Human PTH-(7-84) inhibits bone resorption in vitro via actions independent of the type 1 PTH/PTHrP receptor
Human PTH-(7-84) inhibits bone resorption in vitro via actions independent of the type 1 PTH/PTHrP receptor
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DOI：
10.1210/en.143.1.171
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发表时间：
2002-01-01
期刊：
影响因子：
4.8
通讯作者：
Bringhurst, FR
中科院分区：
文献类型：
--
作者：
Divieti, P;John, MR;Bringhurst, FR
哺乳动物甲状旁腺激素的线性序列由84个氨基酸组成，其中只有最大的氨基末端部分，即甲状旁腺素-(1-34)，是该激素通过1型甲状旁腺素/甲状旁腺素受体(PTH1R)介导的矿质离子稳态的经典作用所必需的。与甲状旁腺激素的N末端一样，甲状旁腺激素的羧基(C)末端序列在物种间高度保守，各种循环的甲状旁腺激素C片段是由完整的甲状旁腺激素的外周代谢产生的，或者直接由甲状旁腺以钙依赖的方式分泌。某些人工合成的PTH C片段作用于骨和软骨细胞，这是PTH-(1-34)所不具有的，并且PTH C肽已被证实与骨细胞特异结合，其中PTH1R的表达被基因打靶消除。人(H)PTH-(784)多肽最近被证明能抑制hPTH-(1-34)或hPTH-(1-84)对去甲状旁腺动物的降钙作用。为了确定hPTH-(7-84)的体内抗癌作用是否源于对骨的直接作用，我们研究了hPTH-(7-84)对小鼠骨髓原代培养的破骨细胞形成和体外完整骨吸收的影响。人(H)甲状旁腺素-(7-84)(300 NM)使新生小鼠颅骨中预先结合的Ca-45的基础释放减少了50%(9.6+/-1.9%vs.17.8+/-5.7%；P
The linear sequence of intact mammalian PTH consists of 84 amino acids, of which only the most amino(N)-terminal portion, i.e. PTH-(1-34), is required for the classical actions of the hormone on mineral ion homeostasis mediated by the type 1 PTH/PTHrP receptor (PTH1R). Like the N-terminus, the carboxyl (C)-terminal sequence of PTH is highly conserved,among species, and various circulating PTH C-fragments are generated by peripheral metabolism of intact PTH or are directly secreted, in a calcium-dependent manner, by the parathyroid glands. Certain synthetic PTH C-fragments exert actions on bone and cartilage cells that are not shared by PTH-(1-34), and specific binding of PTH C-peptides has been demonstrated in bone cells in which PTH1R expression was eliminated by gene targeting. The peptide human (h) PTH-(784) recently was shown to inhibit the calcemic actions of hPTH-(1-34) or hPTH-(1-84) in parathyroidectomized animals. To determine whether this anticalcemic effect of hPTH-(7-84) in vivo might result from direct actions on bone, we studied its effects on both resorption of intact bone in vitro and formation of osteoclasts in primary cultures of murine bone marrow. Human (h) PTH-(7-84) (300 nM) reduced basal 72-h release of preincorporated Ca-45 from neonatal mouse calvariae by 50% (9.6+/-1.9% vs. 17.8+/-5.7%; P