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 mouse Col1a1-Cre transgene minimally impacts bone mass in mice, but deleting Kindlin-2 using the 10-kb mouse Dmp1-Cre transgene, 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.

中文翻译：

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焦点粘附蛋白 Kindlin-2 调节小鼠骨稳态。

我们最近的研究表明，粘着斑蛋白 Kindlin-2 对于软骨形成和早期骨骼发育至关重要。在这里，我们发现使用 2.3 kb 小鼠 Col1a1-Cre 转基因从成骨细胞中删除 Kindlin-2 对小鼠骨量的影响最小，但使用 10 kb 小鼠 Dmp1-Cre 转基因删除 Kindlin-2，其目标是骨细胞和成熟成骨细胞，导致小鼠骨质明显减少。Kindlin-2 缺失会减少骨微环境中的成骨细胞数量，但会增加破骨细胞和脂肪细胞数量。Kindlin-2 缺失会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 的上调可逆转 Kindlin-2 缺陷引起的骨质减少。Kindlin-2 的缺失还会增加骨细胞中 RANKL 的表达，并增加破骨细胞的形成和骨吸收。骨细胞中 Kindlin-2 的缺失可促进骨细胞/骨髓单核细胞共培养物中破骨细胞的形成，而抗 RANKL 中和抗体可显着阻断该过程。最后，Kindlin-2 缺失会增加骨细胞凋亡并损害骨细胞扩散和树突形成。因此，我们证明了Kindlin-2在骨稳态调节中的重要作用，并为代谢性骨疾病的治疗提供了潜在的靶点。