title: Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis.
abstract: OBJECTIVE
  Aging is a major risk factor for osteoarthritis (OA). Forkhead-box class O (FoxO) transcription factors regulate mechanisms of cellular aging, including protein quality control, autophagy and defenses against oxidative stress. The objective of this study was to analyze FoxO transcription factors in normal, aging and OA cartilage.
  
  
  METHODS
  Knee joints from humans ages 23-90 and from mice at the age of 4-24 months and following surgically induced OA were analyzed for expression of FoxO proteins. Regulation of FoxO protein expression and activation was analyzed in cultured chondrocytes.
  
  
  RESULTS
  Human cartilage expressed FOXO1 and FOXO3 but not FOXO4 proteins. FOXO1 and FOXO3 were more strongly expressed the superficial and mid zone as compared to the deep zone and were mainly localized in nuclei. During human joint aging, expression of FOXO1 and FOXO3 was markedly reduced in the superficial zone of cartilage regions exposed to maximal weight bearing. In OA cartilage, chondrocyte clusters showed strong FOXO phosphorylation and cytoplasmic localization. Similar patterns of FOXO expression in normal joints and changes in aging and OA were observed in mouse models. In cultured chondrocytes, IL-1β and TNF-α suppressed FOXO1, while TGF-β and PDGF increased FOXO1 and FOXO3 expression. FOXO1 and FOXO3 phosphorylation was increased by IL-1β, PDGF, bFGF, IGF-1, and the oxidant t-BHP.
  
  
  CONCLUSIONS
  Normal articular cartilage has a tissue specific signature of FoxO expression and activation and this is profoundly altered in aging and OA in humans and mice. Changes in FoxO expression and activation may be involved in cartilage aging and OA.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: akasaki@scripps.edu.
authors.forename: Y
authors.initials: Y
authors.lastname: Akasaki
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: ort171@poh.osaka-med.ac.jp.
authors.forename: A
authors.initials: A
authors.lastname: Hasegawa
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: saito@scripps.edu.
authors.forename: M
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA; National Research Institute for Child Health and Development, Tokyo, Japan; Department of Systems Bio Medicine, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: asahara@scripps.edu.
authors.forename: H
authors.initials: H
authors.lastname: Asahara
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: yiwamoto@ortho.med.kyushu-u.ac.jp.
authors.forename: Y
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: cchoate@scripps.edu.
authors.forename: M K
authors.initials: MK
authors.lastname: Lotz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007719:Knee Joint / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D014157:Transcription Factors / Q000378:metabolism; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C108803:FOXO4 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D014157:Transcription Factors
keywords: Aging; Cartilage; FoxO; Osteoarthritis