title: Proinflammatory T cells and IL-17 stimulate osteoblast differentiation.
abstract: The local immune response is important to consider when the aim is to improve bone regeneration. Recently T lymphocytes and their associated cytokines have been identified as regulators in fracture callus formation, but it is not known whether T cells affect bone progenitor cells directly. The goal of this in vitro study was to investigate the role of different T cell subsets and their secreted factors on the osteogenic differentiation of human mesenchymal stem cells (MSCs). Significant increases in the alkaline phosphatase activity and the subsequent matrix mineralization by MSCs were found after their exposure to activated T cells or activated T cell-derived conditioned medium. Blocking IFN-γ in the conditioned medium abolished its pro-osteogenic effect, while blocking TGF-β further enhanced osteogenesis. The relative contribution of an anti- or proinflammatory T cell phenotype in MSC osteogenic differentiation was studied next. Enrichment of the fraction of anti-inflammatory regulatory T cells had no beneficial osteogenic effect. In contrast, soluble factors derived from enriched T helper 17 cells upregulated the expression of osteogenic markers by MSCs. IL-17A, and IL-17F, their main proinflammatory cytokines, similarly exhibited strong osteogenic effects when exposed directly to MSCs. IL-17A in particular showed a synergistic action together with bone morphogenetic protein 2. These results indicate that individual T cell subsets, following their activation, affect osteoblast maturation in a different manner through the production of soluble factors. From all T cells, the proinflammatory T cells, including the T helper 17 cells, are most stimulatory for osteogenesis.
authors.affiliation: Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands. Electronic address: m.croes@umcutrecht.nl.
authors.forename: Michiel
authors.initials: M
authors.lastname: Croes
authors.affiliation: Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands. Electronic address: f.c.oner@umcutrecht.nl.
authors.forename: F Cumhur
authors.initials: FC
authors.lastname: Öner
authors.affiliation: Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands. Electronic address: dvanneerven87@gmail.com.
authors.forename: Danihel
authors.initials: D
authors.lastname: van Neerven
authors.affiliation: Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands. Electronic address: ekrem_sabir1990@hotmail.com.
authors.forename: Ekrem
authors.initials: E
authors.lastname: Sabir
authors.affiliation: Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands. Electronic address: m.c.kruyt@umcutrecht.nl.
authors.forename: Moyo C
authors.initials: MC
authors.lastname: Kruyt
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands. Electronic address: t.j.blokhuis@umcutrecht.nl.
authors.forename: Taco J
authors.initials: TJ
authors.lastname: Blokhuis
authors.affiliation: Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands; Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3508 TD Utrecht, The Netherlands. Electronic address: w.dhert@uu.nl.
authors.forename: Wouter J A
authors.initials: WJA
authors.lastname: Dhert
authors.affiliation: Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands. Electronic address: j.alblas@umcutrecht.nl.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Alblas
mesh_terms: D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D020381:Interleukin-17 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016131:Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects
chemical_list: D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D020381:Interleukin-17
keywords: Bone regeneration; Fracture healing; Mesenchymal stem cell; Osteoimmunology; T lymphocytes