title: Inhibition of Osteoarthritis by Adipose-Derived Stromal Cells Overexpressing Fra-1 in Mice.
abstract: OBJECTIVE
  To determine whether overexpression of the activator protein 1 (AP-1) transcription factor Fra-1 in adipose-derived stromal cells (ADSCs) is an effective treatment of collagenase-induced osteoarthritis (OA).
  
  
  METHODS
  OA was induced by injection of collagenase into the knee joints of male C57BL/6 mice. ADSCs were isolated from the inguinal fat pads of 8-week-old wild-type or Fra-1-transgenic mice and injected into the knee joints of mice with collagenase-induced OA 7 days after OA induction. Histologic analyses of cartilage destruction and chondrocyte cell death were performed. Adipogenic differentiation capacity was evaluated, gene expression was analyzed, and cytokine profiling was performed in stromal vascular fractions (SVFs) and ADSCs.
  
  
  RESULTS
  OA-related cartilage destruction and chondrocyte cell death were significantly reduced in mouse knee joints treated with ADSCs from Fra-1-transgenic mice compared to mouse knee joints treated with ADSCs from wild-type mice. This effect did not result from the higher number of adipogenic progenitors observed in SVFs from Fra-1-transgenic compared to wild-type mouse fat pads, since injection of wild-type mouse ADSCs enriched for adipogenic progenitors did not show any additional chondroprotective effects compared to nonsorted ADSCs. However, Fra-1-transgenic mouse ADSCs showed decreased adipogenic differentiation capacity. Moreover, Fra-1 significantly inhibited proinflammatory interleukin-6 and pentraxin 3 expression, while increasing the expression of extracellular matrix proteins, such as periostin and spondin 1. These findings suggest that Fra-1 overexpression leads to an increased chondroprotective effect of ADSCs in OA.
  
  
  CONCLUSIONS
  ADSCs overexpressing Fra-1 effectively protect against OA. Our data indicate that genetic modifications of ADSCs, such as Fra-1 overexpression, may improve their potential to protect articular cartilage against OA-mediated damage.
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Schwabe
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Mireia
authors.initials: M
authors.lastname: Garcia
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Kenia
authors.initials: K
authors.lastname: Ubieta
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hannemann
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Herbort
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany, and University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Luther
authors.affiliation: INSERM U844, Hôpital Saint-Eloi, Montpellier, France.
authors.forename: Daniele
authors.initials: D
authors.lastname: Noël
authors.affiliation: INSERM U844, Hôpital Saint-Eloi, Montpellier, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
authors.affiliation: INSERM U1031, STROMALab, Universite Paul Sabatier, CNRS-EFS-UMR5273, Toulouse, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Casteilla
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany, and University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stock
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Bozec
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D002097:C-Reactive Protein / Q000276:immunology / Q000378:metabolism; D002358:Cartilage, Articular; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism; D017364:Collagenases; D016207:Cytokines / Q000276:immunology; D020869:Gene Expression Profiling; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D013264:Stifle / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D000099169:Fos-Related Antigen 1; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D017364:Collagenases; D016207:Cytokines; D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1; D000099153:Pentraxins