Beyond M1/M2: The Pivotal Role of Macrophage Metabolic Reprogramming in Chronic Bone Disease and Targeted Intervention
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis review discusses the heterogeneity of macrophages beyond the traditional M1/M2 dichotomy and their functional plasticity in the context of bone diseases. Authors also analyzed the role of specific metabolites in the bone homeostasis and possible therapeutic strategies targeting various biochemical pathways. The topic of the paper is actual and promising. Despite this, there are several comments to the article.
Common: When you cite an experimental work, please add the reference before discussion for better understanding (for example, “In the study [ref.]…” or “Liu Y. et all confirmed that…”).
Line (L) 118 – 119. Please explain the statement “In contrast, M2-polarized macrophages play an active role in bone metabolism”. According to the text above and below this statement, no contrast can be seen in the context you have indicated. Please make it more clearly.
L231. Despite the beautiful design, Figure 1 is not really informative. The right panel of the Figure 1 is poorly connected to the left one. The connection between the indicated specific parts of metabolism and corresponding biochemical cascades or mechanisms should be noted (or this relationship should be highlighted in the text above).
L260 - 262. Please explain the logical connection between the first and the second parts of this sentence or reformulate it.
L265 - 299. These statements should be supported by additional references to other studies.
L300. What do you mean by the statement "passive energy reservoir" in the context of bones?
L400 - 402. Please add examples of chronic bone diseases with proper references.
L422. The Figure 2 description contains letters corresponding to parts of this scheme; however, they are absent on the figure. Please add the letters for better navigation.
L423 - 426. Since the Figure 2 illustrates the reprogramming of metabolic pathways using the action of specific experimental drugs as an example, emphasis should also be placed on this in the description of the figure.
L547 - 549. Please add examples of such a diseases.
L510 - 542. This passage is quoted from a single source (Ref. 67). Please revise it and supplement it with references to other studies, if possible.
L575 - 598. These statements should be supported by additional references to other studies.
L790-791. Chapter 5 lacks a discussion of new therapeutic approaches for specific bone diseases. The strategies described below are not universal and may be preferable for the treatment of different chronic bone diseases.
L842. Figure 3 should be more informative.
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsWan et al submit a review entitled "Beyond M1/M2: the Pivotal Role of Macrophage Metabolic
Reprogramming in Chronic Bone Disease and Targeted Intervention".
The review is interesting and has a lot of new informations to deliver. Overall, the review reads fine, and the publications cited are mostly up to date. As this is a review article, I would however recommend that more details be given on the process used to select the publications cited .
Concerning the various aspects described that modulate M1/M2 phenotype, perhaps the epigenetic/ non coding RNA has been a bit neglected. For example, the microRNA miR-223 has been shown to modulate the transtiion from M1 to M2, ntoalby by modulationg nfKB and the compositon of amino-acids (see PMID: 29778662). this could be associated to the discussion as it is in the scope of the review.
Minor
unless I am mistaken ARHGAP is not defined. CEMIP2 ? Pleae check abbreviations.
Line 375 rectify "macrophages are highly plastic and can differentiatE into different phenotypes"
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsTo the Authors:
This manuscript presents a comprehensive review of macrophage metabolic reprogramming and its role in chronic bone diseases. The authors aim to move beyond the traditional M1/M2 polarization paradigm and propose a “metabolism–immunity–bone” axis as a central framework. The topic is timely and relevant, and the manuscript integrates immunometabolism with bone biology, which is of considerable interest to the field.
However, despite its potential, the manuscript currently has several significant issues in terms of novelty, organization, and critical analysis, which limit its suitability for publication in its present form.
Major Comments:
(1) The manuscript is largely descriptive, summarizing existing literature without sufficient critical evaluation. While numerous studies on macrophage polarization and metabolic pathways are presented, there is limited discussion on: (a) conflicting findings in the field, (b) the limitations of current studies (e.g., the heavy reliance on in vitro or animal models), and (c) the robustness and translational relevance of the proposed mechanisms.
(2) Although the concept of immunometabolism is significant, the manuscript does not clearly articulate its novel contribution compared to existing reviews. Similar discussions on macrophage metabolism and bone diseases have been recently reported. The authors should better highlight: (a) what distinguishes this review from prior work, and (b) whether a truly new conceptual framework or synthesis is being proposed.
Minor Comments:
(1) Some abbreviations are excessive and may hinder readability; consider simplifying or limiting their use.
(2) The figures (e.g., Figure 4) are conceptually useful but should be better explained and more tightly linked to the main text.
(3) While the reference list is extensive, the manuscript lacks a synthesis of key studies into coherent, forward-looking conclusions.
(4) Minor formatting issues and inconsistencies are present throughout the manuscript.
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors have done a great job of correcting the comments.
Reviewer 2 Report
Comments and Suggestions for Authorschanges are ok
