Lack of endogenous parathyroid hormone delays fracture healing by inhibiting vascular endothelial growth factor‑mediated angiogenesis.
Lack of endogenous parathyroid hormone delays fracture healing by inhibiting vascular endothelial growth factor‑mediated angiogenesis.
复制标题
内源性甲状旁腺激素缺乏会抑制血管内皮生长因子介导的血管生成，从而延迟骨折愈合
DOI：
10.3892/ijmm.2018.3614
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发表时间：
2018-07
影响因子：
5.4
通讯作者：
Fan J
中科院分区：
文献类型：
--
作者：
Ding Q;Sun P;Zhou H;Wan B;Yin J;Huang Y;Li Q;Yin G;Fan J
据报道，间歇性低剂量注射甲状旁腺激素（PTH）可发挥骨合成代谢作用，促进骨折愈合。血管内皮生长因子（vascular endothelial growth factor，VEGF）是由骨髓间充质干细胞（bone marrow mesenchymal stem cells，BMSCs）和成骨细胞（osteoblasts）分泌的一种重要的促血管生成细胞因子，在血管的发育和再生过程中起着重要的调节作用。为了研究内源性PTH的缺乏是否导致血管生成能力降低，从而通过下调VEGF信号传导途径延迟骨折愈合的过程，产生了PTH敲除（PTHKO）小鼠骨折模型。用X线片和微型计算机断层扫描观察骨折愈合情况。骨合成代谢和血管生成标记物通过免疫组织化学和蛋白质印迹分析进行分析。采用定量聚合酶链反应和蛋白质印迹法检测VEGF及其相关信号通路在小鼠骨髓基质细胞成骨细胞中的表达水平。PTHKO小鼠BMSC来源的成骨细胞中蛋白激酶A（PKA）、磷酸化丝氨酸/苏氨酸蛋白激酶（pAKT）、缺氧诱导因子1α（HIF 1 α）和VEGF的表达水平显著降低。此外，通过免疫组织化学测定，PTHKO小鼠中阳性血小板内皮细胞粘附分子染色减少。PTHKO小鼠HIF 1 α、VEGF、runt相关转录因子2、骨钙素和碱性磷酸酶的表达水平也降低，骨折愈合延迟。总之，缺乏内源性PTH可能通过下调PKA/pAKT/HIF 1 α/VEGF通路的活性来降低BMSC来源的成骨细胞中的VEGF表达，从而通过引起血管生成和成骨减少来影响软骨内骨形成，最终导致骨折愈合延迟。
Intermittent low-dose injections of parathyroid hormone (PTH) have been reported to exert bone anabolic effects and to promote fracture healing. As an important proangiogenic cytokine, vascular endothelial growth factor (VEGF) is secreted by bone marrow mesenchymal stem cells (BMSCs) and osteoblasts, and serves a crucial regulatory role in the process of vascular development and regeneration. To investigate whether lack of endogenous PTH causes reduced angiogenic capacity and thereby delays the process of fracture healing by downregulating the VEGF signaling pathway, a PTH knockout (PTHKO) mouse fracture model was generated. Fracture healing was observed using X-ray and micro-computerized tomography. Bone anabolic and angiogenic markers were analyzed by immunohistochemistry and western blot analysis. The expression levels of VEGF and associated signaling pathways in murine BMSC-derived osteoblasts were measured by quantitative polymerase chain reaction and western blot analysis. The expression levels of protein kinase A (PKA), phosphorylated-serine/threonine protein kinase (pAKT), hypoxia-inducible factor-1α (HIF1α) and VEGF were significantly decreased in BMSC-derived osteoblasts from PTHKO mice. In addition, positive platelet endothelial cell adhesion molecule staining was reduced in PTHKO mice, as determined by immunohistochemistry. The expression levels of HIF1α, VEGF, runt-related transcription factor 2, osteocalcin and alkaline phosphatase were also decreased in PTHKO mice, and fracture healing was delayed. In conclusion, lack of endogenous PTH may reduce VEGF expression in BMSC-derived osteoblasts by downregulating the activity of the PKA/pAKT/HIF1α/VEGF pathway, thus affecting endochondral bone formation by causing a reduction in angiogenesis and osteogenesis, ultimately leading to delayed fracture healing.
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