RANK–RANKL–OPG Axis in MASLD: Current Evidence Linking Bone and Liver Diseases and Future Perspectives

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article presents a comprehensive narrative review on the potential role of the RANK-RANKL-OPG axis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), exploring the link between bone metabolism and liver disease. The authors, Federico Monti et al., provide a detailed overview of the current evidence and future perspectives on the involvement of RANK, RANKL, and OPG in MASLD pathophysiology and hepatocellular carcinoma (HCC).This article has several advantages:

Firstly, the article is well-structured, with a clear introduction that sets the stage for the discussion on the RANK-RANKL-OPG axis (RROa) and its implications in MASLD. Secondly, the author conducted a comprehensive search of relevant literature and summarized key studies and findings related to the RROa in bone and liver diseases. Next, the author explores the role of RROa in various aspects of the progression of MASLD, such as insulin resistance, macrophage infiltration, liver fibrosis, and the effect of TNF related apoptosis inducing ligand (TRAIL). By studying the role of RROa in these progressions, seeking potential drugs for treating MASLD with RROa, which is valuable for researchers and clinicians interested in developing new therapies for MASLD. At last, this article discusses the potential use of drugs targeting RROa, such as denosumab, providing a novel perspective for the treatment of MASLD.

However, this article has some disadvantages:

1. The details in Figure 1 do not fully reflect the phased effects of RROa on the development of MASLD. It is recommended to introduce the specific role of RROa in the chronological order of MASLD progression.

2. Although the authors discussed the potential therapeutic significance of denosumab, they did not provide detailed data on the efficacy and safety of the mentioned drug, and why this type of drug was chosen to treat MASLD, because of its advantages in pharmacoeconomics or its low toxicity or other reasons? These discussions are valuable for physicians' clinical decision-making.

3. About the concluding section of the article, the author can analyze the limitations of existing research from a critical perspective, and discuss potential future research directions from a broader perspective, further exploring and verifying the detailed role of the RROa, and exploring new therapeutic targets to expand the application scenarios of related drugs.

Overall, the article provides a valuable overview of the research on the RANK-RANKL-OPG axis in MASLD and its potential implications for the development of new treatments. Well done!

Author Response

The article presents a comprehensive narrative review on the potential role of the RANK-RANKL-OPG axis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), exploring the link between bone metabolism and liver disease. The authors, Federico Monti et al., provide a detailed overview of the current evidence and future perspectives on the involvement of RANK, RANKL, and OPG in MASLD pathophysiology and hepatocellular carcinoma (HCC). This article has several advantages:

 

Firstly, the article is well-structured, with a clear introduction that sets the stage for the discussion on the RANK-RANKL-OPG axis (RROa) and its implications in MASLD. Secondly, the author conducted a comprehensive search of relevant literature and summarized key studies and findings related to the RROa in bone and liver diseases. Next, the author explores the role of RROa in various aspects of the progression of MASLD, such as insulin resistance, macrophage infiltration, liver fibrosis, and the effect of TNF related apoptosis inducing ligand (TRAIL). By studying the role of RROa in these progressions, seeking potential drugs for treating MASLD with RROa, which is valuable for researchers and clinicians interested in developing new therapies for MASLD. At last, this article discusses the potential use of drugs targeting RROa, such as denosumab, providing a novel perspective for the treatment of MASLD.

 

However, this article has some disadvantages:

 

1. The details in Figure 1 do not fully reflect the phased effects of RROa on the development of MASLD. It is recommended to introduce the specific role of RROa in the chronological order of MASLD progression. Thank you for your comment. We fully agree that presenting the consequent steps of RROa involvement in MASLD in chronological order would have improved the coherence of our paper. Unfortunately, by adhering to the current evidence, it is not possible to define the precise timing of action of RROa actors during the natural history of MASLD. We hope that further research may investigate it.

