The Role of Proteasome Inhibitors in Multiple Myeloma Bone Disease and Bone Metastasis: Effects on Osteoblasts and Osteocytes
Round 1
Reviewer 1 Report
The authors gave a nice review of bone remodeling, the role of proteasomes in treatments of certain bone diseases, especially in MM, and proposed the need for bone-targeted proteasome therapy for bone diseases.
Overall, the authors gave a relatively comprehensive review, with some minor suggestions or improvement:
1, Title: since these proteasome inhibitors are mostly used in MM or cancer metathesis to the bone, and not on bone "regeneration", the title shall be revised accordingly.
2, review on bone remodeling: although this information is generally true, the contents did not brend in the rest of the reviews. Perhaps should be removed.
3, please add potential short-comings or side effects for PIs in the bone or other systems to bring in the necessarily of targeted PIs
Author Response
Reviewer 1
The authors gave a nice review of bone remodeling, the role of proteasomes in treatments of certain bone diseases, especially in MM, and proposed the need for bone-targeted proteasome therapy for bone diseases.
Overall, the authors gave a relatively comprehensive review, with some minor suggestions or improvement:
1, Title: since these proteasome inhibitors are mostly used in MM or cancer metathesis to the bone, and not on bone "regeneration", the title shall be revised accordingly.
Response: All authors greatly appreciate the positive commentary on our study, and we thank the reviewer for all the suggestions. The title has been revised. The new title is: “The Role of Proteasome Inhibitors in Multiple Myeloma bone disease and Bone Metastasis: Effects on Osteoblasts and Osteocytes”.
2, review on bone remodeling: although this information is generally true, the contents did not brend in the rest of the reviews. Perhaps should be removed.
Response: We believe that the brief description of the bone remodeling phases and the main cell types involved in this process may help the readers to understand the pre-clinical data reported in the subsequent sections.
3, please add potential short-comings or side effects for PIs in the bone or other systems to bring in the necessarily of targeted PIs
Response: We added the section “Side effects of PIs and future perspective” (page 11, chapter 9) where we briefly described the side effects of PIs and the alternative approaches to selectively delivering PIs into the bone. We cited the latest papers exploring the use of bortezomib and bisphosphonate complex for the local delivery of bortezomib as well as implant coatings, scaffolds, or particle-based materials to enhance bone healing.
Reviewer 2 Report
This research is under the scope of this journal; the topic is interesting for readers and this research deals with potentially significant knowledge to the field.
However, there are some concerns about the present manuscript:
- Minor English spelling erros -
(Abstract) The abstract doesn’t respect the journal’s recommendations. I ask the authors to take advantage of the 200 words available and do an abstract with the required topics.
(Keywords) Please order the keywords alphabetically
(2. Bone remodeling) In the first line, please replace “allow” by “allows”.
(2. Bone remodeling) In line 6, replace “distinguished “ by “distinguish”
(2. Bone remodeling) At the end of the second paragraph, replace “In human“ by “In humans”
(2. Bone remodeling) At the end of the second paragraph, replace “In human“ by “In humans”
These types of small mistakes continue throughout the paper. I would ask the authors to please ask a native speaker to review the paper.
(Review methodology) I believe that, although this is a narrative review, authors should clearly describe the research methodology they used, with which databases were used, research terms and inclusion and exclusion criteria.
(Review methodology) Authors should consider adding a results section for the research methodology and more clearly divide the paper in terms of introduction and discussion.
(Conclusion) Authors seem to have used citations in the conclusions. This is not customary and I would ask the authors to reshape the conclusion to better fit a conclusion from a review paper.
(Conclusion) Only 22% of the literature used by the authors has been published in the last 5 years. I suggest the addition of some more recent references that exist on the topic of bone regeneration.
Some successful recent papers have been published in the last 5 years, which are absent from this review. A clear example of this is, for example, the most accessed paper in an MDPI hournal in 2021 is a paper on the bone regeneration topic, which I advise the authors to cite.
Falacho, R.I.; Palma, P.J.; Marques, J.A.; Figueiredo, M.H.; Caramelo, F.; Dias, I.; Viegas, C.; Guerra, F. Collagenated Porcine Heterologous Bone Grafts: Histomorphometric Evaluation of Bone Formation Using Different Physical Forms in a Rabbit Cancellous Bone Model. Molecules 2021, 26, 1339. https://doi.org/10.3390/molecules26051339
Some others should also be considered.
(Overall) Although the content of the paper seems adequate and presenting a high level of expertise, in terms of form this is not at all adequate for a paper. It almost seems like an introduction from an old-fashioned thesis work. Therefore, my recommendation is that authors do a complete reformulation of the paper’s format and maintain the content, but re-distribute it according to what is required in a proper review.
Author Response
Reviewer 2
This research is under the scope of this journal; the topic is interesting for readers and this research deals with potentially significant knowledge to the field.
However, there are some concerns about the present manuscript:
Minor English spelling erros -
(Abstract) The abstract doesn’t respect the journal’s recommendations. I ask the authors to take advantage of the 200 words available and do an abstract with the required topics.
(Keywords) Please order the keywords alphabetically
(2. Bone remodeling) In the first line, please replace “allow” by “allows”.
(2. Bone remodeling) In line 6, replace “distinguished “ by “distinguish”
(2. Bone remodeling) At the end of the second paragraph, replace “In human“ by “In humans”
These types of small mistakes continue throughout the paper. I would ask the authors to please ask a native speaker to review the paper.
