic states can result in the pooling of intracellular metabolites, several of which can stabilize HIF-1α by interfering with proline-hydroxylase-2 (PHD2). Chondrocytes cultured under increased media availability accelerated tissue deposition (2.2 to 3.5-fold) with the greatest effect occurring at intermediate volumes (2 mL/106 cells). Under higher media volumes, metabolism switched from anaerobic to mixed aerobic-anaerobic. At and beyond this transition, maximal changes in PHD2 activity (- 45%), HIF-1α protein expression (8-fold increase), and HIF-1 gene target expression were observed (2.0 to 2.7-fold increase). Loss-of-function studies using YC-1 (to degrade HIF-1α) confirmed the involvement of HIF-1 signaling under these conditions. Lastly, targeted metabolomic studies of glucose metabolites (14 in total) revealed that both intracellular lactate and succinate correlated with PHD2 activity. Although both metabolites can inhibit PHD2, this effect can most likely be attributed to lactate as succinate was only present in trace amounts. However, addition work (e.g., 13C flux analyses) are required to confirm this assertion. Nevertheless, by harnessing this newly identified metabolic switch, functional engineered cartilage implants may be developed without the need for sophisticated methods which would allow for improved translation into the clinical realm.
11 Jan 2021Submitted to Biotechnology and Bioengineering
12 Jan 2021Submission Checks Completed
12 Jan 2021Assigned to Editor
23 Jan 2021Reviewer(s) Assigned
25 Feb 2021Review(s) Completed, Editorial Evaluation Pending
25 Feb 2021Editorial Decision: Revise Major
26 Mar 20211st Revision Received
26 Mar 2021Assigned to Editor
26 Mar 2021Submission Checks Completed
26 Mar 2021Reviewer(s) Assigned
07 Jun 2021Review(s) Completed, Editorial Evaluation Pending
07 Jun 2021Editorial Decision: Revise Major
25 Jun 20212nd Revision Received
26 Jun 2021Assigned to Editor
26 Jun 2021Submission Checks Completed
09 Jul 2021Editorial Decision: Accept
09 Jul 2021Review(s) Completed, Editorial Evaluation Pending