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.

Antibiotic Treatment Prior to Injury Improves Post-Traumatic Osteoarthritis Outcomes in Mice

“…We found 737 significantly downregulated genes in the AB uninjured group compared to the VEH uninjured group. These genes included regulators of skeletal development ( Alpl [ 37 ], Col6a1 [ 54 ], Col6a2 [ 55 ], Sox9 [ 37 ], Sox11 [ 56 ], and Wnt9a [ 57 ]), Hippo signaling ( Tead1 , Tead4 [ 58 ], and Yap1 [ 59 ]), muscle contraction ( Myh8 , Myh2 , and Myom2 ), and inflammatory response ( Tlr5 [ 60 ], Ccl8 [ 61 ], Cxcl13 [ 37 ], C5ar1 [ 62 ], Cxcr1 [ 63 ], and Foxo6 [ 64 ]). Inflammatory gene comparison between AB injured and uninjured groups compared to the corresponding VEH groups are shown in Figure 5 A and Table 1 .…”

Transcription Factors in Cartilage Homeostasis and Osteoarthritis

“…Besides these, FOXO TFs have also been shown to have a protective role by regulating inflammation and DNA repair. FOXO transcription factors are downstream targets of MAPK signaling, and phosphorylation of FOXO TFs results in its inactivation by inhibiting nuclear entry [ 142 ]. Both IL1β and TNFα increase phosphorylation of FOXO TFs and thus inhibit their activity and reduce their expression in cultured chondrocytes [ 143 ].…”

Osteoarthritis and Cartilage Regeneration: Focus on Pathophysiology and Molecular Mechanisms

“…The expression of FoxOs is reduced with aging and in OA suggesting an important role of FoxOs in joint homeostasis. The review by Wang et al, integrates our recent understanding of FoxOs on oxidative stress-induced chondrocyte dysfunction and highlight their potential as targets for OA treatment [33]. Increased ROS production and oxidative stress upregulate the expression of FoxOs, which in turn enhances the expression of antioxidant enzymes.…”