title: Notch signaling is involved in human articular chondrocytes de-differentiation during osteoarthritis.
abstract: BACKGROUND
  During osteoarthritis (OA), chondrocytes undergo de-differentiation, resulting in the acquisition of a fibroblast-like morphology, decreased expression of collagen type II (colII) and aggrecan, and increased expression of collagen type I (colI), metalloproteinase 13 (MMP13) and nitric oxide synthase (eNOS). Notch signaling plays a crucial role during embryogenesis. Several studies showed that Notch is expressed in adulthood.
  
  
  OBJECTIVE
  The aim of our study was to confirm the involvement of Notch signaling in human OA at in vitro and ex vivo levels.
  
  
  METHODS
  Normal human articular chondrocytes were cultured during four passages either treated or not with a Notch inhibitor: DAPT. Human OA cartilage was cultured with DAPT for five days. Chondrocytes secreted markers and some Notch pathway components were analyzed using Western blotting and qPCR.
  
  
  RESULTS
  Passaging chondrocytes induced a decrease in the cartilage markers: colII and aggrecan. DAPT-treated chondrocytes and OA cartilage showed a significant increase in healthy cartilage markers. De-differentiation markers, colI, MMP13 and eNOS, were significantly reduced in DAPT-treated chondrocytes and OA cartilage. Notch1 expression was proportional to colI, MMP13 and eNOS expression and inversely proportional to colII and aggrecan expression in nontreated cultured chondrocytes. Notch ligand: Jagged1 increased in chondrocytes culture. DAPT treatment resulted in reduced Jagged1 expression. Notch target gene HES1 increased during chondrocyte culture and was reduced when treated with DAPT.
  
  
  CONCLUSIONS
  Targeting Notch signaling during OA might lead to the restitution of the typical chondrocyte phenotype and even to chondrocyte redifferentiation during the pathology.
authors.affiliation: Department of Rheumatology, Immuno-Rheumatology Research Laboratory, La Rabta Hospital, University of Tunis-El Manar , Tunis , Tunisia .
authors.forename: Nadia
authors.initials: N
authors.lastname: Sassi
authors.forename: Nadia
authors.initials: N
authors.lastname: Gadgadi
authors.forename: Lilia
authors.initials: L
authors.lastname: Laadhar
authors.forename: Mohamed
authors.initials: M
authors.lastname: Allouche
authors.forename: Slim
authors.initials: S
authors.lastname: Mourali
authors.forename: Behrouz
authors.initials: B
authors.lastname: Zandieh-Doulabi
authors.forename: Moncef
authors.initials: M
authors.lastname: Hamdoun
authors.forename: Jenneke Klein
authors.initials: JK
authors.lastname: Nulend
authors.forename: Sondès
authors.initials: S
authors.lastname: Makni
authors.forename: Slaheddine
authors.initials: S
authors.lastname: Sellami
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002358:Cartilage, Articular / Q000254:growth & development / Q000378:metabolism; D018929:Cell Culture Techniques; D054337:Cell Dedifferentiation / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D019902:Chondrocytes / Q000378:metabolism; D024043:Collagen Type II / Q000378:metabolism; D004151:Dipeptides / Q000008:administration & dosage; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D024043:Collagen Type II; D004151:Dipeptides; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C078493:HES1 protein, human