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The Role of RANKL and Involvement of Cementum in Orthodontic Root Resorption

Appl. Sci. 2021, 11(16), 7244; https://doi.org/10.3390/app11167244

by Masaru Yamaguchi^1,*

and Hiroyuki Mishima²

Reviewer 1: Anonymous

Reviewer 2: Anonymous

Appl. Sci. 2021, 11(16), 7244; https://doi.org/10.3390/app11167244

Submission received: 23 July 2021 / Revised: 1 August 2021 / Accepted: 2 August 2021 / Published: 6 August 2021

(This article belongs to the Special Issue Orthodontic Root Resorption)

Round 1

Reviewer 1 Report

My previous suggestions were not considered.

However, I still think that in order to be able to assess the quality and significance of the review, it is necessary to briefly describe the methodology used for literature search. Even if this is only implemented by quoting something like: “The authors wish to point out that the manuscript has the character of a personal assessment of the state of the art without the claim of a comprehensive review.”

Author Response

1st, August, 2021

Dear Reviewer 1

Applied Sciences

Special issue

"Orthodontic Root Resorption"

We revised our manuscript entitled “The role of RANKL and the involvement of cementum in orthodontic root resorption” (MDPI Manuscript ID: applsci-1331654) for publication to Applied Science.

We had read the editor’s comments carefully and have revised the manuscript accordingly. We have written all revised words or sentences in our manuscript in yellow highlight in the text.

Owing to the editor’s many thoughtful comments, we believe that our paper has been greatly improved. The answers to the comments raised by the editor are also provided on attached separate pages.

This review described that the role of RANKL and the involvement of cementum in ORR. We hope this review will be interested to the readers of " Applied Science”.

Again, thank you for giving us the opportunity to strengthen our manuscript with your valuable comments and queries. We have worked hard to incorporate your feedback and hope that these revisions persuade you to accept our submission.

Respectfully yours,

Masaru Yamaguchi

Ginza Orthodontic Clinic,

Ginza Granvia 6F, 3-3-14 Ginza, Chuo-ku, Tokyo 104-0061, Japan

Tel: +81-3-3567-5454

Response to Reviewer 1 Comments

Thank you for giving us valuable advice and comments regarding our manuscript. We revise upon the manuscript as follows:

Point 1:

My previous suggestions were not considered.

Response 1: As you indicated, the “Information sources and literature search” was added in the text.

3, L. 67-74.

Information sources and literature search

Although this review is not a systematic review, PubMed was searched up to February 2021. Searches were undertaken with no restrictions on year, publication status, or language. The key word and their combinations used for articles’ search were: orthodontic root resorption, RANKL, cementum, periodontal ligament, orthodontic tooth movement. Furthermore, the following journals were searched manually: “American Journal of Orthodontics and Dentofacial Orthopedics”, “Angle Orthodontists”, “European Journal of Orthodontics”, Journal od World Federation of Orthodontists, and Journal of Dental Research.

Author Response File: Author Response.docx

Reviewer 2 Report

Thank you for sending the revised manuscript to me for review. I am satisfied that my previous comments have been considered. A minor spelling/grammar check is required.

Author Response

1st, August, 2021

Dear Reviewer 2

Applied Sciences

Special issue

"Orthodontic Root Resorption"

We had read the editor’s comments carefully and have revised the manuscript accordingly. We have written all revised words or sentences in our manuscript in yellow highlight in the text.

Owing to the editor’s many thoughtful comments, we believe that our paper has been greatly improved. The answers to the comments raised by the editor are also provided on attached separate pages.

This review described that the role of RANKL and the involvement of cementum in ORR. We hope this review will be interested to the readers of " Applied Science”.

Respectfully yours,

Masaru Yamaguchi

Ginza Orthodontic Clinic,

Ginza Granvia 6F, 3-3-14 Ginza, Chuo-ku, Tokyo 104-0061, Japan

Tel: +81-3-3567-5454

Response to Reviewer 2 Comments

Thank you for giving us valuable advice and comments regarding our manuscript. We revise upon the manuscript as follows:

Point 1:

Thank you for sending the revised manuscript to me for review. I am satisfied that my previous comments have been considered. A minor spelling/grammar check is required.

Response 1: As you indicated, the mistakes of minor spelling/grammar were revised.

