Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice
Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice
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焦点粘附蛋白 Kindlin-2 调节小鼠骨稳态
DOI：
10.1038/s41413-019-0073-8
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发表时间：
2020-01-02
期刊：
影响因子：
12.7
通讯作者：
Xiao, Guozhi
中科院分区：
文献类型：
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作者：
Cao, Huiling;Yan, Qinnan;Xiao, Guozhi
我们最近的研究表明，黏着斑蛋白Kindlin-2对软骨形成和早期骨骼发育至关重要。在这里，我们表明，删除Kindlin-2成骨细胞使用2.3 kb的mouseCol 1a 1-Cretegene影响最小的骨量在小鼠中，但删除Kindlin-2使用10 kb的mouseDmp 1-Cretegene，其目标骨细胞和成熟的成骨细胞，在小鼠中的结果在惊人的骨质减少。Kindlin-2缺失减少了骨微环境中的成骨细胞群体，但增加了骨细胞和脂肪细胞群体。Kindlin-2缺失上调骨细胞中的硬化蛋白，下调成骨细胞中的β-连环蛋白，并在体外和体内抑制成骨细胞的形成和分化。突变细胞中β-catenin的上调逆转了Kindlin-2缺陷诱导的骨质减少。Kindlin-2缺失还增加了骨细胞中RANKL的表达，并增加了破骨细胞形成和骨吸收。骨细胞中Kindlin-2的缺失促进骨细胞/骨髓单核细胞共培养物中破骨细胞的形成，这被抗RANKL中和抗体显著阻断。最后，Kindlin-2缺失增加骨细胞凋亡并损害骨细胞伸展和树突形成。因此，我们证明了Kindlin-2在调节骨稳态中的重要作用，并为代谢性骨病的治疗提供了潜在的靶点。
Our recent studies demonstrate that the focal adhesion protein Kindlin-2 is critical for chondrogenesis and early skeletal development. Here, we show that deleting Kindlin-2 from osteoblasts using the 2.3-kb mouseCol1a1-Cretransgene minimally impacts bone mass in mice, but deleting Kindlin-2 using the 10-kb mouseDmp1-Cretransgene, which targets osteocytes and mature osteoblasts, results in striking osteopenia in mice. Kindlin-2 loss reduces the osteoblastic population but increases the osteoclastic and adipocytic populations in the bone microenvironment. Kindlin-2 loss upregulates sclerostin in osteocytes, downregulates β-catenin in osteoblasts, and inhibits osteoblast formation and differentiation in vitro and in vivo. Upregulation of β-catenin in the mutant cells reverses the osteopenia induced by Kindlin-2 deficiency. Kindlin-2 loss additionally increases the expression of RANKL in osteocytes and increases osteoclast formation and bone resorption. Kindlin-2 deletion in osteocytes promotes osteoclast formation in osteocyte/bone marrow monocyte cocultures, which is significantly blocked by an anti-RANKL-neutralizing antibody. Finally, Kindlin-2 loss increases osteocyte apoptosis and impairs osteocyte spreading and dendrite formation. Thus, we demonstrate an important role of Kindlin-2 in the regulation of bone homeostasis and provide a potential target for the treatment of metabolic bone diseases.