The Roles of Forkhead Box O3a (FOXO3a) in Bone and Cartilage Diseases - A Narrative Review

Abstract

Bone and cartilage diseases are significantly associated with musculoskeletal disability. However, no effective drugs are available to cure them. FOXO3a, a member of the FOXO family, has been implicated in cell proliferation, ROS detoxification, autophagy, and apoptosis. The biological functions of FOXO3a can be modulated by post-translational modifications (PTMs), such as phosphorylation and acetylation. Several signaling pathways, such as MAPK, NF-κB, PI3K/AKT, and AMPK/Sirt1 pathways, have been implicated in the development of bone and cartilage diseases by mediating the expression of FOXO3a. In particular, FOXO3a acts as a transcriptional factor in mediating the expression of various genes, such as MnSOD, CAT, BIM, BBC3, and CDK6. FOXO3a plays a critical role in the metabolism of bone and cartilage. In this article, we mainly discussed the biological functions of FOXO3a in bone and cartilage diseases, such as osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and intervertebral disc degeneration (IDD). FOXO3a can promote osteogenic differentiation, induce osteoblast proliferation, inhibit osteoclast activity, suppress chondrocyte apoptosis, and reduce inflammatory responses. Collectively, up-regulation of FOXO3a expression shows beneficial effects, and FOXO3a has become a potential target for bone and cartilage diseases.

Keywords: FOXO3a; ankylosing spondylitis; intervertebral disc degeneration; osteoarthritis; osteoporosis; rheumatoid arthritis.

Graphical abstract

Figure 1

The sequence and functional domains of FOXO family members are shown. Four FOXO family members (FOXO1, FOXO3a, FOXO4, and FOXO6) have more than 30% of identity in amino acid sequences and appropriate 90% of similarity in the FH domain. There are three CRs, including CR1, CR2, and CR3, in four FOXO family members. FOXO3a contains NES1 and NES2 sequences.

Figure 2

The phosphorylation modification of FOXO3a has been shown. FOXO3a can be phosphorylated by AKT, SGK, AMPK, MST1, MK5, p38, JNK, ERK, and IKK. Phosphorylation at Thr32, Ser253, Ser294, Ser344, Ser425, and Ser644 can induce nuclear export. In contrast, phosphorylation at Ser7, Ser207, Ser212, and Ser574 can induce nuclear translocation. ERK-induced Ser12 phosphorylation and AMPK-induced Ser30 phosphorylation promote the mitochondrial accumulation of FOXO3a.

Figure 3

A schematic diagram shows the regulation of FOXO3a and its role in transcriptional activity. Activated PI3K/AKT can induce FOXO3a phosphorylation and the interaction of p-FOXO3a and 14-3-3, leading to nuclear export. Then, FOXO3a undergoes ubiquitination and proteasomal degradation. IKKs also promote the proteasomal degradation of FOXO3a. However, AMPK and Sirt1 promote FOXO3a nuclear translocation and transcriptional activity in mediating the downstream factors, such as BIM, BBC3, MnSOD, and CD6. Mitochondrial Sirt3 activates FOXO3a, which decreases ROS production by up-regulating MnSOD expression.