title: Inhibition of bone remodeling in young mice by bisphosphonate displaces the plasma cell niche into the spleen.
abstract: The bone marrow provides niches for early B cell differentiation and long-lived plasma cells. Therefore, it has been hypothesized that perturbing bone homeostasis might impact B cell function and Ab production. This hypothesis is highly relevant for patients receiving long-term treatment with antiresorptive drugs. We therefore analyzed the humoral immune response of mice chronically treated with ibandronate, a commonly used bisphosphonate. We confirmed the increased bone mass caused by inhibition of osteoclast activity and also the strongly reduced bone formation because of decreased osteoblast numbers in response to ibandronate. Thus, bisphosphonate drastically inhibited bone remodeling. When ibandronate was injected into mice after a primary immunization to mimic common antiosteoporotic treatments, the generation of the various B cell populations, the response to booster immunization, and the generation of plasma cells were surprisingly normal. Mice also responded normally to immunization when ibandronate was applied to naive mice. However, there, ibandronate shunted the homing of bone marrow plasma cells. Interestingly, ibandronate reduced the numbers of megakaryocytes, a known component of the bone marrow plasma cell niche. In line with normal Ab responses, increased plasma cell populations associated with increased megakaryocyte numbers were then observed in the spleens of the ibandronate-treated mice. Thus, although inhibition of bone remodeling disturbed the bone marrow plasma cell niche, a compensatory niche may have been created by relocating the megakaryocytes into the spleen, thereby allowing normal B cell responses. Therefore, megakaryocytes may act as a key regulator of plasma cell niche plasticity.
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany; Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany; and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Teufel
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany;
authors.forename: Bettina
authors.initials: B
authors.lastname: Grötsch
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany; Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Luther
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany;
authors.forename: Anja
authors.initials: A
authors.lastname: Derer
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany; and.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Division of Molecular Immunology, Nikolaus-Fiebiger Center, Department of Internal Medicine 3, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany j.david@uke.de dmielenz@molmed.uni-erlangen.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Mielenz
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany; Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany; and j.david@uke.de dmielenz@molmed.uni-erlangen.de.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects* / Q000276:immunology; D050071:Bone Density Conservation Agents / Q000009:adverse effects* / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000276:immunology*; D016723:Bone Remodeling / Q000187:drug effects*; D004164:Diphosphonates / Q000009:adverse effects* / Q000494:pharmacology; D000077557:Ibandronic Acid; D008533:Megakaryocytes / Q000276:immunology; D051379:Mice; D010950:Plasma Cells / Q000276:immunology*; D013154:Spleen / Q000276:immunology*
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000077557:Ibandronic Acid