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 PTPepsilon-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.

Alteration of Dickkopf-1 and receptor activator of nuclear factor-κB ligand during PBSC mobilization in healthy donors by G-CSF

“…Recombinant RANKL has been shown to mobilize HSCs in a mouse model. 2 In the present study, we showed that G-CSF induced the expression of plasma sRANKL in healthy donors. This result suggests that G-CSF-induced osteoclastogenesis is involved in the mobilization of PBSCs.…”

“…Further, osteoclasts have a critical role in the mobilization of peripheral HSCs. 2 Although the mechanism by which G-CSF mobilizes PBSCs has been extensively studied, it is still not fully understood. Wnt signaling has been shown to have a central role in the development and homeostasis of bone and also has been implicated in the regulation of hematopoiesis.…”

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

“…Notably, caveolin expression on BM cells is upregulated after ischemia, resulting in a transient CXCR4 sequestration and SDF-1-induced BM cell mobilization [38]. Activation of osteoclasts and cathepsins has also been implicated in the mobilization of the hematopoietic and endothelial progenitor cells [39,40]. Finally, additional molecules such as extracellular matrix (ECM) compounds, matrix degradation products and activated complement proteins have crucial roles in priming CXCR4 + cells and modulating the amplitude of SDF-1 signals [41][42][43].…”

Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization

“…Kollet et al 14 reported that activation of osteoclasts by injection of RANK ligand was associated with moderate HSPC mobilization. Conversely, inhibition of osteoclasts, either genetically by knocking out PTPe or by injecting mice with calcitonin, blunts the mobilization response to G-CSF.…”