Response: All authors greatly appreciate the positive commentary on our study, and we thank the reviewer for all the suggestions. The abstract has been reworded and adapted to the journal’s recommendations (page 1).
All the spelling errors have been corrected throughout the paper.
(Review methodology) I believe that, although this is a narrative review, authors should clearly describe the research methodology they used, with which databases were used, research terms and inclusion and exclusion criteria.
Response: The section “Methods and results” has been added after the introduction to better explain the type of literature search we performed. In this section we described the research methodology, databases, research terms, inclusion and exclusion criteria (page 2, chapter 2).
(Review methodology) Authors should consider adding a results section for the research methodology and more clearly divide the paper in terms of introduction and discussion.
Response: As mentioned above, we added s “Methods and results” section after the introduction. Since this is not a systematic review, we believe that the original organization of the paper fits with the journal’s recommendations. For this reason, we opted to keep all the sections of the manuscript. We also added a section of side effects and future perspective as suggested by the Reviewer 1.
(Conclusion) Authors seem to have used citations in the conclusions. This is not customary and I would ask the authors to reshape the conclusion to better fit a conclusion from a review paper.
Response: We reshaped the conclusion. Now the section has no citations (pages 11 and 12).
(Conclusion) Only 22% of the literature used by the authors has been published in the last 5 years. I suggest the addition of some more recent references that exist on the topic of bone regeneration.
Response: Thank you very much for your suggestion. We added some recent papers. Below you can find some examples:
Donsante, S.; Palmisano, B.; Serafini, M.; Robey, P.G.; Corsi, A.; Riminucci, M. From Stem Cells to Bone-Forming Cells. International journal of molecular sciences 2021.
Baek, D.; Park, K.H.; Lee, K.M.; Jung, S.; Joung, S.; Kim, J.; Lee, J.W. Ubiquitin-specific protease 53 promotes osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. Cell death & disease 2021.
Russow, G.; Jahn, D.; Appelt, J.; Mardian, S.; Tsitsilonis, S.; Keller, J. Anabolic Therapies in Osteoporosis and Bone Regeneration. International journal of molecular sciences.
Rothe, R.; Hauser, S.; Neuber, C.; Laube, M.; Schulze, S.; Rammelt, S.; Pietzsch, J. Adjuvant Drug-Assisted Bone Healing: Advances and Challenges in Drug Delivery Approaches. Pharmaceutics 2020.
Falacho, R.I.; Palma, P.J.; Marques, J.A.; Figueiredo, M.H.; Caramelo, F.; Dias, I.; Viegas, C.; Guerra, F. Collagenated Porcine Heterologous Bone Grafts: Histomorphometric Evaluation of Bone Formation Using Different Physical Forms in a Rabbit Cancellous Bone Model. Molecules 2021.
Wang, M.; Park, S.; Nam, Y.; Nielsen, J.; Low, S.A.; Srinivasarao, M.; Low, P.S. Bone-Fracture-Targeted Dasatinib-Oligoaspartic Acid Conjugate Potently Accelerates Fracture Repair. Bioconjugate chemistry 2018.
Kolk, A.; Tischer, T.; Koch, C.; Vogt, S.; Haller, B.; Smeets, R.; Kreutzer, K.; Plank, C.; Bissinger, O. A novel nonviral gene delivery tool of BMP-2 for the reconstitution of critical-size bone defects in rats. Journal of biomedical materials research. Part A 2016.
Some less recent references are necessary to better describe the original data on the role of proteasome on bone formation. Since this is a literature review, we believe that the citation of the original papers may be useful for the readers to better understand the data. Moreover, the description of specific drugs and their first characterization necessary rely on pioneer papers that must be cited.
Some successful recent papers have been published in the last 5 years, which are absent from this review. A clear example of this is, for example, the most accessed paper in an MDPI hournal in 2021 is a paper on the bone regeneration topic, which I advise the authors to cite.
Falacho, R.I.; Palma, P.J.; Marques, J.A.; Figueiredo, M.H.; Caramelo, F.; Dias, I.; Viegas, C.; Guerra, F. Collagenated Porcine Heterologous Bone Grafts: Histomorphometric Evaluation of Bone Formation Using Different Physical Forms in a Rabbit Cancellous Bone Model. Molecules 2021, 26, 1339. https://doi.org/10.3390/molecules26051339
Some others should also be considered.
Response: Thank you very much for your suggestion. The reference mentioned in your comment has been added.
(Overall) Although the content of the paper seems adequate and presenting a high level of expertise, in terms of form this is not at all adequate for a paper. It almost seems like an introduction from an old-fashioned thesis work. Therefore, my recommendation is that authors do a complete reformulation of the paper’s format and maintain the content, but re-distribute it according to what is required in a proper review.
Response: We thank the reviewer. As reported above, we reworded the abstract according to the journal’s guidelines, Moreover, we added a “Methods and results” section and some recent references. Since this is not a systematic review, we kept the general organization of the paper following the specific guidelines of the journal. We believe that organizing the paper in different chapters may provide a better overview on the effects of proteasome inhibitors on bone remodeling alterations.
Round 2
Reviewer 2 Report
I thank the authors for the prompt response and for the changes.
I believe the paper can now be published.
