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Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells

Abstract

Here we investigated the potential role of bone-resorbing osteoclasts in homeostasis and stress-induced mobilization of hematopoietic progenitors. Different stress situations induced activity of osteoclasts (OCLs) along the stem cell–rich endosteum region of bone, secretion of proteolytic enzymes and mobilization of progenitors. Specific stimulation of OCLs with RANKL recruited mainly immature progenitors to the circulation in a CXCR4- and MMP-9–dependent manner; however, RANKL did not induce mobilization in young female PTPε-knockout mice with defective OCL bone adhesion and resorption. Inhibition of OCLs with calcitonin reduced progenitor egress in homeostasis, G-CSF mobilization and stress situations. RANKL-stimulated bone-resorbing OCLs also reduced the stem cell niche components SDF-1, stem cell factor (SCF) and osteopontin along the endosteum, which was associated with progenitor mobilization. Finally, the major bone-resorbing proteinase, cathepsin K, also cleaved SDF-1 and SCF. Our findings indicate involvement of OCLs in selective progenitor recruitment as part of homeostasis and host defense, linking bone remodeling with regulation of hematopoiesis.

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Figure 1: Bleeding and LPS trigger mobilization of progenitors and formation of OCLs.
Figure 2: SDF-1 and HGF induce formation of TRAP+ OCLs and mobilization of progenitors.
Figure 3: RANKL-mediated mobilization of progenitors.
Figure 4: Mechanisms of mobilization induced by bone-resorbing OCLs.
Figure 5: CTK cleaves SDF-1.
Figure 6: A proposed model for the role of bone-resorbing OCLs in stress-induced stem cell mobilization.

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Acknowledgements

The author extend a special thanks to A. Globerson, D. Zipori, R. Alon and S. Yung for critically reviewing the manuscript and to D. Rashkovan for her assistance. This work was supported in part by the Israel Science Foundation (to T.L. and O.K.) and Ares Serono (to T.L.). T.L. holds The Edith Arnoff Stein Professorial Chair in Stem Cell Research.

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Kollet, O., Dar, A., Shivtiel, S. et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med 12, 657–664 (2006). https://doi.org/10.1038/nm1417

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