Targeting TGF-β signaling, oxidative stress, and cellular senescence rescues osteoporosis in gerodermia osteodysplastica.

IF 8 1区 医学 Q1 CELL BIOLOGY
Aging Cell Pub Date : 2024-09-05 DOI:10.1111/acel.14322
W L Chan, C H Bucher, J Goldes, A C Ma, M Steiner, B M Willie, S Mundlos, U Kornak
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Abstract

GORAB is a key regulator of Golgi vesicle transport and protein glycanation. Loss of GORAB function in gerodermia osteodysplastica (GO) causes shortening of glycosaminoglycan chains, leading to extracellular matrix disorganization that results in wrinkled skin, osteoporosis and elevated TGF-β signaling. In this study, we investigated the role of TGF-β-signaling, oxidative stress, and resulting cellular senescence in the osteoporosis phenotype of GO. Treatment of GorabPrx1 conditional knockouts with the TGF-β neutralizing antibody 1D11 rescued the trabecular bone loss, indicating that TGF-β overactivation causes osteoporosis in GO. Using an inducible knockout system, we demonstrated that TGF-β dysregulation was not a cell-intrinsic effect of GORAB inactivation, but a consequence of a disorganized extracellular matrix. Enhanced TGF-β signaling caused elevated Nox4 expression in GorabPrx1 mutants and in GO patients' fibroblasts, resulting in overproduction of mitochondrial superoxide. The resulting oxidative stress was detected in GORAB null cells and also in wildtype bystander cells. The same effect was observed in zebrafish after TALEN-mediated gorab inactivation, indicating that the pathway is evolutionarily conserved. Treating GorabPrx1 mutants with the antioxidant N-acetylcysteine ameliorated the osteoporosis phenotype. TGF-β induced oxidative stress coincided with accumulation of DNA damage and elevated expression of senescence markers. Inactivation of Cdkn2a in the GorabPrx1 rescued the osteoporosis phenotype. Reduced colony formation and altered subpopulations of bone marrow stromal cells were normalized upon inactivation of Cdkn2a, thus further demonstrating the relevance of cellular senescence in the pathogenesis. Our results shed light on the causative role of a TGF-β-Nox4-senescence axis and therapeutic strategies for GO.

Abstract Image

以 TGF-β 信号、氧化应激和细胞衰老为靶点可拯救老年性骨质疏松症患者的骨质疏松症。
GORAB 是高尔基体囊泡运输和蛋白质糖化的关键调节因子。老年性骨软化症(GO)中 GORAB 功能的缺失会导致糖胺聚糖链缩短,导致细胞外基质紊乱,从而导致皮肤起皱、骨质疏松症和 TGF-β 信号的升高。在这项研究中,我们研究了 TGF-β 信号、氧化应激和由此导致的细胞衰老在 GO 骨质疏松症表型中的作用。用 TGF-β 中和抗体 1D11 处理 GorabPrx1 条件性基因敲除者,可以挽救骨小梁的丢失,这表明 TGF-β 过度激活导致了 GO 骨质疏松症。利用诱导性基因敲除系统,我们证明了 TGF-β 失调不是 GORAB 失活的细胞内在效应,而是细胞外基质紊乱的结果。TGF-β 信号的增强导致了 GorabPrx1 突变体和 GO 患者成纤维细胞中 Nox4 表达的升高,从而导致线粒体超氧化物的过度产生。由此产生的氧化应激可在 GORAB 基因无效细胞和野生型旁观者细胞中检测到。在斑马鱼体内观察到 TALEN 介导的 gorab 失活后也产生了同样的效果,这表明该途径在进化过程中是保守的。用抗氧化剂 N-乙酰半胱氨酸处理 GorabPrx1 突变体可改善骨质疏松症表型。TGF-β诱导的氧化应激与DNA损伤积累和衰老标志物表达升高同时发生。GorabPrx1中的Cdkn2a失活可修复骨质疏松症表型。Cdkn2a 失活后,骨髓基质细胞的集落形成减少和亚群改变恢复正常,从而进一步证明了细胞衰老在发病机制中的相关性。我们的研究结果揭示了TGF-β-Nox4-衰老轴的致病作用以及GO的治疗策略。
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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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