Exosomal circZNF638 promotes postmenopausal osteoporosis progression through MGAT1-mediated SMAD9 glycosylation

PURPOSE: This study aims to investigate the potential regulatory mechanism of circular RNA (circRNA) in postmenopausal osteoporosis (POMP). Understanding the molecular mechanism of POMP is crucial for developing effective therapeutic strategies. MATERIALS AND METHODS: A variety of bioinformatics tools were used to identify candidate circRNAs associated with POMP, and circZNF638 was selected as the target for further investigation. The circular structure of circZNF638 was confirmed through PCR-AGE assay and RNase R treatment. Additionally, exosome identification was performed in osteoclasts with and without circZNF638 overexpression to explore its role in intercellular communication. To assess osteoblast differentiation and mineralization under different experimental conditions, ALP activity detection, alizarin red staining, and Western blot were employed. The levels of N-glycosylation were also meticulously measured. RESULTS: Following the confirmation of the circular structure of circZNF638, it was discovered that exosomal circZNF638 derived from osteoclasts significantly inhibited osteoblast differentiation and mineralization. Mechanistically, circZNF638 was found to recruit EWSR1 to upregulate MGAT1, mediating N-glycosylation of SMAD9, thereby inhibiting osteoblast differentiation and mineralization. CONCLUSIONS: The findings of this study indicate that exosomal circZNF638 derived from osteoclasts plays a pivotal role in promoting the progression of POMP through the MGAT1-mediated N-glycosylation of SMAD9. These insights provide a deeper understanding of the molecular mechanisms underlying POMP.