Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPAR γ/FABP4 signaling in mice

Wanze Tang; Zhen Ding; Huanqing Gao; Qinnan Yan; Jingping Liu; Yingying Han; Xiaoting Hou; Zhengwei Liu; Litong Chen; Dazhi Yang; Guixing Ma; Huiling Cao

doi:10.1016/j.apsb.2023.07.001

Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPAR γ/FABP4 signaling in mice

Acta Pharm Sin B. 2023 Nov;13(11):4535-4552. doi: 10.1016/j.apsb.2023.07.001. Epub 2023 Jul 7.

Authors

Wanze Tang^{1

2}, Zhen Ding¹, Huanqing Gao¹, Qinnan Yan¹, Jingping Liu³, Yingying Han¹, Xiaoting Hou¹, Zhengwei Liu¹, Litong Chen¹, Dazhi Yang², Guixing Ma¹, Huiling Cao¹

Affiliations

¹ Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China.
² The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518055, China.
³ Clinical Laboratory of the Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China.

Abstract

Osteoporosis (OP) is a systemic skeletal disease that primarily affects the elderly population, which greatly increases the risk of fractures. Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass. Kindlin-2 specific deletion (K2KO) controlled by Adipoq-Cre mice or adipose tissue-targeting AAV (AAV-Rec2-CasRx-sgK2) significantly increases bone mass. Mechanistically, Kindlin-2 promotes peroxisome proliferator-activated receptor gamma (PPARγ) activation and downstream fatty acid binding protein 4 (FABP4) expression through stabilizing fatty acid synthase (FAS), and increased FABP4 inhibits insulin expression and decreases bone mass. Kindlin-2 inhibition results in accelerated FAS degradation, decreased PPARγ activation and FABP4 expression, and therefore increased insulin expression and bone mass. Interestingly, we find that FABP4 is increased while insulin is decreased in serum of OP patients. Increased FABP4 expression through PPARγ activation by rosiglitazone reverses the high bone mass phenotype of K2KO mice. Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice. Collectively, our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.

Keywords: AAV-Rec2-CasRx-sgK2; Adipocyte; Bone homeostasis; C75; FAS; Kindlin-2; Osteoporosis; mRNA editing.