Lycium barbarum glycopeptide attenuates orthodontic force-induced alveolar bone loss by activating ATG4D-mediated...

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.

To determine whether LbGP protects alveolar bone during OTM by activating ATG4D-dependent autophagy.

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.

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.

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.