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.