Kollet O, Dar A, Shivtiel S, Kalinkovich A, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med 2006;12:657-64.

Harvesting adequate numbers of mobilized hematopoietic progenitor cells from the blood of patients or donors is the start point for successful hematopoietic cell transplantation. Strategies that increase the cell yield have significant appeal for transplantation. Osteoclasts, themselves derived from hematopoietic stem cells, carve out the marrow space on the endosteal bone region, the niche where hematopoietic stem cells reside. They have long been considered bystanders, not active participants in hematopoietic progenitor cell circulation. In this paper, Kollet et al. link bone remolding with regulation of hematopoiesis and provide evidence that osteoclasts can mediate hematopoietic progenitor cell recruitment into the circulation.

 Following stress-induced situations of bleeding and treatment with lipopolysacchride (LPS), Kollet and colleagues report an increase in osteoclast number and development in endosteal niches in association with mobilization of hematopoietic progenitor cells. The in vivo administration of RANK ligand (RANKL), the osteoclast-differentiating cytokine critical for osteoclastogenesis produced by osteoblasts and thought to link bone production with destruction for balanced skeletal remodeling, was accompanied by increased levels of circulating hematopoietic progenitor cells without affecting neutrophil number (in contrast to mobilization with granulocyte colony-stimulating factor [G-CSF] that induces a significant rise in neutrophil number). Inhibition of osteoclasts with calcitonin reduced progenitor egress during homoeostasis, G-CSF mobilization, and stress situations. The administration of RANKL up-regulated osteoclast expression of the major bone resorbing proteinases MMP-9 and Cathepsin K (CTK) that also were shown to cleave SDF-1 and membrane-bound kit ligand important for stem cell anchorage and quiescence. To further strengthen the relation between osteoclast activation and hematopoietic cell mobilization experiments using mice deficient in the protein tyrosine phosphatase-epsilon (PTPε) that have dysfunctional osteoclasts with no identified hematopoietic disorders, treatment with either RANKL or G-CSF did not result in mobilization of progenitor cells.

The clinical applicability of this study comes quickly to mind — evaluate in animal models of transplantation whether mobilized progenitor cells harvested following osteoclast activation with RANKL restore hematopoiesis in lethally irradiated hosts. If successful, consider osteoclast stimulation using RANKL with or without other mobilizing agents to harvest progenitor cells for use in clinical autologous transplantation protocols, especially in patients deemed “poor mobilizers.” Can osteoclast stimulation with RANKL or its analogue be safely administered to healthy individuals? Does RANKL effect T cell alloimmune reactions? Does RANKL affect cancer stem cells? Concern remains. Some cancers express RANK receptors and have been shown to metastasize to bone marrow niches when RANKL is in large supply. In the long-term understanding, the dynamic between niche and stem cells extend beyond the need for better mobilization strategies for use in hematopoietic cell transplantation. Rather, knowledge about the mechanism(s) that governs stem cell localization and circulation underlies the processes of tissue development, maintenance, regeneration, and repair. Currently, however, we will have to be content with knowing that when osteoclasts get activated, they can chew out stem cells.

Competing Interests

Dr. Lowsky indicated no relevant conflicts of interest.