title: IL-17 inhibits chondrogenic differentiation of human mesenchymal stem cells.
abstract: OBJECTIVE
  Mesenchymal stem cells (MSCs) can differentiate into cells of mesenchymal lineages, such as osteoblasts and chondrocytes. Here we investigated the effects of IL-17, a key cytokine in chronic inflammation, on chondrogenic differentiation of human MSCs.
  
  
  METHODS
  Human bone marrow MSCs were pellet cultured in chondrogenic induction medium containing TGF-β3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression.
  
  
  RESULTS
  Over-expression of cartilage matrix and chondrogenic marker genes was noted in chondrogenic cultures, but was inhibited by IL-17 in a dose-dependent manner. Expression and phosphorylation of SOX9, the master transcription factor for chondrogenesis, were induced within 2 days and phosphorylated SOX9 was stably maintained until day 21. IL-17 did not alter total SOX9 expression, but significantly suppressed SOX9 phosphorylation in a dose-dependent manner. At day 7, IL-17 also suppressed the activity of cAMP-dependent protein kinase A (PKA), which is known to phosphorylate SOX9. H89, a selective PKA inhibitor, also suppressed SOX9 phosphorylation, expression of chondrogenic markers and cartilage matrix, and also decreased chondrogenesis.
  
  
  CONCLUSIONS
  IL-17 inhibited chondrogenesis of human MSCs through the suppression of PKA activity and SOX9 phosphorylation. These results suggest that chondrogenic differentiation of MSCs can be inhibited by a mechanism triggered by IL-17 under chronic inflammation.
authors.affiliation: The First Department of Internal Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Fukuoka, Japan ; Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kondo
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yamaoka
authors.forename: Koshiro
authors.initials: K
authors.lastname: Sonomoto
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Fukuyo
authors.forename: Koichi
authors.initials: K
authors.lastname: Oshita
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Okada
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects*; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D055758:SOX9 Transcription Factor / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D055758:SOX9 Transcription Factor