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

Zhenyu Wu,1,2 Wang Zhan,2 Longhuo Wu,3 Luhu Yu,4 Xunlu Xie,5 Fang Yu,6 Weihao Kong,6 Shengrong Bi,6 Shiwei Liu,6 Guoqiang Yin,7 Jianguo Zhou6 1Department of Medical Imaging, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People’s Republic of China; 2First Clinical Medical College, Gannan Medical University, Ganzhou, 341000, People’s Republic of China; 3College of Pharmacy, Gannan Medical University, Ganzhou, 341000, People’s Republic of China; 4Department of Clinical Laboratory, Ganzhou People’s Hospital, Ganzhou, 341000, People’s Republic of China; 5Department of Pathology, Ganzhou People’s Hospital, Ganzhou, 341000, People’s Republic of China; 6Department of Joint Surgery, Ganzhou People’s Hospital, Ganzhou, 341000, People’s Republic of China; 7Department of Joint Surgery, Ganzhou Hospital Affiliated to Nanchang University, Ganzhou, 341000, People’s Republic of ChinaCorrespondence: Jianguo Zhou, Email [email protected]: 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, osteoporosis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, intervertebral disc degeneration