PDF(Pubmed)
Abstract：
BACKGROUND: Dipeptidyl peptidase 4 (DPP-4) plays a crucial role in breaking down various substrates. It also has effects on the insulin signaling pathway, contributing to insulin resistance, and involvement in inflammatory processes like obesity and type 2 diabetes mellitus. Emerging effects of DPP-4 on bone metabolism include an inverse relationship between DPP-4 activity levels and bone mineral density, along with an increased risk of fractures.
METHODS: The influence of DPP-4 on bone metabolism occurs through two axes. The entero-endocrine-osseous axis involves gastrointestinal substrates for DPP-4, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptides 1 (GLP-1) and 2 (GLP-2). Studies suggest that supraphysiological doses of exogenous GLP-2 has a significant inhibitory effect on bone resorption, however the specific mechanism by which GLP-2 influences bone metabolism remains unknown. Of these, GIP stands out for its role in bone formation. Other gastrointestinal DPP-4 substrates are pancreatic peptide YY and neuropeptide Y-both bind to the same receptors and appear to increase bone resorption and decrease bone formation. Adipokines (e.g., leptin and adiponectin) are regulated by DPP-4 and may influence bone remodeling and energy metabolism in a paracrine manner. The pancreatic-endocrine-osseous axis involves a potential link between DPP-4, bone, and energy metabolism through the receptor activator of nuclear factor kappa B ligand (RANKL), which induces DPP-4 expression in osteoclasts, leading to decreased GLP-1 levels and increased blood glucose levels. Inhibitors of DPP-4 participate in the pancreatic-endocrine-osseous axis by increasing endogenous GLP-1. In addition to their glycemic effects, DPP-4 inhibitors have the potential to decrease bone resorption, increase bone formation, and reduce the incidence of osteoporosis and fractures. Still, many questions on the interactions between DPP-4 and bone remain unanswered, particularly regarding the effects of DPP-4 inhibition on the skeleton of older individuals.
CONCLUSIONS: The elucidation of the intricate interactions and impact of DPP-4 on bone is paramount for a proper understanding of the body\'s mechanisms in regulating bone homeostasis and responses to internal stimuli. This understanding bears significant implications in the investigation of conditions like osteoporosis, in which disruptions to these signaling pathways occur. Further research is essential to uncover the full extent of DPP-4\'s effects on bone metabolism and energy regulation, paving the way for novel therapeutic interventions targeting these pathways, particularly in older individuals.
METHODS: The influence of DPP-4 on bone metabolism occurs through two axes. The entero-endocrine-osseous axis involves gastrointestinal substrates for DPP-4, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptides 1 (GLP-1) and 2 (GLP-2). Studies suggest that supraphysiological doses of exogenous GLP-2 has a significant inhibitory effect on bone resorption, however the specific mechanism by which GLP-2 influences bone metabolism remains unknown. Of these, GIP stands out for its role in bone formation. Other gastrointestinal DPP-4 substrates are pancreatic peptide YY and neuropeptide Y-both bind to the same receptors and appear to increase bone resorption and decrease bone formation. Adipokines (e.g., leptin and adiponectin) are regulated by DPP-4 and may influence bone remodeling and energy metabolism in a paracrine manner. The pancreatic-endocrine-osseous axis involves a potential link between DPP-4, bone, and energy metabolism through the receptor activator of nuclear factor kappa B ligand (RANKL), which induces DPP-4 expression in osteoclasts, leading to decreased GLP-1 levels and increased blood glucose levels. Inhibitors of DPP-4 participate in the pancreatic-endocrine-osseous axis by increasing endogenous GLP-1. In addition to their glycemic effects, DPP-4 inhibitors have the potential to decrease bone resorption, increase bone formation, and reduce the incidence of osteoporosis and fractures. Still, many questions on the interactions between DPP-4 and bone remain unanswered, particularly regarding the effects of DPP-4 inhibition on the skeleton of older individuals.
CONCLUSIONS: The elucidation of the intricate interactions and impact of DPP-4 on bone is paramount for a proper understanding of the body\'s mechanisms in regulating bone homeostasis and responses to internal stimuli. This understanding bears significant implications in the investigation of conditions like osteoporosis, in which disruptions to these signaling pathways occur. Further research is essential to uncover the full extent of DPP-4\'s effects on bone metabolism and energy regulation, paving the way for novel therapeutic interventions targeting these pathways, particularly in older individuals.
