title: Osteoclast activity modulates B-cell development in the bone marrow.
abstract: B-cell development is dependent on the interactions between B-cell precursors and bone marrow stromal cells, but the role of osteoclasts (OCLs) in this process remains unknown. B lymphocytopenia is a characteristic of osteopetrosis, suggesting a modulation of B lymphopoiesis by OCL activity. To address this question, we first rescued OCL function in osteopetrotic oc/oc mice by dendritic cell transfer, leading to a restoration of both bone phenotype and B-cell development. To further explore the link between OCL activity and B lymphopoiesis, we induced osteopetrosis in normal mice by injections of zoledronic acid (ZA), an inhibitor of bone resorption. B-cell number decreased specifically in the bone marrow of ZA-treated mice. ZA did not directly affect B-cell differentiation, proliferation and apoptosis, but induced a decrease in the expression of CXCL12 and IL-7 by stromal cells, associated with reduced osteoblastic engagement. Equivalent low osteoblastic engagement in oc/oc mice confirmed that it resulted from the reduced OCL activity rather than from a direct effect of ZA on osteoblasts. These dramatic alterations of the bone microenvironment were disadvantageous for B lymphopoiesis, leading to retention of B-cell progenitors outside of their bone marrow niches in the ZA-induced osteopetrotic model. Altogether, our data revealed that OCLs modulate B-cell development in the bone marrow by controlling the bone microenvironment and the fate of osteoblasts. They provide novel basis for the regulation of the retention of B cells in their niche by OCL activity.
authors.affiliation: CNRS, GEPITOS, UMR 6235, Faculté de Médecine, 06100 Nice, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Mansour
authors.forename: Adrienne
authors.initials: A
authors.lastname: Anginot
authors.forename: Stéphane J C
authors.initials: SJ
authors.lastname: Mancini
authors.forename: Claudine
authors.initials: C
authors.lastname: Schiff
authors.forename: Georges F
authors.initials: GF
authors.lastname: Carle
authors.forename: Abdelilah
authors.initials: A
authors.lastname: Wakkach
authors.forename: Claudine
authors.initials: C
authors.lastname: Blin-Wakkach
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D015851:Interleukin-7 / Q000378:metabolism; D038041:Lymphopoiesis / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000166:cytology*; D010022:Osteopetrosis / Q000139:chemically induced; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D054377:Chemokine CXCL12; D004164:Diphosphonates; D007093:Imidazoles; D015851:Interleukin-7; D000077211:Zoledronic Acid