Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice

• Published in: Bone research 2020-01, Vol.8 (1), p.2-2
• Main Authors: Cao, Huiling, Yan, Qinnan, Wang, Dong, Lai, Yumei, Zhou, Bo, Zhang, Qi, Jin, Wenfei, Lin, Simin, Lei, Yiming, Ma, Liting, Guo, Yuxi, Wang, Yishu, Wang, Yilin, Bai, Xiaochun, Liu, Chuanju, Feng, Jian Q, Wu, Chuanyue, Chen, Di, Cao, Xu, Xiao, Guozhi
• Format: Article
• Language: English
• Subjects: Homeostasis
• ISSN: 2095-4700; 2095-6231
• DOI: 10.1038/s41413-019-0073-8

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