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Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice

Bone Research 2020年第1期8卷 26-38页

作者： 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 qfeng Chuanyue Wu Di Chen Xu Cao Guozhi Xiao Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research Shenzhen Key Laboratory of Cell Microenvironmentand Department of BiologySouthern University of Science and TechnologyShenzhen 518055China Key Laboratory of Neuroregeneration of jiangsu and Ministry of Education Co-innovation Center of NeuroregenerationNantong UniversityNantong 226001China Department of Orthopedic Surgery Rush University Medical CenterChicagoIL 60612USA Department of Cell Biology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Orthopedic Surgery New York University School of MedicineNew YorkNY 10003USA Department of Cell Biology New York University School of MedicineNew YorkNY 10016USA Department of Biomedical Sciences Texas A&M University College of DentistryDallasTX 75246USA Department of Orthopedic Surgery The Johns Hopkins UniversityBaltimoreMD 21205USA

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 Col1 a1-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 ofβ-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-RANKLneutralizing antibody. Finally, Kindlin-2 loss increases osteocyte apoptosis and impairs osteocyte spreading and dendrite ***, 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.

关键词： homeostasis Kindlin cytes

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