Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice

Huiling Cao, Qinnan Yan, Dong Wang, Yumei Lai, Bo Zhou, Qi Zhang, Wenfei Jin, Simin Lin, Yiming Lei, Liting Ma, Yuxi Guo, Yishu Wang, Yilin Wang, Xiaochun Bai, Chuanju Liu, Jian Q. Feng, Chuanyue Wu, Di Chen, Xu Cao, Guozhi Xiao

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number2
JournalBone Research
Volume8
Issue number1
DOIs
StatePublished - 2020

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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  • Cite this

    Cao, H., Yan, Q., Wang, D., Lai, Y., Zhou, B., Zhang, Q., Jin, W., Lin, S., Lei, Y., Ma, L., Guo, Y., Wang, Y., Wang, Y., Bai, X., Liu, C., Feng, J. Q., Wu, C., Chen, D., Cao, X., & Xiao, G. (2020). Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice. Bone Research, 8(1), [2]. https://doi.org/10.1038/s41413-019-0073-8