A Molecular Troika of Angiogenesis, Coagulopathy and Endothelial Dysfunction in the Pathology of Avascular Necrosis of Femoral Head: A Comprehensive Review

Round 1

Reviewer 1 Report

In this article, Singh and colleagues provide an in-depth review of the roles of angiogenesis, coagulopathy, and endothelial dysfunction in the development of avascular necrosis of the femoral head (ANFH), a painful condition caused by a halt in blood supply to the femoral head. The authors explore the molecular mechanisms that contribute to ANFH pathology and briefly discuss potential treatment strategies for ANFH, highlighting the need to consider the cumulative effects of these molecular processes rather than their individual impacts. While the article is well-written, there are a few areas that could be improved:

1. The authors could provide a more detailed discussion of the clinical implications of their findings to enhance the practical relevance of their review.
2. While potential treatment strategies for ANFH are mentioned, a more comprehensive discussion would be beneficial, including their mechanisms of action, effectiveness, and potential limitations.
3. The review would benefit from a clear conclusion summarizing the main findings and implications of the studies discussed, providing readers with a concise understanding of the review's overall message and significance.

Author Response

We appreciate the reviewer for the thorough review of our paper and for providing suggestions for its betterment. Please see the point-wise response to every pointer in boldface

In this article, Singh and colleagues provide an in-depth review of the roles of angiogenesis, coagulopathy, and endothelial dysfunction in the development of avascular necrosis of the femoral head (ANFH), a painful condition caused by a halt in blood supply to the femoral head. The authors explore the molecular mechanisms that contribute to ANFH pathology and briefly discuss potential treatment strategies for ANFH, highlighting the need to consider the cumulative effects of these molecular processes rather than their individual impacts. While the article is well-written, there are a few areas that could be improved:

1. The authors could provide a more detailed discussion of the clinical implications of their findings to enhance the practical relevance of their review.

Thanks for the suggestion, we have incorporated three paragraphs under a new title, ‘7. Clinical Implications: A call of a crackling and collapsing bone”

1. While potential treatment strategies for ANFH are mentioned, a more comprehensive discussion would be beneficial, including their mechanisms of action, effectiveness, and potential limitations.

According to the perspective suggested by the reviewer, we have incorporated a few lines regarding the mechanism of action and potential limitations in this regard in the ‘clinical implications’ and ‘future direction’ sections respectively. We request the reviewer that we can only suggest strategies that could be beneficial within the premise of the findings after a careful but comprehensive review of relevant literature. Their effectiveness would be unwrinkled by future trials, hence a line regarding the effectiveness of putative drug therapies has been written in the ‘clinical implications’ section.

1. The review would benefit from a clear conclusion summarizing the main findings and implications of the studies discussed, providing readers with a concise understanding of the review's overall message and significance.

Thanks for the suggestion, we have incorporated a section of the conclusion showing a clear understanding of the message

Reviewer 2 Report

Dear,

Title is my interest and authors reviewed the Molecular Troika of Angiogenesis, Coagulopathy and Endothelial Dysfunction in the Pathology of Avascular Necrosis of the Femoral Head. I suggest authors follow the below comments;

-Abstract is not clear and authors should explain very well the aim of this review

-The epigenetic of stem cells should explain clearly and I suggest authors to make a title as the of epigenetic .........., I suggest the following reference to improve this part (The Role of Epigenetic in Dental and Oral Regenerative Medicine by Different Types of Dental Stem Cells: A Comprehensive Overview Stem Cells International 2022-06-09 | Journal article DOI: 10.1155/2022/5304860 CONTRIBUTORS)

-The in vitro and in vivo (animal test) studies have been missed from your manuscript, it would be great to mention about animal test in bone and angiogenesis and I suggest you the following article to improve your whole text; (Mosaddad, Seyed Ali, Ahmed Hussain, and Hamid Tebyaniyan. "Exploring the Use of Animal Models in Craniofacial Regenerative Medicine: A Narrative Review." Tissue Engineering ja (2023))

- It would be better to make section as conclusion and also, explain the limitations in this section

-Authors should make a section as future direction. 

Author Response

We appreciate the reviewer for the thorough review of our paper and for providing suggestions for its betterment. Please see the point-wise response to every pointer in boldface

Title is my interest and authors reviewed the Molecular Troika of Angiogenesis, Coagulopathy and Endothelial Dysfunction in the Pathology of Avascular Necrosis of the Femoral Head. I suggest authors follow the below comments;

-Abstract is not clear and authors should explain very well the aim of this review

We have written some lines and inserted a few words in the abstract to clear the aim of this review, as suggested.

-The epigenetic of stem cells should explain clearly and I suggest authors to make a title as the of epigenetic .........., I suggest the following reference to improve this part (The Role of Epigenetic in Dental and Oral Regenerative Medicine by Different Types of Dental Stem Cells: A Comprehensive Overview Stem Cells International 2022-06-09 | Journal article DOI: 10.1155/2022/5304860 CONTRIBUTORS)

We request that this review paper was deliberately written to focus on clinical causes and manifestations of these three pathways i.e. impaired angiogenesis, endothelial dysfunction, and coagulopathy. To incorporate a section on epigenetics in this paper, readers must be introduced to the genetic implications of this disease which demands the latest genetic technologies like RNAi, Next-generation high throughput sequencing, DNA chip-based technologies, Microarray, and CRISPR-Cas. I hope you will agree that for such perspectives, it needs a separate full-length paper. We request that please excuse us for our inability to include a section on epigenetics in this paper.

-The in vitro and in vivo (animal test) studies have been missed from your manuscript, it would be great to mention about animal test in bone and angiogenesis and I suggest you the following article to improve your whole text; (Mosaddad, Seyed Ali, Ahmed Hussain, and Hamid Tebyaniyan. "Exploring the Use of Animal Models in Craniofacial Regenerative Medicine: A Narrative Review." Tissue Engineering ja (2023))

We request that we have already included information on putative drug therapies to improve angiogenesis, endothelial dysfunction, and coagulopathy in Table 1, which have been investigated in mouse models. Despite our best efforts, we are unable to find any link of animal models in Craniofacial Regeneration with the present review, therefore we request that this paper cannot be cited.

- It would be better to make section as conclusion and also, explain the limitations in this section

We have added a section of the Conclusion and furnished some lines regarding its limitations.

-Authors should make a section as future direction. 

We have added future directions as a separate section, as suggested.

Round 2

Reviewer 1 Report

The article is significantly improved, and the concerns are addressed satisfactorily.

Reviewer 2 Report

Dear, this paper still is so poor and authors do not want to improve it and ignore the quality and quantity of text. The current version is nothing and I strongly reject it.