Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin
Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin
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DOI：
10.1073/pnas.1203085109
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发表时间：
2012-09-11
影响因子：
11.1
通讯作者：
Ferrari, Serge L.
中科院分区：
文献类型：
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作者：
Bonnet, Nicolas;Conway, Simon J.;Ferrari, Serge L.
Periostin (Postn) 是一种基质细胞蛋白，由骨细胞和骨膜成骨细胞优先表达，以响应机械刺激和甲状旁腺激素 (PTH)。然而，骨膜蛋白表达是否以及如何影响骨合成代谢仍然未知。我们研究了成年 Postn(-/-) 和 Postn(+/+) 小鼠对间歇性 PTH 的骨骼反应。与Postn(+/+)相比，Postn(-/-)小鼠的骨量、皮质骨体积和对PTH的强度反应较低。 Postn(-/-) 小鼠中 PTH 刺激的骨形成指数均显着降低，特别是在骨膜处。此外，在 TOPGAL 报告小鼠中评估，PTH 对 Wnt-β-连环蛋白信号传导的体内刺激在不存在骨膜素的情况下受到抑制（TOPGAL；Postn(-/-) 小鼠）。 PTH 在体外刺激骨膜素并抑制骨和成骨细胞中 MEF2C 和硬化素 (Sost) 的表达。重组骨膜素还抑制通过整合素αVβ3受体介导的Sost表达，而骨膜素阻断抗体阻止PTH对MEF2C和Sost的抑制。反过来，给予Sost阻断抗体可以部分恢复Postn(-/-)小鼠中PTH介导的骨量增加。此外，Postn(-/-) 小鼠的原代成骨细胞自发地和对 PTH 的反应均表现出较低的增殖、矿化和迁移。成骨细胞基因表达水平证实了在有或没有PTH的情况下Postn(-/-)成骨细胞分化的缺陷，以及在没有骨膜素的情况下成骨细胞凋亡增加。这些数据阐明了骨膜素通过调节 Sost、Wnt-β-连环蛋白信号传导和成骨细胞分化对骨合成代谢的复杂作用。
Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn(-/-) and Postn(+/+) mice to intermittent PTH. Compared with Postn(+/+), Postn(-/-) mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn(-/-) mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-beta-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL; Postn(-/-) mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin alpha V beta 3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn(-/-) mice. In addition, primary osteoblasts from Postn(-/-) mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn(-/-) osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt-beta-catenin signaling, and osteoblast differentiation.