The meniscus is vital for maintaining knee homeostasis and function. Meniscal calcification is one of the earliest radiological indicators of knee osteoarthritis (KOA), and meniscal calcification is associated with alterations in biomechanical properties. Meniscal calcification originates from a biochemical process similar to vascular calcification. Advanced glycation end products (AGEs) and their receptors (RAGEs) reportedly play critical roles in vascular calcification. Herein, we investigated whether targeting AGE-RAGE is a potential treatment for meniscal calcification. In our study, we demonstrated that AGE-RAGE promotes the osteogenesis of meniscal cells and exacerbates meniscal calcification. Mechanistically, AGE-RAGE activates mTOR and simultaneously promotes ATF4 accumulation, thereby facilitating the ATF4-mTOR positive feedback loop that enhances the osteogenic capacity of meniscal cells. In this regard, mTOR inhibits ATF4 degradation by reducing its ubiquitination, while ATF4 activates mTOR by increasing arginine uptake. Our findings substantiate the unique role of AGE-RAGE in the meniscus and reveal the role of the ATF4-mTOR positive feedback loop during the osteogenesis of meniscal cells; these results provide potential therapeutic targets for KOA. In our joints, the meniscus is vital for knee stability and function. Sadly, when the meniscus hardens, it can result in a painful ailment called knee osteoarthritis. This study, led by researchers including Yang Zhang, sought to comprehend the early stages of this hardening process to find treatments before it inflicts substantial damage. This research was an experiment involving human tissue samples and cell cultures to understand the disease mechanisms at a cellular level. The findings indicated that higher AGEs levels correlated with more severe hardening. Researchers hope that their work will lead to new treatments that can prevent or slow down the progression of this debilitating condition. Future studies could build on these findings to develop therapies that help maintain knee health and mobility.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.