title: Contribution of the Interleukin-6/STAT-3 Signaling Pathway to Chondrogenic Differentiation of Human Mesenchymal Stem Cells.
abstract: OBJECTIVE
  Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into chondrocytes. Articular cartilage contains MSC-like chondroprogenitor cells, which suggests their involvement in the maintenance of cartilage homeostasis by a self-repair mechanism. Interleukin-6 (IL-6) is a cytokine with a wide range of physiologic functions, which are produced by MSCs in a steady manner and in large quantities. The purpose of this study was to investigate the involvement of IL-6 signaling in MSC differentiation into chondrocytes.
  
  
  METHODS
  Human bone marrow-derived MSCs were cultured using a pellet culture system in medium containing transforming growth factor β3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression.
  
  
  RESULTS
  IL-6 was detected at a high concentration in culture supernatants during chondrogenic differentiation. The expression of the IL-6 receptor (IL-6R) was significantly increased, accompanied by markedly increased phosphorylation and expression of STAT-3. Addition of IL-6 and soluble IL-6R (sIL-6R) to the chondrogenic culture resulted in concentration-dependent increases in cartilage matrix accumulation and cartilage marker gene expression (type II collagen/aggrecan/type X collagen). Phosphorylation of the master transcription factor SOX9 was enhanced upon addition of IL-6 and sIL-6R. STAT-3 knockdown suppressed chondrogenic differentiation. IL-6 and the MSC markers CD166 and nestin were colocalized in macroscopically normal human cartilage taken from the lateral femoral compartment of knees with medial tibiofemoral osteoarthritis.
  
  
  CONCLUSIONS
  During differentiation of human MSCs into chondrocytes, the activation of IL-6/STAT-3 signaling positively regulated chondrogenic differentiation. The presence of IL-6 around MSC-like cells in the cartilage tissue was identified, suggesting that IL-6 contributes to homeostasis and cartilage self-repair by promoting chondrogenic differentiation.
authors.affiliation: University of Occupational and Environmental Health, Kitakyushu, Japan, and Mitsubishi Tanabe Pharma, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kondo
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yamaoka
authors.forename: Kei
authors.initials: K
authors.lastname: Sakata
authors.forename: Koshiro
authors.initials: K
authors.lastname: Sonomoto
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakano
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D002356:Cartilage / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D019902:Chondrocytes / Q000378:metabolism*; D020219:Chondrogenesis / Q000502:physiology*; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053674:Aggrecans; D024043:Collagen Type II; D024121:Collagen Type X; C508600:IL6 protein, human; C508603:IL6R protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human