Calcified Tissue International

, Volume 105, Issue 4, pp 430–445 | Cite as

Coordination of Fusion and Trafficking of Pre-osteoclasts at the Marrow–Bone Interface

  • Kent SøeEmail author
  • Thomas Levin AndersenEmail author
  • Maja Hinge
  • Lars Rolighed
  • Niels Marcussen
  • Jean-Marie Delaisse
Original Research


Fusion is the final osteoclast differentiation step leading to bone resorption. In healthy trabecular bone, osteoclast fusion is restricted to bone surfaces undergoing resorption, and necessarily requires site-specific recruitment of mononucleated pre-osteoclasts originating from the bone marrow. However, the spatiotemporal mechanism coordinating recruitment and fusion is poorly investigated. Herein we identify a collagen/vascular network as a likely structure supporting this mechanism. We therefore used multiplex immunohistochemistry and electron microscopy on human iliac crest bone samples, in combination with functional assays performed in vitro with osteoclasts generated from healthy blood donors. First, we found that putative pre-osteoclasts are in close vicinity of a network of collagen fibers associated with vessels and bone remodeling compartment canopies. Based on 3D-reconstructions of serial sections, we propose that this network may serve as roads leading pre-osteoclasts to resorption sites, as reported for cell migration in other tissues. Importantly, almost all these bone marrow pre-osteoclasts, but only some osteoclasts, express the collagen receptor OSCAR, which is reported to induce fusion competence. Furthermore, differentiating osteoclasts cultured on collagen compared to mineral show higher fusion rates, higher expression of fusogenic cytokines, and a CD47 plasma membrane distribution pattern reported to be typical of a pre-fusion state—thus collectively supporting collagen-induced fusion competence. Finally, these in vitro assays show that collagen induces high cell mobility. The present data lead to a model where collagen fibers/vasculature support the coordination between traffic and fusion of pre-osteoclasts, by serving as a physical road and inducing fusion competence as well as cell mobility.


Collagen Osteoclasts Fusion Recruitment OSCAR 



We wish to thank Jacob Bastholm Olesen, Birgit MacDonald, Kaja Søndergaard Laursen, Karin Trampedach, and Vibeke Nielsen for their excellent technical assistance. This study was financed through general funding by Lillebaelt Hospital, Aarhus University Hospital, and Odense University Hospital.

Author Contributions

Designing research study: KS, TLA, and JMD; conducting experiments: KS and TLA; acquiring data: KS, TLA, MH, LR, and NM; analyzing data: KS, TLA, and JMD; writing the manuscript: KS, TLA, and JMD; editing and correcting the manuscript: KS, TLA, MH, LR, NM, and JMD; final approval of manuscript: KS, TLA, MH, LR, NM, and JMD.

Compliance with Ethical Standards

Conflict of interest

Kent Søe, Thomas Levin Andersen, Maja Hinge, Lars Rolighed, Niels Marcussen, and Jean-Marie Delaisse declare that they have no conflict of interests.

Human and Animal Rights and Informed Consent

All procedurse performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (The Scientific Eithical Committee for the Region of Southern Denmark S-20070121 and S20070019) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

223_2019_575_MOESM1_ESM.mp4 (1021 kb)
Supplementary material 1 (MP4 1021 kb)
223_2019_575_MOESM2_ESM.docx (2.3 mb)
Supplementary material 2 (DOCX 2380 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Clinical Cell Biology, Department of Regional Health Research, Vejle Hospital – Lillebaelt HospitalUniversity of Southern DenmarkVejleDenmark
  2. 2.Department of Internal Medicine, Section of HematologyVejle Hospital – Lillebaelt HospitalVejleDenmark
  3. 3.Breast and Endocrine Section, Department of SurgeryAarhus University HospitalAarhus NDenmark
  4. 4.Department of PathologyOdense University HospitalOdenseDenmark
  5. 5.Clinical Cell Biology, Department of Pathology, Odense University Hospital – Department of Clinical ResearchUniversity of Southern DenmarkOdense CDenmark

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