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Cited by 27Bone Metabolism and DiseasesChemokine receptors and signalingRheumatoid Arthritis Research and Therapies

CXCR4+ CD45− cells are niche forming for osteoclastogenesis via the SDF-1, CXCL7, and CX3CL1 signaling pathways in bone marrow

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Goto, Yoh, Aoyama, Mineyoshi, Sekiya, Takeo, Kakita, Hiroki, Waguri-Nagaya, Yuko, Miyazawa, Ken, Asai, Kiyofumi, Goto, Shigemi·2016·Stem Cells
DOI 10.1002/stem.2440
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Abstract

Bone homeostasis comprises the balance between bone-forming osteoblasts and bone-resorbing osteoclasts (OCs), with an acceleration of osteoclastic bone resorption leading to osteoporosis. OCs can be generated from bone marrow cells (BMCs) under the tightly regulated local bone environment. However, it remained difficult to identify the critical cells responsible for providing an osteoclastogenesis niche. In this study, we used a fluorescence-activated cell sorting technique to determine the cell populations important for forming an appropriate microenvironment for osteoclastogenesis and to verify the associated interactions between osteoclast precursor cells and non-OCs. We isolated and removed a small cell population specific for osteoclastogenesis (CXCR4+ CD45−) from mouse BMCs and cultured the remaining cells with receptor activator of nuclear factor-kappa B ligand (RANKL) and macrophage-colony stimulating factor. The resulting cultures showed significantly less large osteoclast formation. Quantitative RT-PCR analysis revealed that these CXCR4+ CD45− cells expressed low levels of RANK and RANKL, but high levels of critical chemokines including stromal cell derived factor 1 (SDF-1), chemokine (C-X-C motif) ligand 7 (CXCL7), and chemokine (C-X3-C motif) ligand 1 (CX3CL1). Furthermore, an SDF-1-specific antibody strongly suppressed OC formation in RAW264.7 cells and antibodies against SDF-1, CXCL7, and CX3CL1 suppressed OC formation in BMCs. These results suggest that isolated CXCR4+ CD45− cells support an appropriate microenvironment for osteoclastogenesis with a direct effect on the cells expressing SDF-1, CXCL7, and CX3CL1 receptors. The regulation of CXCR4+ CD45− cell function might therefore inform therapeutic strategies for diseases involving loss of bone homeostasis.

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  • Circulating CXCR4-expressing HSCs are attracted to bone surfaces by gradients of SDF-1 (CXCL12) secreted by CXCR4+ CD45−, stromal, and endothelial marrow cells.

    “Circulating CXCR4-expressing HSCs are attracted to bone surfaces by gradients of SDF-1 (CXCL12) secreted by CXCR4+ CD45−, stromal, and endothelial marrow cells [14,17].”

    From Osteoclasts and Microgravity (2020) · cites this paper as [14]

    The Introduction says bone-marrow stromal cells secrete SDF-1 and attract CXCR4-positive cells along its concentration gradient. The section on chemokine expression reports SDF-1 in CXCR4-positive CD45-negative cells. Neither passage establishes that the attracted cells are circulating HSCs, that they move to bone surfaces, or that endothelial marrow cells secrete SDF-1. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • CXCR4+ CD45− cells support an appropriate microenvironment for osteoclastogenesis, with a direct effect on cells expressing SDF-1, CXCL7, and CX3CL1 receptors.

    “Their findings suggest that CXCR4+ CD45− cells support an appropriate microenvironment for osteoclastogenesis, with a direct effect on cells expressing SDF-1, CXCL7, and CX3CL1 receptors [14].”

    From Osteoclasts and Microgravity (2020) · cites this paper as [14]

    The Conclusion says CXCR4+ CD45− cells may form a niche that supports osteoclastogenesis, and the Discussion reports their release of SDF-1, CXCL7, and CX3CL1. The SDF-1/CXCR4 Signaling for OC Formation section reports effects of blocking these chemokines on osteoclast formation, but does not establish a direct effect of the CXCR4+ CD45− cells on cells shown to express all three corresponding receptors. No page numbers are available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • A small population of CXCR4+ CD45− bone marrow cells provides a niche for osteoclastogenesis.

    “Goto and associates have provided evidence that a small population of cysteine x cysteine receptor 4+ cluster of differentiation 45− (CXCR4+ CD45−) bone marrow cells provide a niche for osteoclastogenesis.”

    From Osteoclasts and Microgravity (2020) · cites this paper as [14]

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Authors
Goto, Y., Aoyama, M., Sekiya, T., Kakita, H., Waguri-Nagaya, Y., Miyazawa, K., Asai, K., & Goto, S.
Affiliations
  • Aichi Gakuin University (JP)
  • Nagoya City University (JP)
  • Aichi Medical University (JP)
  • Department of Joint Surgery for Rheumatic Diseases, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
Corresponding author
Aoyama, Mineyoshi
ORCID
Venue
Stem Cells
Publisher
Oxford University Press (OUP)
Published
2016-07-08
Volume
34
Issue
11
Pages
2733-2743
ISSN
  • 1066-5099 (ISSN-L)
  • 1549-4918
DOI
10.1002/stem.2440
OpenAlex
W2461879822
Cited by
27
References
1
Citations by year
2025: 3 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 1
FWCI
1.39
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Stem Cells (publishedVersion)
  • PubMed (publishedVersion)
Funders
KAKENHI (25461651, 23591509)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords
osteoclastogenesis, bone marrow microenvironment, CXCL12, CXCL7, fractalkine, chemokine signaling, bone homeostasis, osteoporosis, RANKL, RANK, osteoclast precursor cells, bone resorption
MeSH terms
Animals, Antibodies, Bone Marrow Cells, Cell Differentiation, Flow Cytometry, Gene Expression Regulation, Male, Osteoblasts, Osteoclasts, Osteogenesis, Tibia, Signal Transduction, Macrophage Colony-Stimulating Factor, Leukocyte Common Antigens, Receptors, CXCR4, Chemokines, CXC, Mice, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Chemokine CXCL12, Chemokine CX3CL1, Primary Cell Culture

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