 

2. Although the authors discussed the potential therapeutic significance of denosumab, they did not provide detailed data on the efficacy and safety of the mentioned drug, and why this type of drug was chosen to treat MASLD, because of its advantages in pharmacoeconomics or its low toxicity or other reasons? These discussions are valuable for physicians' clinical decision-making. Thank you, we improved the paragraph following your suggestion.

 

3. About the concluding section of the article, the author can analyze the limitations of existing research from a critical perspective, and discuss potential future research directions from a broader perspective, further exploring and verifying the detailed role of the RROa, and exploring new therapeutic targets to expand the application scenarios of related drugs. Thank you, we appreciate your advice and enriched the conclusion paragraph considering the limitation of current evidence and highlighting the need for further investigation.

Reviewer 2 Report

Comments and Suggestions for Authors

In their paper, the authors set out to trace the current state of knowledge regarding the involvement of bone regulatory factors known as the RANK-RANKL-OPG axis in metabolic dysfunction-associated steatotic liver disease. The article is logically structured and can serve as a resource for readers less familiar with the topic. Nevertheless, the paper has some shortcomings that should be corrected before possible publication.

 

Line 19 - is the state of transplantation in the US any indication? How does it compare to other such countries including European ones? Such information is irrelevant to the research undertaken by the authors.

Line 32 - the abbreviation NAFLD is not used even once in the text. What then is the point and purpose of its introduction? Similarly, OCIF (L97) or PTH (L107). Please once again check all abbreviations.

Line 36 - please decide on one abbreviation: T2D (line 26) or T2DM (line 201).

Line 63 - when writing a review article, it is important to show what databases the authors used, what keywords they included. How many articles in total they analyzed, which ones they rejected and why, etc. In contrast, in this article there is not a word about such methodology which is a major limitation.

Line 64 - from the point of view of histology, bone is connective tissue. Other tissues are: muscle tissue, nerve tissue and epithelial tissue. However, there is no "bone tissue". Similarly, "lymphoid tissue" (L133) also does not exist histologically.

Figures - a weakness of the article is its graphic layout. In fact, each of the chapters could be accompanied by a graphic illustrating the relationships and metabolic pathways discussed. Meanwhile, there is literally one figure in the article and it is quite general. This raises a deficiency.

Line 411 - does this reference have no authors?

Author Response

In their paper, the authors set out to trace the current state of knowledge regarding the involvement of bone regulatory factors known as the RANK-RANKL-OPG axis in metabolic dysfunction-associated steatotic liver disease. The article is logically structured and can serve as a resource for readers less familiar with the topic. Nevertheless, the paper has some shortcomings that should be corrected before possible publication. We would like to thank the reviewer for the kind words.

 

• Line 19 - is the state of transplantation in the US any indication? How does it compare to other such countries including European ones? Such information is irrelevant to the research undertaken by the authors. Thank you for your suggestion; we eliminated the sentence.
• Line 32 - the abbreviation NAFLD is not used even once in the text. What then is the point and purpose of its introduction? We thank you for your comment. We mentioned the term NAFLD since was the previous term for that condition. We then used the current correct term (MASLD/MASH) throughout the paper.
• Similarly, OCIF (L97) or PTH (L107). Please once again check all abbreviations. We appreciate your comment. We checked and corrected all the abbreviations.
• Line 36 - please decide on one abbreviation: T2D (line 26) or T2DM (line 201). Thank you for the comment. We corrected the abbreviations and decided on T2D.
• Line 63 - when writing a review article, it is important to show what databases the authors used, what keywords they included. How many articles in total they analyzed, which ones they rejected and why, etc. In contrast, in this article there is not a word about such methodology which is a major limitation. We thank the reviewer for the useful comment. We added a paragraph in which data sources and searches are clarified. Since we aimed to produce a narrative review the Prisma flowchart was not added.
• Line 64 - from the point of view of histology, bone is connective tissue. Other tissues are: muscle tissue, nerve tissue and epithelial tissue. However, there is no "bone tissue". Similarly, "lymphoid tissue" (L133) also does not exist histologically. From the point of view of histology, we fully agree with you that bone tissue is a specific subtype of connective tissue. However, we chose to use this expression because is commonly used in the field of bone metabolism disease and it has been even used in the Consensus Development Conference’s definition of osteoporosis (https://link.springer.com/content/pdf/10.1007/BF01880454.pdf).

