TY - JOUR
T1 - Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis
AU - Akasaki, Y.
AU - Hasegawa, A.
AU - Saito, M.
AU - Asahara, H.
AU - Iwamoto, Y.
AU - Lotz, M. K.
N1 - Funding Information:
This study was supported by National Institutes of Health grants AG007996 and AR050631 , the Sam and Rose Stein Endowment Fund , a grant from National Center for Child Health and Development (20A-3) and the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation .
PY - 2014/1
Y1 - 2014/1
N2 - 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. Design: 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.
AB - 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. Design: 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.
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U2 - 10.1016/j.joca.2013.11.004
DO - 10.1016/j.joca.2013.11.004
M3 - Article
C2 - 24269635
AN - SCOPUS:84891739222
SN - 1063-4584
VL - 22
SP - 162
EP - 170
JO - Osteoarthritis and Cartilage
JF - Osteoarthritis and Cartilage
IS - 1
ER -