Csf1 from marrow adipogenic precursors is required for osteoclast formation and hematopoiesis in bone

  1. Leilei Zhong
  2. Jiawei Lu
  3. Jiankang Fang
  4. Lutian Yao
  5. Wei Yu
  6. Tao Gui
  7. Michael Duffy
  8. Nicholas Holdreith
  9. Catherine Bautista
  10. Xiaobin Huang
  11. Shovik Bandyopadhyay
  12. Kai Tan
  13. Chider Chen
  14. Yongwon Choi
  15. Jean X Jiang
  16. Shuying Yang
  17. Wei Tong
  18. Nathanial Dyment
  19. Ling Qin  Is a corresponding author
  1. University of Pennsylvania, United States
  2. Children's Hospital of Philadelphia, United States
  3. The University of Texas Health Science Center at San Antonio, United States

Abstract

Colony stimulating factor 1 (Csf1) is an essential growth factor for osteoclast progenitors and an important regulator for bone resorption. It remains elusive which mesenchymal cells synthesize Csf1 to stimulate osteoclastogenesis. We recently identified a novel mesenchymal cell population, marrow adipogenic lineage precursors (MALPs), in bone. Compared to other mesenchymal subpopulations, MALPs expressed Csf1 at a much higher level and this expression was further increased during aging. To investigate its role, we constructed MALP-deficient Csf1 CKO mice using AdipoqCre. These mice had increased femoral trabecular bone mass, but their cortical bone appeared normal. In comparison, depletion of Csf1 in the entire mesenchymal lineage using Prrx1Cre led to a more striking high bone mass phenotype, suggesting that additional mesenchymal subpopulations secrete Csf1. TRAP staining revealed diminished osteoclasts in the femoral secondary spongiosa region of Csf1 CKOAdipoq mice, but not at the chondral-osseous junction nor at the endosteal surface of cortical bone. Moreover, Csf1 CKOAdipoq mice were resistant to LPS-induced calvarial osteolysis. Bone marrow cellularity, hematopoietic progenitors, and macrophages were also reduced in these mice. Taken together, our studies demonstrate that MALPs synthesize Csf1 to control bone remodeling and hematopoiesis.

Data availability

Pre-aligned scRNA-seq matrix files were acquired from previously published dataset GEO GSE145477 and snRNA-seq matrix files were from GSE176171 (mouse), human scRNA-seq matrix files were acquired from EMBL-EBI E-MTAB-9139 (human).All data are available as source data files with submission.

The following previously published data sets were used

Article and author information

Author details

  1. Leilei Zhong

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  2. Jiawei Lu

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  3. Jiankang Fang

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  4. Lutian Yao

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  5. Wei Yu

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  6. Tao Gui

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  7. Michael Duffy

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  8. Nicholas Holdreith

    Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    No competing interests declared.
  9. Catherine Bautista

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  10. Xiaobin Huang

    Department of Oral and Maxillofacial Surgery/Pharmacology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  11. Shovik Bandyopadhyay

    Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    No competing interests declared.
  12. Kai Tan

    Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    No competing interests declared.
  13. Chider Chen

    Department of Oral and Maxillofacial Surgery/Pharmacology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2899-1208
  14. Yongwon Choi

    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  15. Jean X Jiang

    Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    Jean X Jiang, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2185-5716
  16. Shuying Yang

    Department of Oral and Maxillofacial Surgery/Pharmacology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7126-6901
  17. Wei Tong

    Department of Pediatrics, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  18. Nathanial Dyment

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8708-112X
  19. Ling Qin

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    For correspondence
    qinling@pennmedicine.upenn.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2582-0078

Funding

National Institute on Aging (R01AG069401)

  • Ling Qin

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR078650)

  • Ling Qin

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R00AR067283)

  • Nathanial Dyment

National Institute on Aging (R01AG045040)

  • Jean X Jiang

Welch Foundation (AQ-1507)

  • Jean X Jiang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal work performed in this report was approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Pennsylvania under Protocol 806887. University Laboratory Animal Resources (ULAR) of the University of Pennsylvania is responsible for the procurement, care, and use of all university-owned animals as approved by IACUC. Animal facilities in the University of Pennsylvania meet federal, state, and local guidelines for laboratory animal care and are accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International.

Copyright

© 2023, Zhong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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https://doi.org/10.7554/eLife.82112

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