On the other side, when we speak about lymphoid tissue we refer to mucosa-associated lymphoid tissues (MALT), as expressed in the text, which is a specific entity in the lymphatic system.

• Figures - a weakness of the article is its graphic layout. In fact, each of the chapters could be accompanied by a graphic illustrating the relationships and metabolic pathways discussed. Meanwhile, there is literally one figure in the article and it is quite general. This raises a deficiency.

Thank you, we appreciate your suggestion and we improved the paper with two more images hoping to clarify and graphically highlight the topics discussed.

 

• Line 411 - does this reference have no authors? Thank you, we fixed the typo.

Reviewer 3 Report

Comments and Suggestions for Authors

This review discussed the  association between Metabolic dysfunction-associated steatotic liver disease (MASLD) and bone-linked problems. The review is interesting and delivers novel insights into the field of bone and liver diseases. there are minor issues to address.

1. All abbreviations in the abstract should be deciphered ( RANK, RANKL etc).

2. Authors missed to discuss the role of steroid hormones/estrogens in AMSLD/bone health axis. Estrogens are important hormones in the regulation of bone health. Estrogens are involved into regulation of liver  pathologies. Immune regulation is also influenced by estrogens. Estorgen can regulate sphingolipid signalling (https://pubmed.ncbi.nlm.nih.gov/29385066/).  can Estrogen be involved into bone-liver/MASLD axis? speculative suggestions can be mentioned at least in short.

3. Role of TNF is very interesting. However, authors may need to mention the role of TNF in the regulation of lipid signaling in more details. TNF can regulate sphingolipid signaling which can be potentially associated with bone and liver health ( see this https://pubmed.ncbi.nlm.nih.gov/38698424/).

4. Sphingolipids are important for the bone health see this https://pubmed.ncbi.nlm.nih.gov/36656634/.  therefore, this part can be mentioned in the subsections with RANKL.

 

Comments on the Quality of English Language

minor editing is required.

Author Response

This review discussed the association between Metabolic dysfunction-associated steatotic liver disease (MASLD) and bone-linked problems. The review is interesting and delivers novel insights into the field of bone and liver diseases. There are minor issues to address.

• All abbreviations in the abstract should be deciphered (RANK, RANKL etc). Thank you for your comment. We deciphered all abbreviations.
• Authors missed to discuss the role of steroid hormones/estrogens in MASLD/bone health axis. Estrogens are important hormones in the regulation of bone health. Estrogens are involved into regulation of liver pathologies. Immune regulation is also influenced by estrogens. Estrogen can regulate sphingolipid signalling (https://pubmed.ncbi.nlm.nih.gov/29385066/).  Can Estrogen be involved into bone-liver/MASLD axis? Speculative suggestions can be mentioned at least in short.
• Role of TNF is very interesting. However, authors may need to mention the role of TNF in the regulation of lipid signaling in more details. TNF can regulate sphingolipid signaling which can be potentially associated with bone and liver health (see this https://pubmed.ncbi.nlm.nih.gov/38698424/).
• Sphingolipids are important for the bone health see this https://pubmed.ncbi.nlm.nih.gov/36656634/ (Bone circuitry and interorgan skeletal crosstalk).  Therefore, this part can be mentioned in the subsections with RANKL.

Thank you for these intriguing suggestions. We really appreciate and take into account your advice. We choose to highlight the importance of sphingolipid signalling in bone and liver health and their possible role in linking them in the L120-121 and L217-222.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors responded to my comments in a meaningful way.

Author Response

Thank you for your feedback.