Endogenous parathyroid hormone-related protein compensates for the absence of parathyroid hormone in promoting bone accrual in vivo in a model of bone marrow ablation
Endogenous parathyroid hormone-related protein compensates for the absence of parathyroid hormone in promoting bone accrual in vivo in a model of bone marrow ablation
复制标题
内源性甲状旁腺激素相关蛋白补偿甲状旁腺激素的缺乏，在骨髓消融模型中促进体内骨生成
DOI：
10.1002/jbmr.2000
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发表时间：
2013
影响因子：
6.2
通讯作者：
Miao Dengshun
中科院分区：
文献类型：
--
作者：
Zhu Qi;Zhou Xichao;Zhu Min;Wang Qian;Goltzman David;Karaplis Andrew;Miao Dengshun
为了评估甲状旁腺功能减退对体内成骨和骨转换的影响，在8周龄野生型和甲状旁腺素缺失（PTH-/-）小鼠的胫骨中进行骨髓消融（BMX），并在BMX后5天至3周分析新形成的骨组织。在BMX后1周，与野生型小鼠相比，PTH−/−小鼠骨干区域的骨小梁体积、成骨细胞数量、碱性磷酸酶阳性面积、I型胶原阳性面积、PTH受体阳性面积、钙敏感受体阳性面积和骨形成相关基因的表达均显著降低。相反，在BMX后2周，PTH-/-小鼠中与成骨细胞骨累积相关的所有参数均显著增加。在BMX后5天，野生型小鼠中出现了活性抗酒石酸酸性磷酸酶（TRAP）阳性破骨细胞，但在PTH−/−小鼠中未检测到。在BMX后1周，PTH−/−小鼠中NF-κB配体（RANKL）/骨保护素（OPG）受体激活剂的mRNA水平和TRAP阳性破骨细胞表面的比率仍降低，但在BMX后2周增加。在PTH−/−小鼠中，BMX后1周和2周，甲状旁腺相关蛋白（PTHrP）的mRNA和蛋白水平的表达水平均显著上调。为了确定BMX后2周时PTH-/-小鼠中新形成的骨增加是否是由于PTHrP的代偿作用，制备了PTH-/-PTHrP+/-小鼠，并将这些小鼠中新形成的骨组织与BMX后2周时的PTH-/-和野生型小鼠进行了比较。与PTH−/−小鼠相比，PTH−/−PTHrP+/−小鼠中与成骨细胞骨形成和骨细胞骨吸收相关的所有参数均显著降低。这些结果表明，PTH缺乏本身损害骨生成，破骨细胞生成，和osteocytes骨吸收，而随后上调PTHrP在成骨细胞补偿增加骨积累。© 2013美国骨与矿物质研究学会
To assess the effect of hypoparathyroidism on osteogenesis and bone turnover in vivo, bone marrow ablation (BMXs) were performed in tibias of 8‐week‐old wild‐type and parathyroid hormone–null (PTH−/−) mice and newly formed bone tissue was analyzed from 5 days to 3 weeks after BMX. At 1 week after BMX, trabecular bone volume, osteoblast numbers, alkaline phosphatase‐positive areas, type I collagen‐positive areas, PTH receptor–positive areas, calcium sensing receptor–positive areas, and expression of bone formation–related genes were all decreased significantly in the diaphyseal regions of bones of PTH−/−mice compared to wild‐type mice. In contrast, by 2 weeks after BMX, all parameters related to osteoblastic bone accrual were increased significantly in PTH−/−mice. At 5 days after BMX, active tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclasts had appeared in wild‐type mice but were undetectable in PTH−/−mice, Both the ratio of mRNA levels of receptor activator of NF‐κB ligand (RANKL)/osteoprotegerin (OPG) and TRAP‐positive osteoclast surface were still reduced in PTH−/−mice at 1 week but were increased by 2 weeks after BMX. The expression levels of parathyroid hormone–related protein (PTHrP) at both mRNA and protein levels were upregulated significantly at 1 week and more dramatically at 2 weeks after BMX in PTH−/−mice. To determine whether the increased newly formed bones in PTH−/−mice at 2 weeks after BMX resulted from the compensatory action of PTHrP, PTH−/−PTHrP+/−mice were generated and newly formed bone tissue was compared in these mice with PTH−/−and wild‐type mice at 2 weeks after BMX. All parameters related to osteoblastic bone formation and osteoclastic bone resorption were reduced significantly in PTH−/−PTHrP+/−mice compared to PTH−/−mice. These results demonstrate that PTH deficiency itself impairs osteogenesis, osteoclastogenesis, and osteoclastic bone resorption, whereas subsequent upregulation of PTHrP in osteogenic cells compensates by increasing bone accrual. © 2013 American Society for Bone and Mineral Research