摘要：
背景：二肽基肽酶4（DPP-4）在分解各种底物中起关键作用。它也对胰岛素信号通路有影响，导致胰岛素抵抗，并参与炎症过程，如肥胖和2型糖尿病。DPP-4对骨代谢的新作用包括DPP-4活性水平与骨矿物质密度之间的反比关系。伴随着骨折的风险增加。
方法：DPP-4对骨代谢的影响通过两个轴发生。肠-内分泌-骨轴涉及DPP-4的胃肠底物,包括葡萄糖依赖性促胰岛素多肽(GIP)和胰高血糖素样肽1(GLP-1)和2(GLP-2)。研究表明，超生理剂量的外源性GLP-2对骨吸收有显著的抑制作用，然而,GLP-2影响骨代谢的具体机制尚不清楚.其中,GIP因其在骨形成中的作用而脱颖而出。其他胃肠道DPP-4底物是胰腺肽YY和神经肽Y-两者都与相同的受体结合并且似乎增加骨吸收并减少骨形成。脂肪因子(例如，瘦素和脂联素）受DPP-4调节，可能以旁分泌方式影响骨重塑和能量代谢。胰腺-内分泌-骨轴涉及DPP-4，骨，和能量代谢通过核因子κB受体激活剂配体（RANKL），诱导DPP-4在破骨细胞中的表达，导致GLP-1水平降低和血糖水平升高。DPP-4的抑制剂通过增加内源性GLP-1参与胰腺-内分泌-骨轴。除了它们的血糖效应，DPP-4抑制剂具有降低骨吸收的潜力，增加骨形成，减少骨质疏松和骨折的发生率。尽管如此，关于DPP-4和骨骼之间相互作用的许多问题仍然没有答案，特别是关于DPP-4抑制对老年人骨骼的影响。
结论：阐明DPP-4对骨骼的复杂相互作用和影响对于正确理解人体调节骨骼稳态和对内部刺激的反应的机制至关重要。这种理解在骨质疏松症等疾病的调查中具有重要意义，其中这些信号通路发生中断。进一步的研究对于揭示DPP-4对骨代谢和能量调节的全面影响至关重要。为针对这些途径的新型治疗干预铺平了道路，尤其是老年人。
方法：DPP-4对骨代谢的影响通过两个轴发生。肠-内分泌-骨轴涉及DPP-4的胃肠底物,包括葡萄糖依赖性促胰岛素多肽(GIP)和胰高血糖素样肽1(GLP-1)和2(GLP-2)。研究表明，超生理剂量的外源性GLP-2对骨吸收有显著的抑制作用，然而,GLP-2影响骨代谢的具体机制尚不清楚.其中,GIP因其在骨形成中的作用而脱颖而出。其他胃肠道DPP-4底物是胰腺肽YY和神经肽Y-两者都与相同的受体结合并且似乎增加骨吸收并减少骨形成。脂肪因子(例如，瘦素和脂联素）受DPP-4调节，可能以旁分泌方式影响骨重塑和能量代谢。胰腺-内分泌-骨轴涉及DPP-4，骨，和能量代谢通过核因子κB受体激活剂配体（RANKL），诱导DPP-4在破骨细胞中的表达，导致GLP-1水平降低和血糖水平升高。DPP-4的抑制剂通过增加内源性GLP-1参与胰腺-内分泌-骨轴。除了它们的血糖效应，DPP-4抑制剂具有降低骨吸收的潜力，增加骨形成，减少骨质疏松和骨折的发生率。尽管如此，关于DPP-4和骨骼之间相互作用的许多问题仍然没有答案，特别是关于DPP-4抑制对老年人骨骼的影响。
结论：阐明DPP-4对骨骼的复杂相互作用和影响对于正确理解人体调节骨骼稳态和对内部刺激的反应的机制至关重要。这种理解在骨质疏松症等疾病的调查中具有重要意义，其中这些信号通路发生中断。进一步的研究对于揭示DPP-4对骨代谢和能量调节的全面影响至关重要。为针对这些途径的新型治疗干预铺平了道路，尤其是老年人。