Author Response File: Author Response.docx

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Title: The role of RANKL and the involvement of cementum in orthodontic root resorption

Author: Masaru Yamaguchi *

Summary: The authors have conducted a review of existing literature concerning the role of RANKL and cementum in orthodontic root resorption (ORR). They summarized ORR and its impacts on treatment planning and outcomes. According to this review, previous study has found that when the PDL and cementoblasts are exposed to excessive orthodontic force, they produced RANKL. This relationship could influence the occurrence of ORR. They also found that cementum hardness and Ca/P ratio differs between individuals and this difference might impact a patient’s predisposition for developing ORR.

Response: This paper alternates between redundant descriptions of literature that can be found in other review articles (on the biology of orthodontic tooth movement) and sections that do not make sense, conceptually or grammatically. The main hypothesis of this paper (that cementum hardness and Ca/P ratio influences amount of ORR) is poorly supported and repeated in several sections without a significant literature review linking these concepts. The main hypothesis of this review needs to be further supported. This manuscript requires extensive rewriting and proof reading, with major restructuring. It still may not be suitable for publication.

Major Revisions

Abstract: “It has been shown that the hardness of the cementum in human maxillary premolars differs among individuals. Furthermore, this difference is reported to be attributed to differences in the Calcium (Ca)/ Phophorous (P) ratio. These findings suggest that the hardness and Ca/P ratio of the cementum might be involved in ORR caused by orthodontic forces.”
1. How do these findings suggest that hardness and Ca/P ratio might modulate ORR? Are teeth with softer cementum or different Ca/P ratios at increased risk of ORR? Is there data suggesting this? Providing a better tie between one idea and the next would be helpful for the abstract.
There are significant typos throughout this paper (some of which are included in the minor revisions below). We recommend a careful and thorough proofreading of this document, with rewriting of many sections.
Introduction: “Recent studies reported that the presence of individual differences in the hardness of apex of the cementum, particularly in the calcium (Ca)/ phophorous (P) ratio in human, and suggested that the hardness and Ca/P ratio of the cementum might be involved in the occurrence of ORR.”
1. What is the “apex of the cementum”? I think you mean the hardness of cementum near the apex. These sentences need to be rewritten to make sense and improve clarity in general.
2. What data suggests that hardness and Ca/P ratio might be involved in ORR occurrence? Please connect these dots both here and in the abstract. It is too great a leap and there needs to be a connecting sentence of data suggesting that hardness and Ca/P ratio is linked to ORR prevalence.
Section 2: “As presented in Figure 2, if the patient's sensitivity to root resorption is compared to glass and water, the risk factor (water droplets) drops and the glass (sensitivity) is gradually filled when orthodontic treatment is started. Root re- sorption does not occur until the glass is full, but root resorption occurs when it spills (Figure 2).”
1. We do not find this comparison particularly illuminating. In this scenario, what is causing the water in the glass to spill? What tips patients from having risk factors and an innate sensitivity to having ORR? This makes it seem like a threshold model, rather than a linear correlation between risk factors and ORR (which seems to contradict a fair bit of literature). Please clarify the value of this analogy or remove it.
2. Figure 2, and its explanation, need to be reworked or preferably, removed. The description needs grammatical editing and should be reworked to make the explanation of the figure clearer. The caption also has grammatical errors. The set-up of this figure could also be improved. The location and sizing of the text should be uniform. The text should also be center justified rather than left justified. The figures in this paper are generally too large and take up too much page space.
Sections 3 and 4 are redundant with many other reviews on the biology of orthodontic tooth movement and orthodontic textbooks. It does not reveal additional conclusions that are not present in many other reviews. These sections can be greatly shortened.
Section 5: “Interestingly, cementoblasts have also investigated the relationship between inflammatory cytokines and mechanical stress in vitro.” à This does not make sense.
Section 5: “According to Kikuta et al. [30], excessive orthodontic forces stimulate the process of ORR via RANKL and IL-6 production in hPDL cells.” à This is a key connection that could be expanded upon in section 5, particularly in the 2^nd paragraph that follows.
Section 6, 1.Hardness of cementum- This review is proposing that cementum hardness may play a role in ORR. But the authors do not reference any studies to that effect. The most I could find was the following sentence: “The hardness might be a major factor affecting the structure of cementum, particularly during root resorption caused by orthodontic forces”. There is no data supporting this claim in the review. The lengthy discussion of cementum hardness and tissue mineral density is much too long and seems somewhat irrelevant to the point of the review.
1. A large portion of the review focuses primarily on the Darendeliler paper (a prior paper from the author’s group), dedicating the better part of two pages to summarizing their findings. Are there no other studies relating root resorption and cementum hardness? A single sentence stating that there is variation in cementum’s TMD and hardness would suffice. A better discussion would be of literature tying differences in cementum hardness/TMD to ORR incidence clinically, in an animal or human model.
2. The authors also dedicated 2 large figures to data from this paper. I believe these could be condensed into one smaller figure or removed completely (Figure 4 and 5).
Section 6, 2. Difference of chemical composition of cementum- Should be numbered #2.
1. “Subsequently, to elucidate the relationship between the hardness of cementum and degree of resorption, Yao-Umezawa et al. [42] used the pit formation assay to demonstrate that the resorbed area in the soft group was increased to a greater extent than those in the moderate and hard groups (Figure 6).”
  1. à This is a key point that needs to be highlighted in the abstract, intro and expanded upon. This clarifies how softness could be tied to increased resorption. This is the only true data supporting the main hypothesis of the paper that I could locate.
2. “If the hardness of cementum of the cementum can be estimated based on the value of enamel, it might be possible to accurately evaluate the risk of root resorption in each patient during.” à This does not make sense, both grammatically and conceptually. What is the “value of enamel”?
Section 7: “One of the explanations for these phenomena may be the resistance to cementum hardness. In other words, the amount of root resorption may be less in teeth with hard cementum exposed to heavy forces during treatment, leading to the production of large amounts of RANKL by the PDL cells or cementoblast. Alternatively, high rot re- sorption might occur in teeth with soft cementum exposed to light force with suppressed amounts of RANKL produced.”
1. This keeps being stated throughout this paper without sufficient evidence to tie these phenomenon together, apart from the few points described above.
2. Root, not rot
3. Cementoblasts- needs to be plural
Section 7: Despite the similarity in the amount of RANKL is produced, teeth with hard cementum might present with lesser root resorption than those with soft cementum.
1. This does not make sense. Where do you discuss similarity in RANKL production? Is it earlier in the paper? Again, we need more data in this review supporting this model and the inherent hypotheses.
Section 8: conclusion: This review attempts to demonstrate that the hardness and Ca/P ratio of the cementum might be involved in ORR caused by orthodontic forces.
1. Again, the review does not demonstrate that hardness and Ca/P ratio is involved in ORR. Yes, more work may need to be done in this field, but to review a literature, existing published works must be described that link ORR and Ca/P and hardness. This review does not appear to represent or describe a large enough body of existing literature on this topic to justify a review.
2. A more robust conclusion is required. What specific gaps do you see in the literature and what can researchers do to fill these gaps?

