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Osteoclasts Derive Predominantly from Bone Marrow–Resident CX3CR1+ Precursor Cells in Homeostasis, whereas Circulating CX3CR1+ Cells Contribute to Osteoclast Development during Fracture Repair

Sanja Novak, Emilie Roeder, Judith Kalinowski, Sandra Jastrzebski, Hector L. Aguila, Sun-Kyeong Lee, Ivo Kalajzic and Joseph A. Lorenzo
J Immunol February 15, 2020, 204 (4) 868-878; DOI: https://doi.org/10.4049/jimmunol.1900665
Sanja Novak
*Department of Reconstructive Sciences, UConn Health, Farmington, CT 06030;
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Emilie Roeder
*Department of Reconstructive Sciences, UConn Health, Farmington, CT 06030;
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Judith Kalinowski
†Department of Medicine, UConn Health, Farmington, CT 06030;
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Sandra Jastrzebski
†Department of Medicine, UConn Health, Farmington, CT 06030;
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Hector L. Aguila
‡Department of Immunology, UConn Health, Farmington, CT 06030;
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Sun-Kyeong Lee
§University of Connecticut Center on Aging, UConn Health, Farmington, CT 06030; and
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Ivo Kalajzic
*Department of Reconstructive Sciences, UConn Health, Farmington, CT 06030;
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Joseph A. Lorenzo
†Department of Medicine, UConn Health, Farmington, CT 06030;
¶Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030
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Key Points

  • OCP express CX3CR1 and, in unperturbed conditions, differentiate into osteoclasts.

  • The contribution of circulating CX3CR1+ OCP to OC development is low during homeostasis.

  • Mature OC can originate from circulating CX3CR1+ cells during fracture repair.

Abstract

Osteoclasts (OC) originate from either bone marrow (BM)–resident or circulating myeloid OC progenitors (OCP) expressing the receptor CX3CR1. Multiple lines of evidence argue that OCP in homeostasis and inflammation differ. We investigated the relative contributions of BM-resident and circulating OCP to osteoclastogenesis during homeostasis and fracture repair. Using CX3CR1-EGFP/TRAP tdTomato mice, we found CX3CR1 expression in mononuclear cells, but not in multinucleated TRAP+ OC. However, CX3CR1-expressing cells generated TRAP+ OC on bone within 5 d in CX3CR1CreERT2/Ai14 tdTomato reporter mice. To define the role that circulating cells play in osteoclastogenesis during homeostasis, we parabiosed TRAP tdTomato mice (CD45.2) on a C57BL/6 background with wild-type (WT) mice (CD45.1). Flow cytometry (CD45.1/45.2) demonstrated abundant blood cell mixing between parabionts after 2 wk. At 4 wk, there were numerous tdTomato+ OC in the femurs of TRAP tdTomato mice but almost none in WT mice. Similarly, cultured BM stimulated to form OC demonstrated multiple fluorescent OC in cell cultures from TRAP tdTomato mice, but not from WT mice. Finally, flow cytometry confirmed low-level engraftment of BM cells between parabionts but significant engraftment in the spleens. In contrast, during fracture repair, we found that circulating CX3CR1+ cells migrated to bone, lost expression of CX3CR1, and became OC. These data demonstrate that OCP, but not mature OC, express CX3CR1 during both homeostasis and fracture repair. We conclude that, in homeostasis mature OC derive predominantly from BM-resident OCP, whereas during fracture repair, circulating CX3CR1+ cells can become OC.

This article is featured in In This Issue, p.731

Footnotes

  • This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Award R01 AR048714 to J.A.L. and Awards AR055607 and AR070813 to I.K.

  • Abbreviations used in this article:

    BM
    bone marrow
    BMM
    BM macrophage/monocyte
    OC
    osteoclast
    OCP
    OC progenitor
    WT
    wild-type.

  • Received June 13, 2019.
  • Accepted December 12, 2019.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 204 (4)
The Journal of Immunology
Vol. 204, Issue 4
15 Feb 2020
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Osteoclasts Derive Predominantly from Bone Marrow–Resident CX3CR1+ Precursor Cells in Homeostasis, whereas Circulating CX3CR1+ Cells Contribute to Osteoclast Development during Fracture Repair
Sanja Novak, Emilie Roeder, Judith Kalinowski, Sandra Jastrzebski, Hector L. Aguila, Sun-Kyeong Lee, Ivo Kalajzic, Joseph A. Lorenzo
The Journal of Immunology February 15, 2020, 204 (4) 868-878; DOI: 10.4049/jimmunol.1900665

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Osteoclasts Derive Predominantly from Bone Marrow–Resident CX3CR1+ Precursor Cells in Homeostasis, whereas Circulating CX3CR1+ Cells Contribute to Osteoclast Development during Fracture Repair
Sanja Novak, Emilie Roeder, Judith Kalinowski, Sandra Jastrzebski, Hector L. Aguila, Sun-Kyeong Lee, Ivo Kalajzic, Joseph A. Lorenzo
The Journal of Immunology February 15, 2020, 204 (4) 868-878; DOI: 10.4049/jimmunol.1900665
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