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Aging-Associated Methylmalonic Acid Limits Chaperone-Mediated Autophagy to Suppress Osteogenic Differentiation of Mesenchymal Stem Cells

Objectives: Methylmalonic acid (MMA), a byproduct of propionate metabolism, has been identified as an aging-associated metabolite. This study aims to investigate the role of MMA in the osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) during age-related bone loss and to elucidate the underlying mechanism.
Methods: Young (2 months) and aged (18 months) mice was administrated with MMA for μCT analysis of femoral trabecular bone parameters. Osteoblastic mineralization and differentiation of BMMSCs with MMA treatment were analyzed by Alizarin-Red staining, qPCR of osteoblast marker genes and RNA-seq. For the underlying mechanisms, chaperone-mediated autophagy (CMA) activity was assessed by CMA reporter KFERQ-PA-mCherry and LAMP-2A+ HSC70+ vesicles after MMA supplement in vivo and in vitro. Proteomics was performed to explore the tarted protein of MMA-regulated CMA. And the therapeutic effects of CMA activator were also evaluated on MMA-accelerated and aging-related bone loss.
Results: MMA exacerbated age-related bone loss in both young and aged mice, as evidenced by decreased bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th). Additionally, MMA reduced mineralized nodules and the expression levels of Runx2, Sp7, Spp1, Alpl, and Bglap in BMMSCs under osteoblast culture conditions. RNA-seq analysis revealed downregulation of the BMP/Smad and PTH/Pth1r pathways, together indicating the inhibitory effects of MMA on the osteoblast differentiation of BMMSCs. Mechanistically, MMA suppressed LAMP2A expression, thereby impairing the CMA-mediated degradation of Sufu, a repressor of the Hedgehog pathway. Therapeutically, activation of CMA mitigated MMA-accelerated and aging-related bone loss in vivo.
Conclusions: Aging-associated methylmalonic acid limits chaperone-mediated autophagy to suppress osteogenic differentiation of mesenchymal stem cells, thereby fostering aging-related bone loss.
Division:
Meeting: 2025 IADR/PER General Session & Exhibition (Barcelona, Spain)
Location: Barcelona, Spain
Year: 2025
Final Presentation ID: 0559
Abstract Category|Abstract Category(s): Mineralized Tissue
Authors
  • Gu, Yuting  ( Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , Shanghai , China )
  • Yu, Weijun  ( Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , Shanghai , China )
  • Lin, Lu  ( Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , Shanghai , China )
  • Li, Guanglong  ( Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , Shanghai , China )
  • Tang, Minhao  ( Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , Shanghai , China )
  • Jin, Min  ( Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , Shanghai , China )
  • Lu, Eryi  ( Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , Shanghai , China )
    • Support Funding Agency/Grant Number: National Natural Science Foundation of China (52171075, 82271589, 82401140)
    Financial Interest Disclosure: NONE
    SESSION INFORMATION
    Poster Session
    Mineralized Tissue I
    Thursday, 06/26/2025 , 11:00AM - 12:15PM