Minor Revisions

ORR is not an “accidental symptom;” it is an unintended side effect of treatment. A symptom is an effect that a patient will self-report; patients usually do not self-report their own root resorption.
Abstract: The cementum, which covers the root of the tooth, is composed of thin calcified tissue produced by cementoblasts. à This is unneeded background for the audience in an abstract.
“Recent studies demonstrated that cementoblasts and PDL produced RANKL, thus indicating that RANKL produced by PDL cells and cementoblasts might play a role in ORR during orthodontic tooth movement.”
“This review aimed to identify the role of RANKL and the involvement of cementum in ORR.”
Introduction, paragraph 2: “The receptor activator of nuclear factor-kappa ligand (RANKL), and its two receptors RANK and osteoprotegerin (OPG), are known to be involved in this remodeling process [4].” This sentence should be reworked to make the “remodeling process” you are referring to clearer. This line is referring to the previous sentence, but further elaboration would be helpful.
Introduction, paragraph 2: “The RANKL/RANK/OPG system plays a critical role in the induction of bone remodeling.”
Introduction, paragraph 2: “RANKL is expressed in the osteoblast cell lineage, and it exerts its effect by binding to the RANK receptor on osteoclasts.”
Introduction, paragraph 3: “Recent studies reported that the presence of individual differences in the hardness of the apex of the cementum, particularly in the calcium (Ca)/ phophorous (P) ratio in humans, and suggested that the hardness and Ca/P ratio of the cementum might be involved in the occurrence of ORR.” Awkward sentence, rework.
Last line of the introduction: This paper aimed to review the role of both RANKL and the cementum in ORR.
Risk factors of ORR: “ORR is one of the accidental signs observed during orthodontic treatment: severe ORR could affect the outcome of the treatment.”
Risk factors of ORR: “Samandara et al. [5] reported that ORR is a multifactorial complication that occurs when multiple risk factors (patient- or treatment- related) are overlapped overlap (Figure 1).”

