Tang Wanze, Ding Zhen, Gao Huanqing, Yan Qinnan, Liu Jingping, Han Yingying, Hou Xiaoting, Liu Zhengwei, Chen Litong, Yang Dazhi, Ma Guixing, Cao Huiling
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.
The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518055, China.
Acta Pharm Sin B. 2023 Nov;13(11):4535-4552. doi: 10.1016/j.apsb.2023.07.001. Epub 2023 Jul 7.
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 mice or adipose tissue-targeting AAV (AAV-Rec2-CasRx-sgK2) significantly increases bone mass. Mechanistically, Kindlin-2 promotes peroxisome proliferator-activated receptor gamma (PPAR) 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 PPAR 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 PPAR 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/PPAR/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.
骨质疏松症（OP）是一种主要影响老年人群的全身性骨骼疾病，会大幅增加骨折风险。在此我们报告，脂肪组织中Kindlin-2的表达在衰老和高脂饮食喂养期间会增加，并伴有骨量减少。由小鼠控制的Kindlin-2特异性缺失（K2KO）或靶向脂肪组织的腺相关病毒（AAV-Rec2-CasRx-sgK2）可显著增加骨量。从机制上讲，Kindlin-2通过稳定脂肪酸合酶（FAS）来促进过氧化物酶体增殖物激活受体γ（PPAR）的激活及下游脂肪酸结合蛋白4（FABP4）的表达，而FABP4的增加会抑制胰岛素表达并降低骨量。抑制Kindlin-2会导致FAS降解加速、PPAR激活及FABP4表达降低，从而增加胰岛素表达和骨量。有趣的是，我们发现OP患者血清中FABP4增加而胰岛素减少。通过罗格列酮激活PPAR增加FABP4表达可逆转K2KO小鼠的高骨量表型。用C75抑制FAS可模拟K2KO小鼠的高骨量表型。总体而言，我们的研究在脂肪组织中建立了一种新的Kindlin-2/FAS/PPAR/FABP4/胰岛素轴来调节骨量，并有力地表明FAS和Kindlin-2是新的潜在靶点，C75或AAV-Rec2-CasRx-sgK2治疗是OP治疗的潜在策略。
