中文版 | English
题名

脂肪细胞Kindlin-2调节骨稳态的作用及机制研究

其他题名
THE ROLE AND MECHANISM OF ADIPOCYTE KINDLIN-2 IN REGULATING BONE HOMEOSTASIS
姓名
姓名拼音
TANG Wanze
学号
12031166
学位类型
博士
学位专业
0710 生物学
学科门类/专业学位类别
07 理学
导师
杨大志
导师单位
南方科技大学第一附属医院深圳市人民医院
论文答辩日期
2024-05-09
论文提交日期
2024-07-01
学位授予单位
南方科技大学
学位授予地点
深圳
摘要

骨质疏松症是广泛影响老年人群体的全身性骨骼疾病,其主要特征是由于骨吸收与骨形成之间的不平衡导致的骨量减少和骨微结构损伤,显著增加骨折风险。目前用于治疗骨质疏松症的药物均存在不同程度的不良反应。脂肪组织不仅是重要的内分泌器官,还在调节骨稳态中发挥重要作用。研究发现,脂肪组织中Kindlin-2的表达随年龄增加而增加,并且与骨量呈负相关。然而,脂肪细胞Kindlin-2在调节骨稳态中的具体机制尚不清楚。本研究旨在探讨脂肪细胞中的Kindlin-2是否以及如何调节骨稳态,并验证调控其表达是否可能成为治疗骨质疏松症的新策略。

本研究发现,脂肪细胞特异性敲除Kindlin-2增强成骨分化和骨形成,进而上调全身骨量,而对破骨细胞形成和骨吸收影响有限。同时,Kindlin-2缺失导致Fabp4血清水平显著下降。Fabp4是胰岛素的负调节因子,其表达降低显著提高胰岛及血清中的胰岛素信号。骨组织中的胰岛素及其下游信号pIRS1表达增强,这解释了脂肪细胞Kindlin-2缺失小鼠的高骨量表型。

机制上,我们定义了脂肪细胞中的Kindlin-2/Fas/PPARγ/Fabp4新的代谢轴。我们证明Kindlin-2能与Fas相互作用并稳定Fas蛋白水平,从而增强PPARγ活性和Fabp4表达。因此,Kindlin-2的缺失下调Fas蛋白,抑制PPARγ活性,进而抑制Fabp4表达,Fabp4表达降低致使胰岛素表达增加和骨量上升。与之相一致的是,与正常对照组相比,骨质疏松症患者的FABP4血清水平增加,而胰岛素水平降低。此外,罗格列酮激活PPARγ并促进Fabp4表达,从而逆转脂肪细胞中Kindlin-2缺失引起的高骨量表型。相反,C75通过抑制Fas降低了PPARγFabp4表达,并模拟脂肪细胞中Kindlin-2缺失引起的高骨量表型。同时,腹腔注射Rec2-sgK2降低了小鼠脂肪组织的Kindlin-2FasPPARγFabp4表达,并增加了骨量,这进一步证明了脂肪细胞中的Kindlin-2/Fas/PPARγ/Fabp4新的代谢轴的正确性。

综上所述,我们的研究发现脂肪细胞中Kindlin-2的缺失能够促进骨形成,从而上调全身骨量;建立了一个新的脂肪组织中的Kindlin-2/Fas /PPARγ/Fabp4/胰岛素代谢轴,能够调节骨稳态,具有重要的转化意义,为通过靶向脂肪细胞治疗骨量相关疾病提供了潜在的新策略。

其他摘要

Osteoporosis (OP), predominantly affecting the elderly, increases fracture risk. We demonstrate that Kindlin-2 expression in adipose tissue rises with age, inversely correlating with bone mass. Eliminating Kindlin-2 in adipocytes elevates bone mass by promoting osteoblast differentiation and bone formation, marginally affecting osteoclast activity and bone resorption. Kindlin-2 deletion significantly reduces serum Fabp4 — a negative insulin expression regulator — boosting insulin signaling in islets and serum. This, alongside increased bone tissue insulin signaling, as evidenced by higher pIRS1 levels, accounts for the observed high bone mass in adipocyte-specific Kindlin-2-deficient mice. Mechanistically, we define the novel Kindlin-2/Fas/PPARγ/Fabp4 axis in adipocytes. We demonstrate that Kindlin-2 interacts with and stabilizes Fas, leading to enhanced activation of PPARγ and an increase in Fabp4 expression. Consequently, the loss of Kindlin-2 results in the downregulation of Fas protein, leading to inhibition of PPARγ activation, which results in suppression of Fabp4 expression, and the decreased Fabp4 expression leads to the increased insulin expression and bone mass. This observation aligns with our findings that, compared with normal controls, patients with OP exhibit elevated serum levels of FABP4 alongside reduced insulin levels. PPARγ activation by Rosiglitazone, increasing Fabp4 expression, counteracts high bone mass from adipocyte Kindlin-2 deletion. Pharmacological inhibition of Fas by C75 decreases PPARγ and Fabp4 expression and phenocopies the high bone mass phenotype caused by Kindlin-2 deletion in adipocyte. Intraperitoneal injection of Rec2-sgK2 decreases Fas, PPARγ and Fabp4 expression and increases bone mass in mice. 
Collectively, our study establishes a novel Kindlin-2/ Fas/ PPARγ/ Fabp4/ insulin axis in adipose tissue modulating bone homeostasis, which is of great translational significance, providing potential therapeutic strategies for treatment of bone loss related diseases by targeting adipocytes.

关键词
其他关键词
语种
中文
培养类别
独立培养
入学年份
2020
学位授予年份
2024-06
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唐菀泽. 脂肪细胞Kindlin-2调节骨稳态的作用及机制研究[D]. 深圳. 南方科技大学,2024.
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