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To investigate the role of DPP-4 inhibition in inflammation-induced bone resorption, we evaluated the effect of a DPP-4 inhibitor on LPS-induced osteoclast formation and bone-resorption in vivo. Our results showed that the DPP-4 inhibitor inhibited LPS-induced osteoclast formation and bone resorption in vivo, while also suppressing LPS-induced RANKL, TNF-α, and M-CSF expression in vivo. However, the DPP-4 inhibitor did not directly inhibit RANKL-induced osteoclast formation, TNF-α-induced osteoclast formation, osteoclast precursor cell viability, or LPS-induced RANKL expression in stromal Triflurdine in vitro. Furthermore, although the DPP-4 inhibitor prevented LPS-induced TNF-α expression in macrophages in vivo, TNF-α expression in macrophages was not inhibited in the LPS and DPP-4 co-treated macrophages, compared with those treated with LPS in vitro. These results suggest a potential role for DPP-4 inhibition in inflammation-induced bone resorption through indirect modulation of osteoclasts, although our results were inadequate to fully elucidate the underlying mechanisms. In a rat model, DPP-4 inhibition by linagliptin improved vascular dysfunction and oxidative stress levels after LPS injection, demonstrated by a reduced number of infiltrating CD11b/c-positive cells in the vessel wall and reduced adhesion of human monocytes and granulocytes to cultured endothelial cells . Furthermore, DPP-4 inhibition resulted in improved survival, vascular inflammation, and dysfunction in animals with LPS-induced endotoxemia. Thus, DPP-4 inhibition attenuated LPS-induced effects . In this study, DPP-4 inhibition impeded LPS-induced effects, which constituted osteoclast formation, bone resorption, and expression of osteoclast-related cytokines. Our results were consistent with those of other studies. The histological results in this study revealed the inhibitory capacity of exogenous DPP-4 inhibitor during LPS-induced osteoclast formation. Daily injection of 30 μg/day (nearly 1.5 mg/kg/day) linagliptin as DPP-4 inhibitor (a total of 150 μg DPP-4 inhibitor) was sufficient to effectively inhibit LPS-induced osteoclast formation in vivo. Previous studies used 3–5 mg/kg/day linagliptin by gavage, once daily for 5–6 days [45,46]. We used a lower dose, which was sufficient to evoke the inhibitory effects of linagliptin. Expression levels of osteoclast markers, such as TRAP and cathepsin K mRNA, were also significantly reduced in the LPS and DPP-4 inhibitor co-administered group, compared with the LPS-administered group. Furthermore, we evaluated the inhibitory effect of DPP-4 inhibitor on LPS-induced bone resorption. The magnitude of bone resorption was evaluated by bone destruction area and serum CTX level. We found that bone destruction was significantly lower in the LPS and DPP-4 inhibitor co-administered group than in the LPS-administered group. These results indicated that both functional markers and the erosive capacity of osteoclasts were inhibited by DPP-4 inhibitor in vivo. Some studies have investigated the relationship between the use of DPP-4 inhibitors and fracture risk; they showed that DPP-4 inhibitors can reduce the risk of fractures. Notably, DPP-4 inhibitors improve bone metabolism by increasing bone density and bone quality. DPP-4 inhibitors can upregulate bone formation markers and downregulate bone resorption markers [, , , ]. In the present study, we found that DPP-4 inhibition also attenuated inflammation-induced bone resorption. Thus, DPP-4 inhibition may be useful as a therapy for inflammation-induced bone-resorbing diseases. We suspect that DPP-4 inhibitor suppresses LPS-induced osteoclast formation and bone resorption in vivo through either of two possible mechanisms. One mechanism involves the DPP-4 inhibitor blocking expression of LPS-induced cytokines that are related to osteoclast formation. RANKL, TNF-α, and M-CSF are important factors for osteoclast formation [10,14,15]; many papers have indicated that LPS can induce TNF-α and RANKL expression in vivo [21,47,22]. In this study, TNF-α, RANKL, and M-CSF mRNA expression was elevated in LPS-administered mice. In contrast, TNF-α, RANKL, and M-CSF mRNA expression was inhibited in DPP-4 inhibitor and LPS co-administered mice, compared with LPS-administered mice. Our results were compatible with the hypothesis that DPP-4 inhibitor suppresses osteoclast formation by inhibiting the expression of LPS-induced osteoclast-related cytokines. The other possible mechanism of DPP-4 inhibitor suppression is that DPP-4 inhibitor directly inhibits osteoclast formation by affecting cell differentiation or proliferation of osteoclast precursors. Our results indicated no inhibitory effect of DPP-4 inhibitor on RANKL and TNF-α-induced osteoclast formation, suggesting that the DPP-4 inhibitor was incapable of regulating the differentiation of osteoclast precursors induced by RANKL or TNF-α. Furthermore, we evaluated whether the DPP-4 inhibitor affected cell viability of osteoclast precursors. The levels of cell viability did not differ after culture for 5 days in all cultures. We performed a dose-dependent experiment. Notably, 0, 1, 10 100 and 1000 ng/ml DPP-4 inhibitor did not inhibit RANKL-induced osteoclast formation, TNF-α-induced osteoclast formation, or cell viability (Supplement Fig.1). Taken together, our data suggest that the inhibitory effect of the DPP-4 inhibitor on osteoclast formation might not arise from a direct action of the inhibitor on osteoclast precursors. As DPP-4 inhibitor can inhibit the function of DPP-4, we evaluated whether DPP-4 is important for osteoclast formation. The addition of several doses of DPP-4 did not affect osteoclast formation, suggesting that the in vivo inhibition of osteoclast formation might not be a result of inhibited DPP-4 function.