Department of Endocrinology, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Rd, Shanghai, 200065, China.
Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
J Bone Miner Metab. 2018 Sep;36(5):560-572. doi: 10.1007/s00774-017-0873-0. Epub 2017 Nov 9.
wnt/β-catenin signaling has been shown to influence bone homeostasis and is important for parathyroid hormone (PTH)-induced bone gain. To further understand the role of β-catenin in the early stages of osteoblastic lineage cells for postnatal bone homeostasis and the anabolic actions of PTH on bone, we examined mice with postnatal disruption of β-catenin in osterix-expressing cells (β-catenin KO mice) by mating floxed β-catenin mice with transgenic mice expressing cre under the control of the osterix promoter suppressible by doxycycline. After withdrawal of doxycycline, β-catenin KO mice developed progressive bone loss, ectopic cartilage formation, accumulation of mesenchymal stromal cells, and bone marrow adiposity. The β-catenin-defective osteoblasts sorted by flow cytometry from β-catenin KO mice exhibited decreased EdU incorporation, increased annexin V activity, and profound alterations in gene expression including wnt target genes, osteoclast regulators, and osteoblast markers. A dramatic increase in osteoclasts was observed in both neonatal and postnatal β-catenin KO mice. Intermittent administration of PTH for 4 weeks significantly increased bone mass in control mice; however, this anabolic effect of PTH was substantially blunted in β-catenin KO mice. Our data indicate that β-catenin in osterix-expressing cells is required for postnatal osteoblast differentiation, osteoblast proliferation, and bone resorption, and is essential for the anabolic actions of PTH in bone.
wnt/β-catenin 信号通路已被证实会影响骨内稳态，并且对于甲状旁腺激素（PTH）诱导的骨量增加很重要。为了进一步了解β-catenin 在成骨细胞谱系细胞中的作用，以了解其在出生后骨内稳态和 PTH 对骨的合成代谢作用中的作用，我们通过交配 floxed β-catenin 小鼠和表达 cre 的转基因小鼠，研究了出生后在osterix 表达细胞中破坏β-catenin（β-catenin KO 小鼠）的作用，cre 的表达受 osterix 启动子控制，可被强力霉素抑制。停用强力霉素后，β-catenin KO 小鼠逐渐出现骨丢失、异位软骨形成、间充质基质细胞积累和骨髓脂肪化。通过流式细胞术从β-catenin KO 小鼠中分离的β-catenin 缺陷型成骨细胞，EdU 掺入减少，膜联蛋白 V 活性增加，基因表达发生深刻改变，包括 wnt 靶基因、破骨细胞调节因子和成骨细胞标志物。在新生和出生后β-catenin KO 小鼠中均观察到破骨细胞数量显著增加。间歇性给予 PTH 治疗 4 周可显著增加对照组小鼠的骨量；然而，这种 PTH 的合成代谢作用在β-catenin KO 小鼠中显著减弱。我们的数据表明，osterix 表达细胞中的β-catenin 对于成骨细胞分化、成骨细胞增殖和骨吸收是必需的，并且对于 PTH 在骨中的合成代谢作用是必不可少的。
