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

Tang，Wanze1,2; Ding，Zhen1; Gao，Huanqing1; Yan，Qinnan1; Liu，Jingping3; Han，Yingying1; Hou，Xiaoting1; Liu，Zhengwei1; Chen，Litong1; Yang，Dazhi2; Ma，Guixing1; Cao，Huiling1

2023

10.1016/j.apsb.2023.07.001

Acta Pharmaceutica Sinica B   Impact Factor & Quartile

2211-3835

2211-3843

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.

AAV-Rec2-CasRx-sgK2 Adipocyte Bone homeostasis C75 FAS Kindlin-2 mRNA editing Osteoporosis

SCI

English

First ; Corresponding

National Key Research and Development Program of China[2019YFA0906001];National Outstanding Youth Science Fund Project of National Natural Science Foundation of China[81972100];National Outstanding Youth Science Fund Project of National Natural Science Foundation of China[82022047];

WOS:001108213000001

2-s2.0-85168342131

Scopus

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

Tang，Wanze,Ding，Zhen,Gao，Huanqing,et al. Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPARγ/FABP4 signaling in mice[J]. Acta Pharmaceutica Sinica B,2023,13(11):4535-4552.

Tang，Wanze.,Ding，Zhen.,Gao，Huanqing.,Yan，Qinnan.,Liu，Jingping.,...&Cao，Huiling.(2023).Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPARγ/FABP4 signaling in mice.Acta Pharmaceutica Sinica B,13(11),4535-4552.

Tang，Wanze,et al."Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPARγ/FABP4 signaling in mice".Acta Pharmaceutica Sinica B 13.11(2023):4535-4552.