Abstract: BACKGROUND: Linagliptin exhibits the capacity to regulate macrophage polarization, shifting them from the pro-inflammatory M1 phenotype towards the anti-inflammatory M2 phenotype. This alteration results in a dampened release of inflammatory mediators, thereby mitigating local inflammation. 
OBJECTIVE: To explore the effects of linagliptin on macrophage polarization, osteoclast activation, and inflammatory osteolysis elicited by wear particles.
METHODS: (1) Cell experiments: For macrophage polarization, RAW264.7 cells were cultured and divided into four groups: the control group received high-glucose culture medium; the M1-induced group received M1-inducing culture medium (high-glucose culture medium containing 100 ng/mL lipopolysaccharide and 20 ng/mL interferon-γ) to simulate an inflammatory environment; the low- and high-dose linagliptin groups were treated with 50 and 200 nmol/L linagliptin, respectively, for 4 hours before exposure to M1-inducing culture medium. After 24 hours of macrophage polarization induction, immunofluorescence staining and RT-PCR were performed. For osteoclast activation, RAW264.7 cells were cultured and divided into four groups: the control group was cultured with high-glucose culture medium, the osteoclast-induced group and low- and high-dose linagliptin groups were subjected to osteoclast induction. After osteoclast formation, cells were treated with linagliptin (50 and 200 nmol/L) for 3 days. Subsequently, cell tartrate-resistant acid phosphatase staining and RT-PCR were performed. (2) Animal experiments: Twenty-four male C57BL/6J mice were randomly divided into four groups: sham operation group, model group, low-dose linagliptin group, and high-dose linagliptin group. The model group, low-dose linagliptin group, and high-dose linagliptin group were induced to establish a cranial bone resorption model by injecting titanium particle suspension onto the surface of the skull. Starting from the 2nd day after modeling, the low- and high-dose linagliptin groups were orally administered linagliptin (2 and 10 mg/kg, respectively) once daily. After modeling for 3 weeks, serum macrophage polarization marker protein and inflammatory factor levels were detected; skull samples were collected for micro-CT scanning, bone parameter analysis, and hematoxylin-eosin staining to evaluate osteolysis and morphological changes.
RESULTS AND CONCLUSION: (1) Cell experiments: Both low and high doses of linagliptin significantly suppressed M1 polarization while promoting M2 polarization compared to the M1-induced group (P < 0.01). Notably, the high-dose group exhibited a more pronounced inhibitory effect (P < 0.01). Inflammatory factor mRNA expression was elevated in the M1-induced group compared with the control group (P < 0.01), whereas inflammatory factor mRNA expression was significantly lower in the low- and high-dose linagliptin groups compared with the M1-induced group (P < 0.01). There was a significant upregulation of mRNA expression of osteoclast functional markers in the osteoclast-induced group compared with the control group (P < 0.01). Conversely, both low and high doses of linagliptin led to a substantial downregulation of mRNA expression of these markers compared with the osteoclast-induced group (P < 0.01), with the high-dose group exhibiting a more pronounced reduction. (2) Animal experiments: Titanium particle implantation induced cranial bone resorption damage in mice. Treatment with linagliptin effectively mitigated this bone resorption, with the high-dose group showing superior efficacy. To conclude, linagliptin has been shown to modulate macrophage polarization, inhibit osteoclast activation, and have a protective effect on the skeletal system.   
中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: linagliptin, macrophage polarization, osteoclast activation, abrasion particles, aseptic prosthesis loosening, periprosthetic osteolysis