Peer Review History

Original SubmissionJuly 8, 2021
Decision Letter - Subburaman Mohan, Editor

PONE-D-21-22335

Recovery of the maternal skeleton after lactation is impaired by advanced maternal age but not by reduced IGF availability in the mouse

PLOS ONE

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Subburaman Mohan

Academic Editor

PLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

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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5. Review Comments to the Author

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Reviewer #1: Authors have examined the effects of lactation on femoral trabecular and cortical bone. They evaluated the effects of breeding, timing (pre- and postweaning), aging (2, 5 and 7 months) and genotype (Pappako/ko vs. Pappafl/fl). Results clearly indicated a reduction of bone traits by lactation, but only cortical bone was recovered in 2 months aged mice. Pappa2 deletion, and the disturbance of IGF1 and IGFBP5, did not enhanced the reduction or blocked the recovery. However, aging (5 and 7 months) affects cortical bone recovery in bred mice.

A very interesting study that shows the role of lactation and after lactation (postweaning) on bone traits during aging. I have two questions about the rationale of the main results:

1. If I can understand, authors did not find impairments in cortical bone recovery of Pappa2 deletion mice at 2, 5 and 7 months old (genotype effect). But, I would like to know if authors found genotype*age interaction and single effects of Pappa2 deletion on bone traits at 2, 5 and 7 months in mice collected 3 weeks after weaning compared to the respective Pappa2 floxed control mice and AMC mice. Table 4 did not describe this important question.

2. The effects of breeding and recovery on bone traits were not associated with IGF1 impairments. However, could IGF1 impairment in Pappa2 ko mice be associated with changes in bone traits such as trabecular thickness and cortical area fraction?

Reviewer #2: The main goal of this study was to understand how age of pregnancy, lactation, and IGF-1 state affect bone. The authors used control and PAPPA2 KO dams at 2, 5, and 7 months of age and evaluated their femurs 3 weeks postpartum either with or without lactation period. Age matched virgin females were used as controls. The study included sufficient sample size, it was well designed and controlled for litter size of the lactating dams. Cortical and trabecular compartments of the femur were analyzed by mCT. Serum ELISA assays were used to determine the levels of IGF-1 and the IGFBP5.

The authors found that 2 months old dams recovered their cortical bone traits after lactation, independent of PAPPA2 state. Older dams (at 5 and 7 months old) were not able to recover cortical bone parameters. No changes were observed in trabecular bone of older dams, likely due to the low basal BV/TV% seen in that age.

Overall, the study is informative and has interesting implications to late pregnancies and breastfeeding in humans.

However, there are several concerns that need to be addressed:

1. The study lacks mechanistical outcome.

2. Justification of the skeletal site chosen for analysis; Loss of trabecular bone during pregnancy and lactation is often seen in the vertebral body. The trabecular bone at the femur distal metaphysis reduces dramatically between 2-4 months even in virgin mice.

3. Were calcium levels measured in serum/urine during pregnancy/lactation?

4. What is the predicted mechanism by which cortical bone area reduces after pregnancy/lactation? Endocortical resorption? Any evidence?

5. What is the predicted mechanism by which cortical bone area recovers? Periosteal/endosteal apposition?

6. Was the food intake and metabolic rate of the PAPPA2KO dams similar to that of controls?

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Reviewer #1: No

Reviewer #2: No

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Revision 1

Our letter responding to each point has been uploaded.

Attachments
Attachment
Submitted filename: Response to Reviewers.docx
Decision Letter - Subburaman Mohan, Editor

Recovery of the maternal skeleton after lactation is impaired by advanced maternal age but not by reduced IGF availability in the mouse

PONE-D-21-22335R1

Dear Dr. Christians,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Subburaman Mohan

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Formally Accepted
Acceptance Letter - Subburaman Mohan, Editor

PONE-D-21-22335R1

Recovery of the maternal skeleton after lactation is impaired by advanced maternal age but not by reduced IGF availability in the mouse

Dear Dr. Christians:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Subburaman Mohan

Academic Editor

PLOS ONE

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