Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

  1. Gustavo A Gomez
  2. Charles H Rundle
  3. Weirong Xing
  4. Chandrasekhar Kesavan
  5. Sheila Pourteymoor
  6. Robert E Lewis
  7. David R Powell
  8. Subburaman Mohan  Is a corresponding author
  1. VA Loma Linda Healthcare System, United States
  2. Loma Linda University Medical Center, United States
  3. University of Nebraska Medical Center, United States
  4. Lexicon Pharmaceuticals, United States

Peer review process

This article was accepted for publication as part of eLife's original publishing model.

History

  1. Version of Record published
  2. Accepted
  3. Preprint posted
  4. Received

Decision letter

  1. Mone Zaidi
    Senior and Reviewing Editor; Icahn School of Medicine at Mount Sinai, United States

Our editorial process produces two outputs: (i) public reviews designed to be posted alongside the preprint for the benefit of readers; (ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.

Decision letter after peer review:

Thank you for submitting your article "Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity" for consideration by eLife. Your article has been reviewed by 2 peer reviewers, one of whom is a member of our Board of Reviewing Editors, and the evaluation has been overseen by Mone Zaidi as the Senior Editor. The reviewers have opted to remain anonymous.

Essential revisions:

1) The paper clearly shows evidence for KSR2 regulation of mTOR signaling. However, one question that is not addressed relates to how a scaffolding protein such as KSR2 regulates mTOR signaling. Please address the potential connection between KSR2 and mTOR.

2) Serum assays of bone turnover markers were done using serum from 6-month-old mice that reveal no differences. Are there measurements of serum bone formation markers in younger mice?

3) The paper proposes an interesting mechanism involving adipsin for KSR2 regulation of marrow adipose tissue. Are there other candidates that could be involved?

4) If there are data, the inclusion of circulating serum markers like the adiponectin data would be interesting. Similarly, any ex vivo experiments from the conditional knock out which presumably does not have the same serum marker changes would be interesting to include and discuss, if available.

Reviewer #1 (Recommendations for the authors):

1) The authors clearly show evidence for KSR2 regulation of mTOR signaling. However, one question that is not addressed relates to how a scaffolding protein such as KSR2 regulates mTOR signaling. The authors should address the potential connection between KSR2 and mTOR.

2) Serum assays of bone turnover markers were done using serum from 6-month-old mice that reveal no differences. Have the authors measured serum bone formation markers in younger mice?

3) The authors propose an interesting mechanism involving adipsin for KSR2 regulation of marrow adipose tissue. Are there other candidates that could be involved?

https://doi.org/10.7554/eLife.82810.sa1

Author response

Essential revisions:

1) The paper clearly shows evidence for KSR2 regulation of mTOR signaling. However, one question that is not addressed relates to how a scaffolding protein such as KSR2 regulates mTOR signaling. Please address the potential connection between KSR2 and mTOR.

Studies have shown that KSR2 is a scaffold protein that interact with RAF and MEK to facilitate activation of the ERK/MAPK module (PMID:11850406). In addition, a recent study demonstrated that KSR1 and KSR2 when expressed at high levels can activate the MAPK pathway-independently of RAS (PMID:35313064). Based on the published data that ERK effects on osteoblasts is mediated via mTOR signaling (PMID:35975983), it is possible that KSR2 effects on bone are via MAPK mediated regulation of mTOR signaling. Our future studies will investigate this possibility.

2) Serum assays of bone turnover markers were done using serum from 6-month-old mice that reveal no differences. Are there measurements of serum bone formation markers in younger mice?

We agree, given that serum of younger mice is more relevant to the data presented, we obtained measurements from mice at 8 weeks and reported the relevant data in place of that from 6-month-old mice in the manuscript. Our new data show that serum levels of P1NP (bone formation marker) was increased while that of CTX (bone resorption marker) was unchanged in the Ksr2 knock out mice. The corresponding text was modified.

3) The paper proposes an interesting mechanism involving adipsin for KSR2 regulation of marrow adipose tissue. Are there other candidates that could be involved?

Definitely. We focused our attention on adipsin because the recent publication clearly shows it has a convincing effect on regulating bone marrow stem cell fate towards adipocytes at the expense of osteoblasts. The bone marrow stem cell fate decision is regulated by multiple factors including many known, and potentially unknown, growth factors and hormones (PMID:26868907). Interestingly, nonendocrinological neural regulation mechanisms also contribute to marrow adipose tissue formation (PMID:33766429). Also, factors secreted by osteoblasts such as Osteopontin have been shown to locally regulate bone marrow adipose tissue (PMID:24123709). Therefore, KSR2 might modulate bone marrow stem cell fate by regulation of adipsin expression, as well as the response to signaling by other factors, which await further investigation.

4) If there are data, the inclusion of circulating serum markers like the adiponectin data would be interesting. Similarly, any ex vivo experiments from the conditional knock out which presumably does not have the same serum marker changes would be interesting to include and discuss, if available.

Thank you for this suggestion. Unfortunately, we do not have any serum left to perform additional measurements on adipocyte markers and it will take considerable amount of time to generate additional mice needed for this work. We are in the process of generating additional mice to address further questions on how KSR2 regulates the fate of bone marrow stem cells towards adipocytes/osteoblasts and we hope to include serum measurements of adipocyte markers during the course of these investigations.

https://doi.org/10.7554/eLife.82810.sa2

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  1. Gustavo A Gomez
  2. Charles H Rundle
  3. Weirong Xing
  4. Chandrasekhar Kesavan
  5. Sheila Pourteymoor
  6. Robert E Lewis
  7. David R Powell
  8. Subburaman Mohan
(2022)
Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity
eLife 11:e82810.
https://doi.org/10.7554/eLife.82810

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https://doi.org/10.7554/eLife.82810