Key Takeaways & Executive Findings
- •• FoxO3a regulates bone metabolism by modulating oxidative stress and autophagy in bone cells, influencing proliferation, differentiation, and apoptosis. • FoxO3a promotes osteogenic differentiation of bone marrow mesenchymal stem cells and osteoprogenitor cells via autophagy activation, while inhibiting osteoclastogenesis. • FoxO3a protects osteocytes and chondrocytes from oxidative stress and senescence, reducing bone loss and osteoarthritis progression. • FoxO3a is implicated in the pathology of osteoporosis, osteoarthritis, osteonecrosis of the femoral head, and malignant bone tumors, making it a potential therapeutic target.
Abstract
BACKGROUND: Bone metabolism disorders can cause the occurrence of bone-related diseases, and forkhead box transcription factor O3 (FoxO3a) can affect the processes of proliferation, differentiation and apoptosis of bone tissue cells by regulating oxidative stress and autophagy levels, and thereby regulate the bone metabolism. OBJECTIVE: To systematically analyze the relevant research literature on the regulation of bone metabolism by FoxO3a and its mechanism of action in bone diseases and to provide a reference for subsequent studies targeting FoxO3a in the treatment of bone diseases. METHODS: Literature searches were conducted using the following strategies: CNKI (China National Knowledge Infrastructure): SU=FoxO3a OR SU=Foxo3 OR SU=Forkhead box O3 OR SU=AND SU=Forkhead box transcription factor O3) AND SU=bone; WanFang Medical Database: Subject:("FoxO3a") OR Subject:("Foxo3") OR Subject:("Forkhead box O3") OR Subject:("Forkhead box transcription factor O3") AND Subject:("bone"); PubMed: ((FoxO3a) OR (Foxo3) OR (Forkhead box O3))AND ((bone) OR (Skeleton)). Outdated, repetitive, low-quality, and irrelevant studies were excluded, and 56 articles were finally included for review. RESULTS AND CONCLUSION: ①FoxO3a and bone marrow mesenchymal stem cells: FoxO3a can promote the formation of osteogenic lineage and promote early osteogenic differentiation by activating autophagy. Meanwhile, FoxO3a exhibits antioxidant properties in bone marrow mesenchymal stem cells, protecting cells from oxidative stress-induced senescence. ②FoxO3a and osteoblasts: FoxO3a can inhibit osteogenesis by interfering with the Wnt/β-catenin pathway in osteoblasts, while it can activate antioxidant enzymes to protect mature osteoblasts. FoxO3a can promote the proliferation of osteoprogenitor cells and promote osteogenic differentiation by activating autophagy. ③FoxO3a and osteoclasts: FoxO3a expression can resist oxidative stress and activate autophagy to inhibit osteoclastogenesis. ④FoxO3a and osteocytes: FoxO3a can protect osteocytes through antioxidant effects, and can also reduce bone loss by inhibiting p16 and p53 signaling pathways and inhibiting senescence-associated secretory phenotype. ⑤FoxO3a and chondrocytes: FoxO3a plays a protective role in chondrocytes in osteoarthritis, inhibiting chondrocyte breakdown or apoptosis, promoting chondrocyte extracellular matrix synthesis, and inhibiting chondrocyte hypertrophy; however, high co-expression of FoxO3a and Runt-related transcription factor 1 in chondrocytes promotes early chondrogenesis and terminal hypertrophy of chondroprogenitor cells. ⑥FoxO3a affects bone metabolism by participating in processes such as oxidative stress resistance and regulation of autophagy, and participates in the pathological processes of various bone-related diseases.
1. Introduction
Forkhead box transcription factor O3 (FoxO3a), also known as FoxO3, is a human protein encoded by the FoxO3 gene. It is a key transcription factor mediating various physiological and pathological processes, including apoptosis, proliferation, cell cycle progression, survival, and DNA damage response. In mammals, the forkhead box O family includes FoxO1, FoxO3, FoxO4, and FoxO6, which are widely expressed in various tissues and organs. Among them, FoxO3a is most abundantly expressed in bone and bone tissue cells [1].
Bone is a dynamic organ maintained by strictly regulated mechanisms. Under physiological conditions, bone homeostasis is maintained by the intricate balance between bone formation and bone resorption. Under pathological conditions, bone homeostasis is disrupted: oxidative stress-induced DNA damage, apoptosis, and cellular senescence are important causes of tissue dysfunction and bone homeostasis imbalance [2]. As an important transcriptional regulator, FoxO3a plays a crucial role in the cytoplasm or nucleus, regulating the expression of target genes involved in oxidative stress resistance, autophagy, and cell cycle arrest, thereby influencing bone cell fate and bone metabolism.
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Han Jie, Hu Tianfa, Wu Yachao, Nong Bin, Yu Kailong (2026). Forkhead box transcription factor O3 affects bone metabolism and participates in the pathological processes of various bone-related diseases. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21242
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Frequently Asked Questions
What is the role of FoxO3a in bone metabolism?
FoxO3a regulates bone metabolism by modulating oxidative stress and autophagy in bone cells, affecting their proliferation, differentiation, and apoptosis. It promotes osteogenic differentiation of mesenchymal stem cells and osteoprogenitor cells, inhibits osteoclastogenesis, and protects osteocytes and chondrocytes from oxidative stress and senescence.
How does FoxO3a affect osteoporosis?
FoxO3a influences osteoporosis by regulating the balance between bone formation and resorption. It promotes osteoblast differentiation and function, inhibits osteoclast activity, and protects osteocytes from apoptosis and senescence, thereby reducing bone loss.
What is the relationship between FoxO3a and osteoarthritis?
In osteoarthritis, FoxO3a protects chondrocytes by inhibiting their breakdown and apoptosis, promoting extracellular matrix synthesis, and suppressing hypertrophy. However, high co-expression with Runx1 may promote early chondrogenesis and terminal hypertrophy, indicating a complex role.
Can FoxO3a be a therapeutic target for bone diseases?
Yes, FoxO3a is a promising therapeutic target for bone diseases such as osteoporosis, osteoarthritis, and osteonecrosis. Modulating FoxO3a activity could help restore bone homeostasis and treat these conditions.
What are the main signaling pathways involving FoxO3a in bone cells?
FoxO3a interacts with several pathways, including Wnt/β-catenin, PI3K/AKT, and autophagy pathways. It also regulates oxidative stress response genes and senescence-related pathways like p16/p53.
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