Role of Forkhead Box O Transcription Factors in Oxidative Stress-Induced Chondrocyte Dysfunction: Possible Therapeutic Target for Osteoarthritis?

Abstract

Chondrocyte dysfunction occurs during the development of osteoarthritis (OA), typically resulting from a deleterious increase in oxidative stress. Accordingly, strategies for arresting oxidative stress-induced chondrocyte dysfunction may lead to new potential therapeutic targets for OA treatment. Forkhead box O (FoxO) transcription factors have recently been shown to play a protective role in chondrocyte dysfunction through the regulation of inflammation, autophagy, aging, and oxidative stress. They also regulate growth, maturation, and matrix synthesis in chondrocytes. In this review, we discuss the recent progress made in the field of oxidative stress-induced chondrocyte dysfunction. We also discuss the protective role of FoxO transcription factors as potential molecular targets for the treatment of OA. Understanding the function of FoxO transcription factors in the OA pathology may provide new insights that will facilitate the development of next-generation therapies to prevent OA development and to slow OA progression.

Keywords: FoxO; aging; articular cartilage; autophagy; chondrocyte dysfunction; molecular target; osteoarthritis; oxidative stress.

Figure 1

Signaling pathways of oxidative stress in chondrocyte senescence. Reactive oxygen species (ROS) are a main cause of senescence and they regulate signaling molecules, such as mitogen-activated protein kinases (MAPKs) (ERK/P38), P16, P21, and P53, which are eventually responsible for senescence. COL II = collagen type II, COL I = collagen type I, GADD45 β = DNA damage-inducible protein 45 β, C/EBP β = CCAAT/enhancer binding protein β, PCNA = proliferating cell nuclear antigen, MMPs = matrix metalloproteinases.

Figure 2

Inducers of oxidative stress in chondrocytes. Inducers of oxidative stress increase chondrocyte senescence, chondrocyte apoptosis, and inflammatory signaling and decrease chondrocyte autophagy, antioxidant capacity, and matrix synthesis.

Figure 3

Activation or inhibition of Forkhead box O (FoxO) through ROS-induced posttranslational modifications. An increase in intracellular ROS induces the activation of the kinases JNK and Akt and inhibits the deacetylase SIRT1 and Wnt/β-catenin signaling. The dephosphorylation and acetylation status of FoxO can lead to the induction of a specific subset of genes that regulates cellular detoxification. FoxO = Forkhead box O transcription factor, ROS = reactive oxygen species, FRE = FoxO response element, SOD = superoxide dismutase, GADD45 = growth arrest and DNA damage 45, OPG = osteoprotegerin, TCF/LEF = T-cell-specific transcription factor/lymphoid enhancing factor, Axin = axis inhibition, APC = adenomatous polyposis coli.

Figure 4

The protective role of FoxOs in osteoarthritic chondrocytes. In chondrocytes, FoxO activity is affected by three factors: growth factors (such as IGF-1 and insulin) and inflammatory cytokines (such as IL-1β and TNF-α) stimulate Akt activity, and the activation of Akt leads to the phosphorylation and inactivation of FoxO. During oxidative stress, the inhibition of Akt activity induces the nuclear accumulation and activation of FoxO. In the nucleus, FoxO recognizes and binds to FoxO response element (FRE). Activated FoxO thus regulates the transcriptional activity of its downstream targets, making possible the regulation of many chondrocyte processes, including proliferation, differentiation, and autophagy; apoptosis; and antioxidant capacity. FoxO = Forkhead box O transcription factor, IGF-1 = insulin-like growth factor-1, IL-1β = interleukin-1β, TNF-α = tumor necrosis factor-α, Akt = protein kinase B, FRE = FoxO response element.