Next we evaluated whether DPP inhibitor suppressed osteoclas
Next, we evaluated whether DPP-4 inhibitor suppressed osteoclast formation by downregulating LPS-induced RANKL expression in stromal cells; DPP-4 inhibitor did not inhibit LPS-induced RANKL expression. Furthermore, we evaluated the effect of DPP-4 on LPS-induced RANKL expression in stromal cells, but found no effect of DPP-4 on LPS-induced RANKL expression. These results suggest that the inhibitory effect on LPS-induced RANKL expression might not be a result of direct action of DPP-4 inhibitor on stromal DNA Damage DNA Repair Library or a result of inhibited DPP-4 function. As our in vivo result showed lower RANKL expression in calvarial bones, other mechanisms may exist that modulate RANKL expression.
Since macrophages are the major source of TNF-α, we also evaluated whether DPP-4 inhibitor impacted LPS-induced TNF-α expression in peritoneal macrophages. In our study, DPP-4 inhibitor inhibited LPS-induced TNF-α expression in macrophages in vivo. However, our in vitro results indicated that TNF-α mRNA expression was not reduced in macrophages that were treated with LPS and DPP-4, compared with those that were treated with LPS alone. It is likely that other cells or mediators participate in the inhibitory effect of the DPP-4 inhibitor. Further research is required to clarify this issue. In contrast with our results, a previous study has reported that DPP-4 inhibitor suppressed LPS-induced TNF-α expression in cultured monocytes . The discrepant results between the two studies might be related to the use of different DPP-4 inhibitors. We used linagliptin in the present study, whereas the other investigators used anagliptin. As TNF-α can induce osteoclast formation and promote RANKL and M-CSF expression in stromal cells , the in vivo inhibition of LPS-induced osteoclast formation by DPP-4 inhibitor may be caused by the prevention of LPS-induced TNF-α expression in macrophages and the subsequent suppression of RANKL and M-CSF expression in stromal cells (Fig. 6).
Declarations of interest
Acknowledgments This work was supported in part by a JSPS KAKENHI grant from the Japan Society for the Promotion of Science (No. 16K11776 to H. K., No. 17K17306 to K. S., No. 16K20637 to K. K., No. 16K20636 to M. S.). The funding agency did not influence the study design; the collection, analysis and interpretation of data; the writing of the report; or the decision to submit the paper for publication.
Introduction Myocardial infarction (MI) is one of the major complications of type 2 diabetes mellitus (T2DM). MI-induced myocardial ischemia causes necrosis and inflammation of myocardium, and subsequently the repair process of injured tissue occurs. This repair process, so called cardiac remodeling, is regulated predominantly by cardiac fibroblasts. They contribute to tissue replacement and interstitial fibrosis following cardiac injury. The excessive synthesis of extracellular matrix causes loss of elasticity and contractility of the heart. Some known oral hypoglycemic agents for T2DM, such as pioglitazone (thiazolidinediones) and metformin (biguanides), are reported to suppress the development of cardiac remodeling experimentally.2, 3 However, in clinical settings, there is little evidence of anti-remodeling effect of these agents, apart from inhibitors of renin-angiotensin system and beta-adrenergic antagonists. DPP-4 (also known as CD26) is a novel therapeutic target for T2DM. DPP-4 is a membrane-bound X-prolyl dipeptidyl peptidase, which involves the degradation of chemokines, such as stromal-cell derived factor 1 (SDF-1) and macrophage derived chemokine, and incretins, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).4, 5, 6 Therefore, it is thought that DPP-4 inhibitors not only improve impaired glucose tolerance but also have anti-inflammatory effect and other pleiotropic extra-pancreatic effects. It has been known that both GLP-1 and SDF-1 have cardioprotective effect for ischemic myocardium,7, 8, 9 and several papers experimentally demonstrated that DPP-4 inhibitors attenuate cardiac remodeling after MI via the upregulation of their substrates.10, 11 However, it remains unclear whether cardioprotective effect of DPP-4 inhibitors depends only on blockage of degradation of DPP-4 substrates. Therefore, we investigated whether DPP-4 inhibitors have a cardioprotective effect independently of DPP-4.