title: Treatment efficacy of adipose-derived stem cells in experimental osteoarthritis is driven by high synovial activation and reflected by S100A8/A9 serum levels.
abstract: OBJECTIVE
  Synovitis is evident in a substantial subpopulation of patients with osteoarthritis (OA) and is associated with development of pathophysiology. Recently we have shown that adipose-derived stem cells (ASC) inhibit joint destruction in collagenase-induced experimental OA (CIOA). In the current study we explored the role of synovitis and alarmins S100A8/A9 in the immunomodulatory capacity of ASCs in experimental OA.
  
  
  METHODS
  CIOA, characterized by synovitis, and surgical DMM (destabilization of medial meniscus) OA were treated locally with ASCs. Synovial activation, cartilage damage and osteophyte size were measured on histological sections. Cytokines in synovial washouts and serum were determined using Luminex or enzyme-linked immunosorbent assay (S100A8/A9), mRNA levels with reverse-transcriptase (RT)-qPCR.
  
  
  RESULTS
  Local administration of ASCs at various time-points (days 7 or 14) after DMM induction had no effect on OA pathology. At day 7 of CIOA, already 6 h after ASC injection mRNA expression of pro-inflammatory mediators S100A8/A9, interleukin-1beta (IL-1β) and KC was down-regulated in the synovium. IL-1β protein, although low, was down-regulated by ASC-treatment of CIOA. S100A8/A9 protein levels were very high at 6 and 48 h and were decreased by ASC-treatment. The protective action of ASC treatment in CIOA was only found when high synovial inflammation was present at the time of deposition which was reflected by high serum S100A8/A9 levels. Finally, successful treatment resulted in significantly lower levels of serum S100A8/A9.
  
  
  CONCLUSIONS
  Our study indicates that synovial activation rapidly drives anti-inflammatory and protective effects of intra-articularly deposited ASCs in experimental OA which is reflected by decreased S100A8/A9 levels.
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Rik.Schelbergen@radboudumc.nl.
authors.forename: R F
authors.initials: RF
authors.lastname: Schelbergen
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: van Dalen
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: ter Huurne
authors.affiliation: Institute of Immunology, University of Munster, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Roth
authors.affiliation: Institute of Immunology, University of Munster, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Vogl
authors.affiliation: Inserm U844, Hôpital Saint-Eloi, Montpellier, France.
authors.forename: D
authors.initials: D
authors.lastname: Noël
authors.affiliation: Inserm U844, Hôpital Saint-Eloi, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Jorgensen
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: F A
authors.initials: FA
authors.lastname: van de Loo
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A B
authors.initials: AB
authors.lastname: Blom
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Peter.vanLent@radboudumc.nl.
authors.forename: P L E M
authors.initials: PL
authors.lastname: van Lent
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D001169:Arthritis, Experimental / Q000628:therapy*; D040501:Calgranulin A / Q000097:blood* / Q000235:genetics; D040502:Calgranulin B / Q000097:blood* / Q000235:genetics; D002358:Cartilage, Articular / Q000378:metabolism; D017364:Collagenases / Q000633:toxicity; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008592:Menisci, Tibial / Q000601:surgery*; D051379:Mice; D020370:Osteoarthritis, Knee / Q000378:metabolism / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology; D013583:Synovial Membrane / Q000378:metabolism*; D013585:Synovitis / Q000378:metabolism / Q000628:therapy
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D012333:RNA, Messenger; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; D017364:Collagenases
keywords: Adipose stem cells; Animal models; Experimental OA; S100; Synovitis