Glutamine metabolism modulates chondrocyte inflammatory response
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Curated by eLife
Evaluation Summary:
This manuscript focuses on identifying how metabolism can influence the response of cartilage cells to inflammation. This has relevance to the painful disease known as osteoarthritis. Modulation of cell metabolism in the right direction can serve to protect joint cartilage from the negative effects of inflammation which causes onset and disease progression.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
Osteoarthritis is the most common joint disease in the world with significant societal consequences but lacks effective disease-modifying interventions. The pathophysiology consists of a prominent inflammatory component that can be targeted to prevent cartilage degradation and structural defects. Intracellular metabolism has emerged as a culprit of the inflammatory response in chondrocytes, with both processes co-regulating each other. The role of glutamine metabolism in chondrocytes, especially in the context of inflammation, lacks a thorough understanding and is the focus of this work. We display that mouse chondrocytes utilize glutamine for energy production and anabolic processes. Furthermore, we show that glutamine deprivation itself causes metabolic reprogramming and decreases the inflammatory response of chondrocytes through inhibition of NF-κB activity. Finally, we display that glutamine deprivation promotes autophagy and that ammonia is an inhibitor of autophagy. Overall, we identify a relationship between glutamine metabolism and inflammatory signaling and display the need for increased study of chondrocyte metabolic systems.
Article activity feed
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Evaluation Summary:
This manuscript focuses on identifying how metabolism can influence the response of cartilage cells to inflammation. This has relevance to the painful disease known as osteoarthritis. Modulation of cell metabolism in the right direction can serve to protect joint cartilage from the negative effects of inflammation which causes onset and disease progression.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
This manuscript describes in detail the role of glutamine in chondrocyte metabolism. The authors provide an extensive investigation into the anabolic respiratory effects of glutamine deprivation including its effect on other sources of energy such as glycolysis. Their premise is also backed up by several modes of investigation, including the use of the pharmacological inhibitor CB-839. The manuscript is decently written and there are numerous well-laid-out figures to support conclusions.
The main issue at hand is the reconciliation of the hypothesis with other recent work targeting this area. For example, Ma et a. Clin Sci (2022) recently published a paper demonstrating that glutamine supplementation, as opposed to deprivation, leads to a reduction in osteoarthritis symptoms and reduction in NF-kappaB …
Reviewer #1 (Public Review):
This manuscript describes in detail the role of glutamine in chondrocyte metabolism. The authors provide an extensive investigation into the anabolic respiratory effects of glutamine deprivation including its effect on other sources of energy such as glycolysis. Their premise is also backed up by several modes of investigation, including the use of the pharmacological inhibitor CB-839. The manuscript is decently written and there are numerous well-laid-out figures to support conclusions.
The main issue at hand is the reconciliation of the hypothesis with other recent work targeting this area. For example, Ma et a. Clin Sci (2022) recently published a paper demonstrating that glutamine supplementation, as opposed to deprivation, leads to a reduction in osteoarthritis symptoms and reduction in NF-kappaB activity. While it is possible for both mechanisms (e.g. deprivation and supplementation) to lead to similar outcomes, exploration of this topic would be of interest to the readership.
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Reviewer #2 (Public Review):
In this manuscript, the authors investigate the effect of inflammation on chondrocyte metabolism and demonstrate that glutamine deprivation regulates NFkB-inflammatory pathways. Specifically, the authors show that IL-1B alters the expression of key glutamine metabolic enzymes in primary murine chondrocytes and validate these observations in human cells extracted from OA. They go on to show that glutamine deprivation enhances cell death of chondrocytes and reduces intracellular ATP suggesting a critical role of glutamine in chondrocyte metabolism. Furthermore, glutamine deprivation leads to reduced glycolysis and metabolic reprogramming which in turn affects IL-6, MMP13 expression, and NF-kB activity. These data are well-documented with dose responses in controlled experiments. Then the authors highlight the …
Reviewer #2 (Public Review):
In this manuscript, the authors investigate the effect of inflammation on chondrocyte metabolism and demonstrate that glutamine deprivation regulates NFkB-inflammatory pathways. Specifically, the authors show that IL-1B alters the expression of key glutamine metabolic enzymes in primary murine chondrocytes and validate these observations in human cells extracted from OA. They go on to show that glutamine deprivation enhances cell death of chondrocytes and reduces intracellular ATP suggesting a critical role of glutamine in chondrocyte metabolism. Furthermore, glutamine deprivation leads to reduced glycolysis and metabolic reprogramming which in turn affects IL-6, MMP13 expression, and NF-kB activity. These data are well-documented with dose responses in controlled experiments. Then the authors highlight the effects of glutamine deprivation in autophagy which can be rescued by ammonia which inhibits autophagy via the autophagosome-lysosome fusion. This pathway needs to be better clarified or the statement toned down as LC3I/II ratios are missing and are required to measure the autophagic flux. Overall this is a well-written manuscript that is likely to have a strong impact on chondrocyte metabolism research.
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Reviewer #3 (Public Review):
In this manuscript, the authors investigated the role of glutamine metabolism in chondrocytes and in the context of inflammation. Thus, they report that chondrocytes use glutamine for their energy production and anabolic functions. Moreover, they found that removal of glutamine resulted in metabolic reprogramming and decreased inflammatory response of chondrocytes. They attributed this anti-inflammatory response to decreased NF-κB activity. Moreover, the removal of glutamine promoted autophagy. This is a very interesting study and the vast majority of the conclusions are supported by strong data.
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