title: Interleukin-22 drives the proliferation, migration and osteogenic differentiation of mesenchymal stem cells: a novel cytokine that could contribute to new bone formation in spondyloarthropathies.
abstract: The SpAs are genetically and therapeutically linked to IL-23, which in turn regulates IL-22, a cytokine that has been implicated in the regulation of new bone formation in experimental models. We hypothesize that IL-22, a master regulator of stem cells in other niches, might also regulate human mesenchymal stem cell (MSC) osteogenesis.
  The effects of IL-22 on in vitro MSC proliferation, migration and osteogenic differentiation were evaluated in the presence or absence of IFN-γ and TNF (to ascertain IL-22 activity in pro-inflammatory environments). Colorimetric XTT assay, trans-well migration assays, quantitative real-time PCR (qRT-PCR) for MSC lineage markers and osteogenesis assays were used.
  Combined treatment of MSC with IL-22, IFN-γ and TNF resulted in increased MSC proliferation ( P = 0.008) and migration ( P = 0.04), an effect that was not seen in cells treated with IL-22 alone and untreated cells. Osteogenic and adipogenic, but not chondrogenic, transcription factors were upregulated by IL-22 alone ( P < 0.05). MSC osteogenesis was enhanced following IL-22 exposure ( P = 0.03, measured by calcium production). The combination of IFN-γ and TNF with or without IL-22 suppressed MSC osteogenesis ( P = 0.03).
  This work shows that IL-22 is involved in human MSC proliferation/migration in inflammatory environments, with MSC osteogenesis occurring only in the absence of IFN-γ/TNF. These effects of IL-22 on MSC function is a novel pathway for exploring pathological, post-inflammation osteogenesis in human SpA.
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.|Department of Obstetrics and Gynaecology, Mansoura University Hospitals, Mansoura University, Mansoura, Egypt.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: El-Zayadi
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.|NIHR-Leeds Musculoskeletal and Biomedical Research Unit, Chapel Allerton, Leeds Teaching Hospital Trust, Leeds, West Yorkshire, UK.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Jones
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.|NIHR-Leeds Musculoskeletal and Biomedical Research Unit, Chapel Allerton, Leeds Teaching Hospital Trust, Leeds, West Yorkshire, UK.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Churchman
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Baboolal
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cuthbert
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.|Clinical Pathology Department, Mansoura University Hospitals, Mansoura University, Mansoura, Egypt.
authors.forename: Jehan J
authors.initials: JJ
authors.lastname: El-Jawhari
authors.affiliation: Department of Obstetrics and Gynaecology, Mansoura University Hospitals, Mansoura University, Mansoura, Egypt.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Badawy
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
authors.forename: Adewonuola A
authors.initials: AA
authors.lastname: Alase
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.|Clinical Pathology Department, Mansoura University Hospitals, Mansoura University, Mansoura, Egypt.
authors.forename: Yasser M
authors.initials: YM
authors.lastname: El-Sherbiny
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.|NIHR-Leeds Musculoskeletal and Biomedical Research Unit, Chapel Allerton, Leeds Teaching Hospital Trust, Leeds, West Yorkshire, UK.
authors.forename: Dennis
authors.initials: D
authors.lastname: McGonagle
mesh_terms: D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018123:Receptors, Interleukin / Q000378:metabolism; D025242:Spondylarthropathies / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D000097043:Interleukin-22
chemical_list: D016207:Cytokines; D007371:Interferon-gamma; D007378:Interleukins; D018123:Receptors, Interleukin; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C439524:TNF protein, human; C415369:interleukin-22 receptor
keywords: IL-22; IL-23 axis; mesenchymal stem cells; osteogenesis; spondyloarthropathy