title: 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.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Kollet
authors.forename: Ayelet
authors.initials: A
authors.lastname: Dar
authors.forename: Shoham
authors.initials: S
authors.lastname: Shivtiel
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalinkovich
authors.forename: Kfir
authors.initials: K
authors.lastname: Lapid
authors.forename: Yejezkel
authors.initials: Y
authors.lastname: Sztainberg
authors.forename: Melania
authors.initials: M
authors.lastname: Tesio
authors.forename: Robert M
authors.initials: RM
authors.lastname: Samstein
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.forename: Asaf
authors.initials: A
authors.lastname: Spiegel
authors.forename: Ari
authors.initials: A
authors.lastname: Elson
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D000818:Animals; D001862:Bone Resorption; D001842:Bone and Bones / Q000033:anatomy & histology*; D002352:Carrier Proteins / Q000378:metabolism; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D019718:Receptors, CXCR4 / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D019718:Receptors, CXCR4; D019089:Stem Cell Factor; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D017027:Protein Tyrosine Phosphatases; C098067:Ptpre protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D020780:Matrix Metalloproteinase 9