FTO-mediated SMAD2 m6A modification protects cartilage against Osteoarthritis

Abstract

N6-methyladenosine (m6A) modification is one of the most prevalent forms of epigenetic modification and plays an important role in the development of degenerative diseases such as osteoarthritis (OA). However, the evidence concerning the role of m6A modification in OA is insufficient. Here, m6A modification was increased in human OA cartilage and degenerated chondrocytes. Among all of the m6A enzymes, the expression of the demethylase fat mass and obesity-associated protein (FTO) decreased dramatically. Conditional knockout of FTO in chondrocytes accelerates OA progression. FTO transcription is regulated by runt-related transcription factor-1 (RUNX1). Reduced FTO elevates m6A modification at the adenosine N6 position in SMAD family member 2 (SMAD2) mRNA, whose stability is subsequently modulated by the recruited m6A reader protein YTH N6-methyladenosine RNA binding protein F2 (YTHDF2). Collectively, these findings reveal the function and mechanism of the m6A family member FTO in OA progression. Therefore, reducing m6A modification to increase SMAD2 stability by activating FTO might be a potential therapeutic strategy for OA treatment. Osteoarthritis is a widespread joint disease-causing pain and disability. It involves the deterioration of joint cartilage and bone, but the exact reasons are unclear. This study aimed to investigate the role of a specific change in RNA molecules, called N6-methyladenosine, in OA development. The researchers focused on the enzyme FTO, which can remove this change, and its effect on cartilage cells in mice. They used different methods, including genetic modification to create mice lacking FTO in their cartilage cells, to see how changes in m6A levels affect OA progression. The main findings show that reducing FTO expression worsens OA progression by affecting the stability and function of specific RNA molecules in cartilage cells. The researchers conclude that targeting the m6A change pathway, especially by modulating FTO activity, could provide new treatment strategies for OA. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.