These grammatical errors continue throughout the entire paper and require a careful proofreading.

Figure 3 needs further explanation. The fonts should also be reworked to make the figure more cohesive.
Figure 7 should also be reworked. There is a floating box around “DP cells” and the text is not aligned in “soft cementum.” What are DP cells? The many different sized fonts are also confusing.

Comments for author File: Comments.docx

Author Response

Response to Reviewer 1 Comments

Thank you for giving us valuable advice and comments regarding our manuscript. We revise upon the manuscript as follows:

Major Revisions

Abstract: “It has been shown that the hardness of the cementum in human maxillary premolars differs among individuals. Furthermore, this difference is reported to be attributed to differences in the Calcium (Ca)/ Phophorous (P) ratio. These findings suggest that the hardness and Ca/P ratio of the cementum might be involved in ORR caused by orthodontic forces.”

Point 1: How do these findings suggest that hardness and Ca/P ratio might modulate ORR? Are teeth with softer cementum or different Ca/P ratios at increased risk of ORR? Is there data suggesting this? Providing a better tie between one idea and the next would be helpful for the abstract.

Response 1: The hardness and Ca/P ratio might modulate directly ORR. As you indicated, the expression was corrected in abstract.

Point 2: There are significant typos throughout this paper (some of which are included in the minor revisions below). We recommend a careful and thorough proofreading of this document, with rewriting of many sections.

Response 2: I am terribly sorry. We corrected mistakes in the text. As you indicated, this text was received professional English editing by MDPI English editing.

Introduction: “Recent studies reported that the presence of individual differences in the hardness of apex of the cementum, particularly in the calcium (Ca)/ phophorous (P) ratio in human, and suggested that the hardness and Ca/P ratio of the cementum might be involved in the occurrence of ORR.”

Point 3: 1. What is the “apex of the cementum”? I think you mean the hardness of cementum near the apex. These sentences need to be rewritten to make sense and improve clarity in general.

Response 3: As you advised, “apex of the cementum” was corrected to “cementum near the apex”.

Point 4: 2. What data suggests that hardness and Ca/P ratio might be involved in ORR occurrence? Please connect these dots both here and in the abstract. It is too great a leap and there needs to be a connecting sentence of data suggesting that hardness and Ca/P ratio is linked to ORR prevalence.

Response 4: The hardness and Ca/P ratio might modulate directly ORR. As you indicated, the expression was corrected in introduction.

Section 2: “As presented in Figure 2, if the patient's sensitivity to root resorption is compared to glass and water, the risk factor (water droplets) drops and the glass (sensitivity) is gradually filled when orthodontic treatment is started. Root re- sorption does not occur until the glass is full, but root resorption occurs when it spills (Figure 2).”

Point 5: 1. We do not find this comparison particularly illuminating. In this scenario, what is causing the water in the glass to spill? What tips patients from having risk factors and an innate sensitivity to having ORR? This makes it seem like a threshold model, rather than a linear correlation between risk factors and ORR (which seems to contradict a fair bit of literature). Please clarify the value of this analogy or remove it.

Response 5: As you advised, Figure 2 was deleted.

Point 6: 2. Figure 2, and its explanation, need to be reworked or preferably, removed. The description needs grammatical editing and should be reworked to make the explanation of the figure clearer. The caption also has grammatical errors. The set-up of this figure could also be improved. The location and sizing of the text should be uniform. The text should also be center justified rather than left justified. The figures in this paper are generally too large and take up too much page space.

Response 6: As you advised, Figure 2 was deleted.

Point 7: Sections 3 and 4 are redundant with many other reviews on the biology of orthodontic tooth movement and orthodontic textbooks. It does not reveal additional conclusions that are not present in many other reviews. These sections can be greatly shortened.

Response 7: As you advised, Sections 3 and 4 were put together as a whole, and it was shortened.

Point 8: Section 5: “Interestingly, cementoblasts have also investigated the relationship between inflammatory cytokines and mechanical stress in vitro.” à This does not make sense.

Response 8: As you advised, this sentence was deleted.

Point 9: Section 5: “According to Kikuta et al. [30], excessive orthodontic forces stimulate the process of ORR via RANKL and IL-6 production in hPDL cells.” à This is a key connection that could be expanded upon in section 5, particularly in the 2^nd paragraph that follows.

