Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Lycium barbarum glycopeptide attenuates orthodontic force-induced alveolar bone loss by activating ATG4D-mediated autophagy.
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Lai Shuang, Zeng Chuanjie, Fu Yizhe, Mu Yandong
Аннотация
BACKGROUND: Orthodontic tooth movement (OTM) requires a delicate balance between osteoclastic bone resorption and osteoblastic bone formation. Excessive mechanical stress disrupts this coupling, leading to alveolar bone loss. Lycium barbarum glycopeptide (LbGP), a natural bioactive compound with antioxidant and immunomodulatory properties, has been reported to regulate bone metabolism. However, its precise mechanism in orthodontic bone remodeling remains unclear.
PURPOSE: To determine whether LbGP protects alveolar bone during OTM by activating ATG4D-dependent autophagy.
METHODS: An OTM rat model was established for assessing the biological effects and underlying mechanisms of LbGP. Micro-CT and histological analyses were performed to evaluate alveolar bone remodeling. In vitro, bone marrow-derived macrophages (BMDMs), human periodontal ligament stem cells (hPDLSCs), and RAW264.7 cells were used to explore the osteoclastogenic and osteogenic responses under mechanical and inflammatory conditions. RNA-seq, siRNA knockdown, and mCherry-GFP-LC3 reporter assays were conducted to elucidate molecular mechanisms.
RESULTS: LbGP preserved alveolar bone architecture and reduced osteoclast accumulation during OTM. Transcriptomic analysis revealed enrichment of autophagy- and lysosome-related pathways, highlighting ATG4D as a key effector. LbGP increased ATG4D expression and autophagic flux in vivo and in vitro. Knockdown of ATG4D abolished LbGP-induced autophagy and reversed its inhibitory effect on RANKL-c-Fos-NFATc1 signaling while promoting osteogenic differentiation of hPDLSCs and shifted macrophages toward an M2 phenotype.
CONCLUSION: LbGP mitigates orthodontic force-induced alveolar bone loss by activating ATG4D-dependent autophagy, which suppresses excessive osteoclastogenesis and promotes osteogenesis. These findings reveal a novel autophagy-centered mechanism for maintaining bone remodeling balance and support LbGP as a promising adjunctive agent in orthodontic-periodontal therapy.
PURPOSE: To determine whether LbGP protects alveolar bone during OTM by activating ATG4D-dependent autophagy.
METHODS: An OTM rat model was established for assessing the biological effects and underlying mechanisms of LbGP. Micro-CT and histological analyses were performed to evaluate alveolar bone remodeling. In vitro, bone marrow-derived macrophages (BMDMs), human periodontal ligament stem cells (hPDLSCs), and RAW264.7 cells were used to explore the osteoclastogenic and osteogenic responses under mechanical and inflammatory conditions. RNA-seq, siRNA knockdown, and mCherry-GFP-LC3 reporter assays were conducted to elucidate molecular mechanisms.
RESULTS: LbGP preserved alveolar bone architecture and reduced osteoclast accumulation during OTM. Transcriptomic analysis revealed enrichment of autophagy- and lysosome-related pathways, highlighting ATG4D as a key effector. LbGP increased ATG4D expression and autophagic flux in vivo and in vitro. Knockdown of ATG4D abolished LbGP-induced autophagy and reversed its inhibitory effect on RANKL-c-Fos-NFATc1 signaling while promoting osteogenic differentiation of hPDLSCs and shifted macrophages toward an M2 phenotype.
CONCLUSION: LbGP mitigates orthodontic force-induced alveolar bone loss by activating ATG4D-dependent autophagy, which suppresses excessive osteoclastogenesis and promotes osteogenesis. These findings reveal a novel autophagy-centered mechanism for maintaining bone remodeling balance and support LbGP as a promising adjunctive agent in orthodontic-periodontal therapy.