Liraglutide regulate osteogenesis-resorption via macrophage under compressive stress

Joint diseases always caused by mechanical pressure induced-inflammation and bone resorption. With advancing age, joint wear-and-tear intensifies while reparative capacity diminishes. Liraglutide is a common medication used to lower blood sugar and improve blood lipids, and it is widely used in elderly patients. This study investigated whether liraglutide (Lira) regulates macrophage-mediated bone metabolism under mechanical pressure and elucidated the molecular mechanisms.

RAW264.7 macrophages were exposed to varying pressures (1-3 g/cm²) via custom-weighted glass coverslips. Cell viability was assessed by CCK-8 and Live/Dead staining. Cells were pretreated with 250 nmol/L Lira, and the expression of osteoclast-related (Piezo1, NFATc1, TRAP) and inflammation-related (TNF-α, iNOS, IL-1β, TRAF6, NF-κB/p-NF-κB) molecules was detected by qRT-PCR, immunofluorescence, and Western blotting. Conditioned media from treated macrophages were used to culture MC3T3-E1 pre-osteoblasts, and osteogenic markers (BMP2, RUNX2, ALP, OCN) were evaluated.

Pressure at 2 g/cm² for 4 h optimally induced osteoclastogenesis and inflammation. Lira did not affect Piezo1 expression but significantly suppressed NFATc1 and TRAP at both mRNA and protein levels. Lira also inhibited the TRAF6-NF-κB pathway, reducing TNF-α, iNOS, and IL-1β expression. Conditioned media from Lira-treated macrophages significantly upregulated BMP2, RUNX2, ALP, and OCN in MC3T3-E1 cells, indicating indirect promotion of osteogenesis.

Liraglutide reverses pressure-induced bone metabolic imbalance through a triple mechanism: inhibiting osteoclastogenesis, attenuating inflammation, and indirectly promoting osteogenesis via macrophage modulation. This study provides the first evidence of liraglutide's molecular network in regulating bone metabolism under mechanical stress, supporting its therapeutic potential in pressure-related degenerative joint diseases such as osteoarthritis and temporomandibular joint osteoarthritis.