Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice Academic Article uri icon

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.

published proceedings

  • Bone Res

author list (cited authors)

  • Cao, H., Yan, Q., Wang, D., Lai, Y., Zhou, B. o., Zhang, Q. i., ... Xiao, G.

citation count

  • 23

complete list of 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

publication date

  • January 2020