title: Bone tissue formation with human mesenchymal stem cells and biphasic calcium phosphate ceramics: the local implication of osteoclasts and macrophages.
abstract: Human mesenchymal stem cells (hMSC) have immunomodulative properties and, associated with calcium phosphate (CaP) ceramics, induce bone tissue repair. However, the mechanisms of osteoinduction by hMSC with CaP are not clearly established, in particular the role of osteoclasts and macrophages. Biphasic calcium phosphate (BCP) particles were implanted with or without hMSC in the paratibial muscles of nude mice. hMSC increased osteoblastic gene expression at 1 week, the presence of macrophages at 2 and 4 weeks, osteoclastogenesis at 4 and 8 weeks, and osteogenesis at 4 and 8 weeks. hMSC disappeared from the implantation site after 2 weeks, indicating that hMSC were inducers rather than effectors of bone formation. Induced blockage of osteoclastogenesis by anti-Rankl treatment significantly impaired bone formation, revealing the pivotal role of osteoclasts in bone formation. In summary, hMSC positively influence the body foreign reaction by attracting circulating haematopoietic stem cells and inducing their differentiation into macrophages M1 and osteoclasts, thus favouring bone formation.
authors.affiliation: INSERM, UMR957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Gamblin
authors.affiliation: INSERM, UMR957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.
authors.forename: Meadhbh A
authors.initials: MA
authors.lastname: Brennan
authors.affiliation: INSERM, UMR957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Renaud
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: INSERM, UMR957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; Equipe LIGUE Nationale Contre le Cancer 2012, Nantes, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lézot
authors.affiliation: INSERM, UMR957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; Equipe LIGUE Nationale Contre le Cancer 2012, Nantes, France; CHU, Hôtel Dieu, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: INSERM, UMR957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; Equipe LIGUE Nationale Contre le Cancer 2012, Nantes, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Trichet
authors.affiliation: INSERM, UMR957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. Electronic address: pierre.layrolle@inserm.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Layrolle
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002516:Ceramics / Q000494:pharmacology*; D005547:Foreign Bodies / Q000209:etiology; D006801:Humans; D006882:Hydroxyapatites / Q000008:administration & dosage / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D019736:Prostheses and Implants / Q000009:adverse effects; D053245:RANK Ligand / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D006882:Hydroxyapatites; D053245:RANK Ligand; C074950:hydroxyapatite-beta tricalcium phosphate
keywords: Foreign body reaction; Macrophages; Osteoclasts; Osteoinduction; mAb anti-RANKL