Hedgehog Signaling Controls Bone Homeostasis by Regulating Osteogenic/Adipogenic Fate of Skeletal Stem/Progenitor Cells in Mice
Hedgehog Signaling Controls Bone Homeostasis by Regulating Osteogenic/Adipogenic Fate of Skeletal Stem/Progenitor Cells in Mice
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Hedgehog 信号通过调节小鼠骨骼干细胞/祖细胞的成骨/脂肪形成命运来控制骨稳态
DOI：
10.1002/jbmr.4485
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发表时间：
2021-12
影响因子：
6.2
通讯作者：
Jianquan Chen
中科院分区：
文献类型：
--
作者：
Liwei Zhang;Xuejie Fu;Li Ni;Cunchang Liu;Yixin Zheng;Hongji You;Meng Li;Chunmei Xiu;Lei Zhang;Tingting Gong;Na Luo;Zunyi Zhang;Guangxu He;Shijun Hu;Huilin Yang;Di Chen;Jianquan Chen
骨骼干/祖细胞可分化为成骨或成脂细胞系。SSPC的谱系分配机制仍不完全清楚。Hedgehog(HH)信号在决定间充质祖细胞在胚胎发生过程中的成骨命运中起着至关重要的作用。然而，目前尚不清楚出生后骨骼中SSPC的谱系分配是否需要HH信号，以及其调节失调是否与年龄相关性骨质疏松症有关。在这里，我们证明了在成人骨骼的成骨分化过程中，干骺端SSPC中的HH信号被激活，并且其活性随着年龄的增长而降低。在Osx-Cre靶向的SSPC和肥大的软骨细胞中，通过基因消融HH信号的关键分子Smo而使HH信号失活，导致骨形成减少和骨髓脂肪增加，这是老年性骨质疏松症的两个关键病理特征。此外，我们发现SModel引起的骨脂失衡表型主要是由于SSPC以成骨分化为代价向成脂谱系异常分配所致，而不是由于软骨细胞加速向脂肪细胞的转分化所致。从机制上讲，我们发现HH信号调节SSPC的成骨细胞与脂肪细胞的命运，部分是通过上调Wnt信号。因此，我们的结果表明，HH信号通过作为Osx-Cre靶向SSPC细胞命运决定的关键开关来调节骨稳态和年龄相关性骨质疏松症，并提示HH信号可能成为治疗骨质疏松和其他代谢性骨病的潜在靶点。
Skeletal stem/progenitor cells (SSPCs) can differentiate into osteogenic or adipogenic lineage. The mechanism governing lineage allocation of SSPCs is still not completely understood. Hedgehog (Hh) signaling plays an essential role in specifying osteogenic fate of mesenchymal progenitors during embryogenesis. However, it is still unclear whether Hh signaling is required for lineage allocation of SSPCs in postnatal skeleton, and whether its dysregulation is related to age-related osteoporosis. Here, we demonstrated that Hh signaling was activated in metaphyseal SSPCs during osteogenic differentiation in the adult skeleton, and its activity decreased with aging. Inactivation of Hh signaling by genetic ablation ofSmo, a key molecule in Hh signaling, inOsx-Cre–targeted SSPCs and hypertrophic chondrocytes led to decreased bone formation and increased bone marrow adiposity, two key pathological features of age-related osteoporosis. Moreover, we found that the bone-fat imbalance phenotype caused bySmodeletion mainly resulted from aberrant allocation of SSPCs toward adipogenic lineage at the expense of osteogenic differentiation, but not due to accelerated transdifferentiation of chondrocytes into adipocytes. Mechanistically, we found that Hh signaling regulated osteoblast versus adipocyte fate of SSPCs partly through upregulating Wnt signaling. Thus, our results indicate that Hh signaling regulates bone homeostasis and age-related osteoporosis by acting as a critical switch of cell fate decisions ofOsx-Cre–targeted SSPCs in mice and suggest that Hh signaling may serve as a potential therapeutic target for the treatment of osteoporosis and other metabolic bone diseases.
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影响因子：
4.6
作者：
C. B. Bai;W. Auerbach;Joon‐Sung Lee;Daniel N. Stephen;A. Joyner
通讯作者：
C. B. Bai;W. Auerbach;Joon‐Sung Lee;Daniel N. Stephen;A. Joyner
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
46.9
作者：
Trapnell C;Williams BA;Pertea G;Mortazavi A;Kwan G;van Baren MJ;Salzberg SL;Wold BJ;Pachter L
通讯作者：
Pachter L
影响因子：
23.9
作者：
Yu B;Huo L;Liu Y;Deng P;Szymanski J;Li J;Luo X;Hong C;Lin J;Wang CY
通讯作者：
Wang CY
一种改进的胶带转移方法，用于快速制备未脱钙成年啮齿动物骨骼的高质量冷冻切片
影响因子：
6.6
作者：
Yang Y;Liu Q;Zhang L;Fu X;Chen J;Hong D
通讯作者：
Hong D