Articular cartilage corefucosylation regulates tissue resilience in osteoarthritis

Reviewer #1 (Public Review):

Summary:
This study is valuable in that it may lead to the discovery of future OA markers, etc., in that changes in glycan metabolism in chondrocytes are involved in the initiation of cartilage degeneration and early OA via hypertrophic differentiation of chondrocytes. However, more robust results would be obtained by analyzing the mechanisms and pathways by which changes in glycosylation lead to cartilage degeneration.

Strengths:
This study is important because it indicates that glycan metabolism may be associated with pre-OA and may lead to the elucidation of the cause and diagnosis of pre-OA.

Weaknesses:
More robust results would be obtained by analyzing the mechanism by which cartilage degeneration induced by changes in glycometabolism occurs.

Reviewer #2 (Public Review):

Summary:
This paper consists of mostly descriptive data, judged from alpha-mannosidase-treated samples, in which they found an increase in core fucose, a product of Fut 8.

Strengths:
This paper is interesting in the clinical field, but unfortunately, the data is mostly descriptive and does not have a significant impact on the scientific community in general.

Weaknesses:
If core fucose is increased, at least the target glycan molecules of core fucose should be evaluated. They also found an increase in NO, suggesting that inflammatory processes also play an important role in OA in addition to glycan changes.
It has already been reported that core fucose is decreased by administration of alpha-mannosidase inhibitors. Therefore, it is expected that alpha-mannosidase administration increases core fucose.

Reviewer #3 (Public Review):

Summary:
In the manuscript "Articular cartilage corefucosylation regulates tissue resilience in osteoarthritis", the authors investigate the glycan structural changes in the context of pre-OA conditions. By mainly conducting animal experiments and glycomic analysis, this study clarified the molecular mechanism of N-glycan core fucosylation and Fut8 expression in the extracellular matrix resilience and unrecoverable cartilage degeneration. Lastly, a comprehensive glycan analysis of human OA cartilage verified the hypothesis.

Strengths:
Generally, this manuscript is well structured with rigorous logic and clear language. This study is valuable and important in the early diagnosis of OA patients in the clinic, which is a great challenge nowadays.

Weaknesses:
I recommend minor revisions:

1. I would suggest the authors prepare an illustrative scheme for the whole study, to explain the complex mechanism and also to summarize the results.

2. Including but not limited to Figures 2A-C, Figures 3A and C, Figure 4B, and Figures 5A and D. The texts in the above images are too small to read, I would suggest the authors remake these images.

3. The paper is generally readable, but the language could be polished a bit. Several writing errors should be realized during the careful check.

4. As several species and OA models were conducted in this study, it would be better if the authors could note the reason behind their choice for it.