Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells
Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells
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DOI：
10.1172/jci119491
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发表时间：
1997-06-15
影响因子：
15.9
通讯作者：
Yamaguchi, A
中科院分区：
文献类型：
--
作者：
Ishizuya, T;Yokose, S;Yamaguchi, A
据报道，PTH在体内间歇给药时发挥骨形成作用。在本研究中，PTH（1-34）的合成代谢对成骨细胞分化的影响进行了检查在体外。从新生大鼠颅盖骨分离的成骨细胞周期性地用PTH（1-34）处理每个48小时孵育周期的前几个小时。当成骨细胞间歇性暴露于PTH仅为第一个小时的每个48小时的孵育周期和培养的其余周期没有激素，成骨细胞分化被抑制抑制碱性磷酸酶活性，骨结节的形成，和碱性磷酸酶，骨钙素和PTH/PTHrP受体的mRNA表达。cAMP/PKA和Ca ~（2+）/PKC的抑制剂和刺激剂实验表明，cAMP/PKA是PTH抑制作用的主要信号转导系统。相反，间歇性暴露于PTH的前6小时，每个48小时周期刺激成骨细胞分化。cAMP/PKA和Ca ~（2+）/PKC系统协同参与了这种合成代谢作用。在48小时孵育周期中连续暴露于PTH强烈抑制成骨细胞分化。虽然cAMP/PKA和Ca ~（2+）/PKC都参与了PTH持续暴露的效应，但它们似乎是独立作用的。IGF-1中和抗体阻断了6 h间歇暴露对碱性磷酸酶活性和骨钙素mRNA表达的刺激作用。抗IGF-I抗体不影响间歇暴露1 h诱导的抑制效应。这些结果表明，PTH对成骨细胞分化的影响取决于体外暴露时间，通过不同的信号转导系统介导。这些体外研究结果至少部分解释了PTH随给药方式而变化的体内作用。
It has been reported that PTH exerts bone-forming effects in vivo when administered intermittently. In the present study, the anabolic effects of PTH(1-34) on osteoblast differentiation were examined in vitro. Osteoblastic cells isolated from newborn rat calvaria were cyclically treated with PTH(1-34) for the first few hours of each 48-h incubation cycle. When osteoblastic cells were intermittently exposed to PTH only for the first hour of each 48-h incubation cycle and cultured for the remainder of the cycle without the hormone, osteoblast differentiation was inhibited by suppressing alkaline phosphatase activity, bone nodule formation, and mRNA expression of alkaline phosphatase, osteocalcin, and PTH/PTHrP receptor. Experiments using inhibitors and stimulators of cAMP/protein kinase A (PKA) and Ca2+/PKC demonstrated that cAMP/PKA was the major signal transduction system in the inhibitory action of PTH. In contrast, the intermittent exposure to PTH for the first 6 h of each 48-h cycle stimulated osteoblast differentiation. Both cAMP/PKA and Ca2+/PKC systems appeared to be involved cooperatively in this anabolic effect. Continuous exposure to PTH during the 48-h incubation cycle strongly inhibited osteoblast differentiation. Although both cAMP/PKA and Ca2+/PKC were involved in the effect of continuous exposure to PTH, they appeared to act independently A neutralizing antibody against IGF-I blocked the stimulatory effect on alkaline phosphatase activity and the expression of osteocalcin mRNA induced by the 6-h intermittent exposure. The inhibitory effect induced by the 1-h intermittent exposure was not affected by anti-IGF-I antibody. These results suggest that PTH has diverse effects on osteoblast differentiation depending on the exposure time in vitro mediated through different signal transduction systems. These in vitro findings explain at least in part the in vivo action of PTH that varies with the mode of administration.