PONE-D-24-08664Osteoporosis induced by cellular senescence: A mathematical modelPLOS ONE

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: This is an interesting mathematical modeling study on age-related bone loss and the role of senescent cells. There are clearly some broad assumptions made in Figure 1, but probably these are reasonable and the resulting models do seem to fit empirical data.

I don't really have expertise to evaluate the mathematics underlying the models.

However, from a biological perspective - in the abstract and throughout the paper - the authors refer to the "proliferation rate" of senescent cells. Note that part of the definition of a senescent cell is growth arrest. These cells are likley being formed and potentially being eliminated at variable rates by the immune system, with a net accrual as people age. So instead of proliferation rate, do the authors mean net formation rate (or something along those lines?) Using "proliferation rate" is not correct in this context.

A second point on page 3 is that it is unclear what the authors mean by deficiency of androgen receptors leading to estrogen deficiency. Note also that most evidence now indicates that the majority of the skeletal effects of androgens even in men are mediated via conversion to estrogen and via the estrogen receptor (for a review, see PMID: 28710257). They should perhaps factor this into their models.

Reviewer #2: This is a very interesting paper. Authors attempted to consider positive and negative factors of bone formation and osteoporosis as well as cell senescence using mathematical modeling methods. The results were able to predict bone loss according to aging as well as benefit of the senolytic drug. However, I think the paper sections need to be reorganized according to Journal format. Some of the introduction parts can be moved to “methods and modeling” section. Figure 1 should be in modeling section and served as hypothesis of the mathematic modeling. The conclusion read like discussion. Authors should consider adding a discussion section and only put the summary of this paper as a conclusion.

Following some comments that need to be revised.

1. Table 6 can be moved to the methods section and show earlier so that the readers know what each variable represents in the equation.

2. Page 2, paragraph 4 “Senescence mesenchymal stem cell (MSC) derived exosomal microRNAs, include miRNA-34 [10–12] and miRNA-183-5p [10, 13, 14].” This sentence read like not a complete sentence.

3. Page 2: Check this sentence for accuracy “Immature MSCs are derived from bone marrow and their recruitment is enhanced by TGF-β [15]”.

4. “The stability of the bone depends on the relative concentration of three proteins: RANK, RANKL and OPG. This statement appears not correct. Maybe “Bone remodeling depends….”. This needs a citation. These three factors regulate osteoclastogenesis or bone resorption.

5. In term of the effect of fisetin on cell senescent and bone loss, reference 53 did not show fisetin had beneficial effects on bone loss of Z24 Progeria mice despite others showed it could decrease senescent cells in other model of progeria mice or normal aging mice (reference 57). So it maybe not be appropriate to use reference 53 as guidance for the mathematic modeling of fisetin.

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Reviewer #1: Yes: Sundeep Khosla

Reviewer #2: No

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Osteoporosis induced by cellular senescence: A mathematical model

PONE-D-24-08664R1

Dear Dr.Siewe,

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Kind regards,

Gary S. Stein

Academic Editor

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