Effects of the glucagon-like peptide-1 receptor agonist PEG-Loxe on diabetic osteoporosis: A mechanistic study

Background

Diabetic osteoporosis is characterized by disrupted bone remodeling involving impaired osteogenesis and excessive osteoclastic activity. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have hypoglycemic benefits, their effects on bone metabolism remain unclear. This study investigates the osteoprotective potential of polyethylene glycol loxenatide (PEG-Loxe), a GLP-1RA hypoglycemic drug.

Methods

In vitro studies involved MC3T3-E1 osteoblasts and RANKL-stimulated RAW264.7 osteoclasts, both treated with 100 nM PEG-Loxe. Osteogenic markers (ALP, Col-1, and Runx2) and osteoclast differentiation were assessed, and HMGB-1 overexpression was used to validate pathway involvement. For in vivo studies, type 2 diabetic ApoE^−/− mice were treated with PEG-Loxe. We examined serum markers (CTX, HMGB-1, TNF-α, and IL-1β) and performed micro-CT and histomorphometric analyses. In clinical research, serum markers and BMD were analysed.

Results

PEG-Loxe has dual regulatory effects. PEG-Loxe can significantly enhance osteoblast differentiation (increased ALP, Col-1 and Runx2 activities, p < 0.001) and suppressing osteoclastogenesis by inhibiting HMGB-1/RAGE/TLR4/NF-κB pathway (p < 0.001). In ApoE^−/− mice, PEG-Loxe increased osteoblasts and reduced osteoclasts. RAGE, HMGB-1, TNF-α, and IL-1β were reduced to varying degrees (p < 0.05; p < 0.01; p < 0.01; p < 0.01). Micro CT scanning of 3D images of mouse femurs showed that PEG-Loxe can increase femoral tissue and reduce porosity. In clinical research,CTX, HMGB-1, TNF-α, and IL-1β were significantly reduced in the PEG-Loxe group compared to the Non-PEG-Loxe group (p < 0.05). There was no significant difference in BMD between the two groups.

Conclusions

PEG-Loxe exerts comprehensive osteoprotective effects in type 2 diabetes by simultaneously promoting osteogenesis and suppressing osteoclastogenesis, through modulation of HMGB-1 signaling. PEG-Loxe can significantly improve bone turnover status and reduce bone resorption levels, with potential osteoprotective effects.