Nmp4/CIZ Suppresses the Response of Bone to Anabolic Parathyroid Hormone by Regulating Both Osteoblasts and Osteoclasts
Nmp4/CIZ Suppresses the Response of Bone to Anabolic Parathyroid Hormone by Regulating Both Osteoblasts and Osteoclasts
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DOI：
10.1007/s00223-011-9496-y
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发表时间：
2011-07-01
影响因子：
4.2
通讯作者：
Bidwell, Joseph P.
中科院分区：
文献类型：
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作者：
Childress, Paul;Philip, Binu K.;Bidwell, Joseph P.
甲状旁腺激素（PTH）如何增加骨量尚不清楚，但了解这一现象对改善骨质疏松症治疗具有重要意义。Nmp 4/CIZ是一种核质穿梭转录抑制因子，可抑制PTH诱导的小鼠股骨小梁成骨细胞基因表达和骨形成刺激的增益。为了进一步表征Nmp 4/CIZ对骨生长的抑制作用，我们用30 μ g/kg/天的人PTH（1-34）或载体（7天/周）间歇性治疗10周龄Nmp 4敲除（KO）和野生型（WT）小鼠2、3或7周。用激素处理的BALB/c小鼠（7周）比WT动物获得更多的椎骨和胫骨松质骨，与股骨中的过度反应平行。有趣的是，在治疗的前2周期间，Nmp 4/CIZ对这种骨刺激的骨形成的抑制并不明显。与无效小鼠增强PTH刺激的骨小梁增加一致，这些动物在治疗3周后表现出增强的骨钙素诱导的血清骨钙素增加。出乎意料的是，Nmp 4-KO小鼠显示出破骨细胞表型。血清C-末端肽，骨吸收的标志物，在无效小鼠中升高，无论治疗。与WT培养物相比，Nmp 4-KO骨髓培养物产生更多的破骨细胞，其表现出升高的再吸收活性。在Nmp 4-KO小鼠中，激素暴露2周后，对成骨细胞和破骨细胞发育至关重要的几个基因的表达升高，但3周后没有。我们建议，Nmp 4/CIZ抑制PTH诱导的骨小梁的改善，通过短暂抑制骨刺激的蛋白质表达的增加，所需的增强活性和数量的成骨细胞和破骨细胞。
How parathyroid hormone (PTH) increases bone mass is unclear, but understanding this phenomenon is significant to the improvement of osteoporosis therapy. Nmp4/CIZ is a nucleocytoplasmic shuttling transcriptional repressor that suppresses PTH-induced osteoblast gene expression and hormone-stimulated gains in murine femoral trabecular bone. To further characterize Nmp4/CIZ suppression of hormone-mediated bone growth, we treated 10-week-old Nmp4-knockout (KO) and wild-type (WT) mice with intermittent human PTH(1-34) at 30 mu g/kg daily or vehicle, 7 days/week, for 2, 3, or 7 weeks. Null mice treated with hormone (7 weeks) gained more vertebral and tibial cancellous bone than WT animals, paralleling the exaggerated response in the femur. Interestingly, Nmp4/CIZ suppression of this hormone-stimulated bone formation was not apparent during the first 2 weeks of treatment. Consistent with the null mice enhanced PTH-stimulated addition of trabecular bone, these animals exhibited an augmented hormone-induced increase in serum osteocalcin 3 weeks into treatment. Unexpectedly, the Nmp4-KO mice displayed an osteoclast phenotype. Serum C-terminal telopeptide, a marker for bone resorption, was elevated in the null mice, irrespective of treatment. Nmp4-KO bone marrow cultures produced more osteoclasts, which exhibited elevated resorbing activity, compared to WT cultures. The expression of several genes critical to the development of both osteoblasts and osteoclasts was elevated in Nmp4-KO mice at 2 weeks, but not 3 weeks, of hormone exposure. We propose that Nmp4/CIZ dampens PTH-induced improvement of trabecular bone throughout the skeleton by transiently suppressing hormone-stimulated increases in the expression of proteins key to the required enhanced activity and number of both osteoblasts and osteoclasts.