Response 9: As you advised, the reference of Kikuta et al. was added to the 2^nd paragraph in section 5.

Section 6, 1. Hardness of cementum- This review is proposing that cementum hardness may play a role in ORR. But the authors do not reference any studies to that effect. The most I could find was the following sentence: “The hardness might be a major factor affecting the structure of cementum, particularly during root resorption caused by orthodontic forces”. There is no data supporting this claim in the review. The lengthy discussion of cementum hardness and tissue mineral density is much too long and seems somewhat irrelevant to the point of the review.

Point 10: 1. A large portion of the review focuses primarily on the Darendeliler paper (a prior paper from the author’s group), dedicating the better part of two pages to summarizing their findings. Are there no other studies relating root resorption and cementum hardness? A single sentence stating that there is variation in cementum’s TMD and hardness would suffice. A better discussion would be of literature tying differences in cementum hardness/TMD to ORR incidence clinically, in an animal or human model.

Response 10: As you advised, there is a lack of proof in the literature, so future outlook was added.

Point 11: 1. The authors also dedicated 2 large figures to data from this paper. I believe these could be condensed into one smaller figure or removed completely (Figure 4 and 5).

Response 11: As you advised, Figures 4, 5 and 6 were removed.

Section 6, 2. Difference of chemical composition of cementum- Should be numbered #2.
1. “Subsequently, to elucidate the relationship between the hardness of cementum and degree of resorption, Yao-Umezawa et al. [42] used the pit formation assay to demonstrate that the resorbed area in the soft group was increased to a greater extent than those in the moderate and hard groups (Figure 6).”

Point 12: à This is a key point that needs to be highlighted in the abstract, intro and expanded upon. This clarifies how softness could be tied to increased resorption. This is the only true data supporting the main hypothesis of the paper that I could locate.

Response 12: As you advised, this point was added to the abstract and introduction.

Point 13: “If the hardness of cementum of the cementum can be estimated based on the value of enamel, it might be possible to accurately evaluate the risk of root resorption in each patient during.” à This does not make sense, both grammatically and conceptually. What is the “value of enamel”?

Response 13: A sentence was added about the correlation between the hardness of the enamel and cementum as follows;

Yamaguchi et al. [39] demonstrated that a positive correlation between the respective hardness of the enamel and cementum in the humans (hardness: r=0.551, p<0.01, elastic modulus: r=0.552, P<0.01).

Section 7: “One of the explanations for these phenomena may be the resistance to cementum hardness. In other words, the amount of root resorption may be less in teeth with hard cementum exposed to heavy forces during treatment, leading to the production of large amounts of RANKL by the PDL cells or cementoblast. Alternatively, high rot re- sorption might occur in teeth with soft cementum exposed to light force with suppressed amounts of RANKL produced.”

Point 14:

This keeps being stated throughout this paper without sufficient evidence to tie these phenomenon together, apart from the few points described above.
Root, not rot

Cementoblasts- needs to be plural

Response 14-1: As you indicated, the description was revised.

14-2: As you advised, “rot” was corrected to “root”.

14-3: As you advised, “Cementoblasts” was corrected to plural.

Section 7: Despite the similarity in the amount of RANKL is produced, teeth with hard cementum might present with lesser root resorption than those with soft cementum.

Point 15:

This does not make sense. Where do you discuss similarity in RANKL production? Is it earlier in the paper? Again, we need more data in this review supporting this model and the inherent hypotheses.

Response 15: As you advised, there is a lack of proof in the literature, so future outlook was added.

Section 8: conclusion: This review attempts to demonstrate that the hardness and Ca/P ratio of the cementum might be involved in ORR caused by orthodontic forces.

Point 16:

Again, the review does not demonstrate that hardness and Ca/P ratio is involved in ORR. Yes, more work may need to be done in this field, but to review a literature, existing published works must be described that link ORR and Ca/P and hardness. This review does not appear to represent or describe a large enough body of existing literature on this topic to justify a review.
A more robust conclusion is required. What specific gaps do you see in the literature and what can researchers do to fill these gaps?

Response 16: As you advised, there is a lack of proof in the literature, so future outlook was added.

Minor Revisions

ORR is not an “accidental symptom;” it is an unintended side effect of treatment. A symptom is an effect that a patient will self-report; patients usually do not self-report their own root resorption.