Gene · 2026
NAT10-mediated ac4C modification of BMP6 regulates osteogenic differentiation of bone marrow-derived mesenchymal stem cells in the pathogenesis of Adolescent idiopathic scoliosis.
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Li Yuezhong, Yang Sen, Zhang Junshan
Аннотация
BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal deformity. Bone morphogenetic protein 6 (BMP6) drives osteogenesis; this study probes BMP6 mechanism and its potential role in the impaired osteogenic differentiation of AIS-BMSCs.
METHODS: AIS-BMSCs were isolated and their surface markers (CD34, CD45, CD90, and CD105) were analyzed by flow cytometry. Osteogenic differentiation was assessed through alizarin red S staining quantification and ALP activity assays, while the expression of osteogenic markers osteocalcin (OCN), runt-related transcription factor 2 (RUNX2), BMP6, N-acetyltransferase 10 (NAT10), and Smad1/5/9 signaling pathway was detected by Western blot. The transcriptional and protein levels of BMP6 and NAT10, as well as knockdown and overexpression efficiencies, were measured by qPCR and Western blot. Cell viability was determined using the CCK-8 assay. Potential N4-acetylcytidine (ac4C) modification sites in BMP6 were predicted using the PACES webserver. The interaction between NAT10 and BMP6 was examined by RNA immunoprecipitation (RIP) and luciferase reporter assays. Rescue assays confirmed NAT10 pro-osteo effect requires BMP6.
RESULTS: AIS-BMSCs showed reduced ALP activity, mineralization capacity, and RUNX2/OCN expression, along with downregulated BMP6 expression; BMP6 re-expression rescued these deficits in vitro. NAT10 mediates ac4C acetylation of BMP6 mRNA, extending its half-life and boosting osteogenesis, whereas inhibition of NAT10 or ac4C modification reversed these effects. BMP6 knockdown abolished NAT10-enhanced mineralization and p-Smad1/5/9, indicating that NAT10 acts via BMP6-Smad1/5/9.
CONCLUSION: NAT10-mediated ac4C modification stabilizes BMP6 mRNA, activates Smad1/5/9, and ameliorates the impaired osteogenic differentiation of AIS-BMSCs in vitro. These findings suggest a potential mechanism by which NAT10-BMP6 signaling may influence osteogenesis in AIS, but they are based solely on in vitro experiments.
METHODS: AIS-BMSCs were isolated and their surface markers (CD34, CD45, CD90, and CD105) were analyzed by flow cytometry. Osteogenic differentiation was assessed through alizarin red S staining quantification and ALP activity assays, while the expression of osteogenic markers osteocalcin (OCN), runt-related transcription factor 2 (RUNX2), BMP6, N-acetyltransferase 10 (NAT10), and Smad1/5/9 signaling pathway was detected by Western blot. The transcriptional and protein levels of BMP6 and NAT10, as well as knockdown and overexpression efficiencies, were measured by qPCR and Western blot. Cell viability was determined using the CCK-8 assay. Potential N4-acetylcytidine (ac4C) modification sites in BMP6 were predicted using the PACES webserver. The interaction between NAT10 and BMP6 was examined by RNA immunoprecipitation (RIP) and luciferase reporter assays. Rescue assays confirmed NAT10 pro-osteo effect requires BMP6.
RESULTS: AIS-BMSCs showed reduced ALP activity, mineralization capacity, and RUNX2/OCN expression, along with downregulated BMP6 expression; BMP6 re-expression rescued these deficits in vitro. NAT10 mediates ac4C acetylation of BMP6 mRNA, extending its half-life and boosting osteogenesis, whereas inhibition of NAT10 or ac4C modification reversed these effects. BMP6 knockdown abolished NAT10-enhanced mineralization and p-Smad1/5/9, indicating that NAT10 acts via BMP6-Smad1/5/9.
CONCLUSION: NAT10-mediated ac4C modification stabilizes BMP6 mRNA, activates Smad1/5/9, and ameliorates the impaired osteogenic differentiation of AIS-BMSCs in vitro. These findings suggest a potential mechanism by which NAT10-BMP6 signaling may influence osteogenesis in AIS, but they are based solely on in vitro experiments.