title: Autophagy protects chondrocytes from glucocorticoids-induced apoptosis via ROS/Akt/FOXO3 signaling.
abstract: OBJECTIVE
  Glucocorticoids (GCs) have been widely used in the management of osteoarthritis (OA) and rheumatoid arthritis (RA). Nevertheless, there has been some concern about their ability of increasing reactive oxygen species (ROS) in the cartilage. Forkhead-box class O (FOXO) transcription factors have been proved to have a protective role in chondrocytes through regulation of autophagy and defending oxidative stress. The objective of this study was to investigate the role of FOXO3 in Dex-induce up-regulation of ROS.
  
  
  METHODS
  Healthy cartilages debris from six patients were used for chondrocytes culture. After the treatment of dexamethasone (Dex), the ROS levels, autophagic flux, the expression of FOXO3 in chondrocytes were measured. RNA interference technique was also used to determine the role of FOXO3 in Dex-induced autophagy. The metabolism of the extra-cellular matrix was also investigated.
  
  
  RESULTS
  Dex increased intracellular ROS level, the expression of Akt, FOXO3 as well as autophagy flux in human chondrocytes. The expression of aggrecanases also increased after the treatment of Dex. Catalase, the ROS scavenger, suppressed Dex-induced up-regulation of autophagy flux and expression of aggrecanases and Akt. MK-2206 and LY294002, the PI3K/Akt inhibitors, repressed Dex-induced up-regulation of FOXO3. Silencing FOXO3 resulted in down-regulation of Dex-induced autophagy. Moreover, knockdown of FOXO3 increased Dex-induced apoptosis as well as ROS levels in chondrocytes. In addition, up-regulation of autophagy by Rapamycin resulted in decreasing ROS level in chondrocytes.
  
  
  CONCLUSIONS
  Dex could advance the degenerative process in cartilage. Autophagy was induced in response to Dex-induced up-regulation of ROS via ROS/Akt/FOXO3 signal pathway.
authors.affiliation: Department of Orthopedic, Xin-hua Hospital, China. Electronic address: Samsonov@126.com.
authors.forename: C
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Orthopedic, Xin-hua Hospital, China. Electronic address: Yiranh@yeah.net.
authors.forename: G-Q
authors.initials: GQ
authors.lastname: Cai
authors.affiliation: Department of Orthopedic, Xin-hua Hospital, China. Electronic address: hadesshen1109@yahoo.com.
authors.forename: J-P
authors.initials: JP
authors.lastname: Peng
authors.affiliation: Department of Orthopedic, Xin-hua Hospital, China. Electronic address: duchemin@163.com.
authors.forename: X-D
authors.initials: XD
authors.lastname: Chen
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002358:Cartilage, Articular / Q000166:cytology; D016022:Case-Control Studies; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D057925:Femoracetabular Impingement / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006621:Hip Joint; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D024042:Collagen Type I; D024043:Collagen Type II; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D003907:Dexamethasone; D051057:Proto-Oncogene Proteins c-akt; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D011348:Procollagen N-Endopeptidase; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D000071121:ADAMTS4 Protein
keywords: Autophagy; Chondrocytes; Dexamethasone; Forkhead-box class O3