Liraglutide, a GLP-1 Receptor Agonist, Mitigates LPS-Induced Osteoclastogenesis and Bone Loss by Downregulating Macrophage TNF-α Expression

Liraglutide reduced LPS-induced bone loss and osteoclast numbers in mice and lowered RANKL and TNF-α mRNA in calvarial tissue. In vitro, it did not directly suppress osteoclast formation or osteoblast RANKL expression, but it did reduce TNF-α mRNA in LPS-stimulated macrophages. The authors conclude that liraglutide protects against inflammatory bone destruction mainly by downregulating macrophage TNF-α.

Journal article — Mouse model plus in vitro study. Population: Mice with LPS-induced calvarial bone loss; cultured osteoclasts, osteoblasts, and macrophages. Interventions: Liraglutide. Cited by 1 other paper.

In mice, liraglutide co-administered with LPS markedly reduced osteoclast numbers and bone resorption areas compared with LPS alone. RANKL and TNF-α mRNA levels were notably lower in the liraglutide plus LPS group than in LPS alone. In vitro, liraglutide did not directly inhibit RANKL-induced or TNF-α-induced osteoclastogenesis, nor did it affect LPS-stimulated RANKL expression in osteoblasts. However, it effectively suppressed TNF-α mRNA expression in LPS-stimulated macrophages.

Researchers studying liraglutide will find a proposed mechanism by which it limits inflammatory bone destruction: suppressing TNF-α in macrophages rather than acting directly on osteoclasts or osteoblasts. The paper does not establish clinical efficacy, dosing, or a direct causal proof of the TNF-α pathway in humans, and it does not show liraglutide inhibiting osteoclast formation directly.

Key findings

• Co-administration of liraglutide with LPS in mice markedly reduced osteoclast numbers compared with LPS alone.
• Bone resorption areas were markedly reduced in mice receiving liraglutide plus LPS versus LPS alone.
• RANKL mRNA expression was notably lower in the liraglutide plus LPS group than in the LPS-alone group.
• TNF-α mRNA expression was notably lower in the liraglutide plus LPS group than in the LPS-alone group.
• Liraglutide had no direct inhibitory effect on RANKL-induced or TNF-α-induced osteoclastogenesis in vitro.
• Liraglutide effectively suppressed TNF-α mRNA expression in LPS-stimulated macrophages.

Limitations

• Findings are from a mouse calvaria model and in vitro cultures, not human subjects.
• The abstract reports no sample size, dose, or quantitative effect sizes.
• Bone-sparing effects are linked to mRNA changes, not directly demonstrated protein-level or functional outcomes.
• No comparison with other GLP-1 receptor agonists or established bone-resorption therapies.

The record

• Journal: International journal of molecular sciences 27(12): 5624
• Published: 2026-06-22
• PMID: 42353338 — DOI: 10.3390/ijms27125624
• MeSH terms: Macrophages, Osteoclasts, Osteoblasts, Animals, Mice, Inbred C57BL, Mice, Bone Resorption, Lipopolysaccharides, Tumor Necrosis Factor-alpha, Down-Regulation, Osteogenesis, Male, RANK Ligand, Liraglutide, Glucagon-Like Peptide-1 Receptor Agonists
• Funding: Japan Society for the Promotion of Science; Japan Society for the Promotion of Science
• Author countries: Japan

Peptide profiles: Liraglutide.

All indexed evidence: Liraglutide trials & papers.

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