title: Effects of Interleukin-17A on Osteogenic Differentiation of Isolated Human Mesenchymal Stem Cells.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is characterized by defective bone repair and excessive destruction and ankylosing spondylitis (AS) by increased ectopic bone formation with syndesmophytes. Since TNF-α and IL-17A are involved in both diseases, this study investigated their effects on the osteogenic differentiation of isolated human bone marrow-derived mesenchymal stem cells (hMSCs).
  
  
  METHODS
  Differentiation of hMSCs into osteoblasts was induced in the presence or absence of IL-17A and/or TNF-α. Matrix mineralization (MM) was evaluated by alizarin red staining and alkaline phosphatase (ALP) activity. mRNA expression was measured by qRT-PCR for bone morphogenetic protein (BMP)-2 and Runx2, genes associated with osteogenesis, DKK-1, a negative regulator of osteogenesis, Schnurri-3 and receptor activator of nuclear factor kappa B ligand (RANKL), associated with the cross talk with osteoclasts, and TNF-α receptor type I and TNF-α receptor type II (TNFRII).
  
  
  RESULTS
  TNF-α alone increased both MM and ALP activity. IL-17A alone increased ALP but not MM. Their combination was more potent. TNF-α alone increased BMP2 mRNA expression at 6 and 12 h. These levels decreased in combination with IL-17A at 6 h only. DKK-1 mRNA expression was inhibited by TNF-α and IL-17A either alone or combined. Supporting an imbalance toward osteoblastogenesis, RANKL expression was inhibited by TNF-α and IL-17A. However, TNF-α but not IL-17 alone decreased Runx2 mRNA expression at 6 h. In parallel, TNF-α but not IL-17 alone increased Schnurri-3 expression with a synergistic effect with their combination. This may be related to an increase of TNFRII overexpression.
  
  
  CONCLUSIONS
  IL-17 increased the effects of TNF-α on bone matrix formation by hMSCs. However, IL-17 decreased the TNF-α-induced BMP2 inhibition. Synergistic interactions between TNF-α and IL-17 were seen for RANKL inhibition and Schnurri-3 induction. Such increase of Schnurri-3 may in turn activate osteoclasts leading to bone destruction as in RA. Conversely, in the absence of osteoclasts, this could promote ectopic bone formation as in AS.
authors.affiliation: Immunogenomics and Inflammation Research Unit EA 4130, Department of Clinical Immunology and Rheumatology, Edouard Herriot Hospital, University of Lyon 1 , Lyon , France.
authors.forename: Bilal
authors.initials: B
authors.lastname: Osta
authors.affiliation: Immunogenomics and Inflammation Research Unit EA 4130, Department of Clinical Immunology and Rheumatology, Edouard Herriot Hospital, University of Lyon 1 , Lyon , France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lavocat
authors.affiliation: Immunogenomics and Inflammation Research Unit EA 4130, Department of Clinical Immunology and Rheumatology, Edouard Herriot Hospital, University of Lyon 1 , Lyon , France.
authors.forename: Assia
authors.initials: A
authors.lastname: Eljaafari
authors.affiliation: Immunogenomics and Inflammation Research Unit EA 4130, Department of Clinical Immunology and Rheumatology, Edouard Herriot Hospital, University of Lyon 1 , Lyon , France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Miossec
keywords: IL-17A; TNF-α; ankylosing spondylitis; mesenchymal stem cell; rheumatoid arthritis