DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH
DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH
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DOI：
10.1096/fj.15-275859
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发表时间：
2016-02-01
期刊：
影响因子：
4.8
通讯作者：
Yakar, Shoshana
中科院分区：
文献类型：
--
作者：
Liu, Zhongbo;Kennedy, Oran D.;Yakar, Shoshana
骨矿物质是在生长过程中获得的，是成人骨骼健康的关键决定因素。在青春期，生长激素（GH）及其下游效应物IGF-1的血清水平升高，并在骨获得中起关键作用。本研究的目的是确定骨细胞如何整合GH/IGF-1的信号，以增强青春期生长期间的骨骼矿化和强度。骨细胞，最丰富的骨细胞，被证明在生长过程中协调骨建模。我们使用牙本质基质蛋白（Dmp）-1介导的Ghr敲除（DMP-GHRKO）小鼠来研究GH/IGF轴在骨细胞中的作用。我们发现，DMP-GHRKO不影响线性生长，但损害整体骨增量。DMP-GHRKO小鼠表现出血清无机磷酸盐和甲状旁腺激素（PTH）水平降低，骨形成指数降低，并与间歇性PTH治疗反应受损相关。使用骨细胞样细胞系沿着体内研究，我们发现PTH通过增加Janus激酶-2和IGF-1 R蛋白水平来敏化骨对GH的反应。我们的结论是，骨骼中内源性分泌的PTH和GHR信号对于建立放射状骨生长和优化生长过程中的矿物质获取是必要的。
Bone minerals are acquired during growth and are key determinants of adult skeletal health. During puberty, the serumlevels of growth hormone (GH) and its downstream effector IGF-1 increase and play critical roles in bone acquisition. The goal of the current study was to determine how bone cells integrate signals from the GH/IGF-1 to enhance skeletal mineralization and strength during pubertal growth. Osteocytes, the most abundant bone cells, were shown to orchestrate bone modeling during growth. We used dentin matrix protein (Dmp)-1-mediated Ghr knockout (DMP-GHRKO) mice to address the role of the GH/IGF axis in osteocytes. We found that DMP-GHRKO did not affect linear growth but compromised overall bone accrual. DMP-GHRKO mice exhibited reduced serum inorganic phosphate and parathyroid hormone (PTH) levels and decreased bone formation indices and were associated with an impaired response to intermittent PTH treatment. Using an osteocyte-like cell line along with in vivo studies, we found that PTH sensitized the response of bone to GH by increasing Janus kinase-2 and IGF-1R protein levels. We concluded that endogenously secreted PTH and GHR signaling in bone are necessary to establish radial bone growth and optimize mineral acquisition during growth.