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Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model
Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model
- 破骨细胞中信号素3A表达的减少导致小鼠GSD模型中淋巴管扩张
- Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Vol. 25, Issue 1, Pages: 38-50(2024)
- Affiliations：
1.Laboratory of Molecular Medicine, College of Life Science and State Key Laboratory of Cell Differentiation and Regulation, Henan Normal University, Xinxiang 453007, China
2.Longhua Hospital & Spine Institute, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
3.Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), Shanghai 201203, China
4.Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester 14642, USA
- Funds：
DOI：10.1631/jzus.B2300180
CLC：- CSTR：
张东芳,徐浩,秦驰等.破骨细胞中信号素3A表达的减少导致小鼠GSD模型中淋巴管扩张[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(01):38-50.
Dongfang ZHANG, Hao XU, Chi QIN, et al. Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 25(1):38-50(2024)
张东芳,徐浩,秦驰等.破骨细胞中信号素3A表达的减少导致小鼠GSD模型中淋巴管扩张[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(01):38-50. DOI： 10.1631/jzus.B2300180.
Dongfang ZHANG, Hao XU, Chi QIN, et al. Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 25(1):38-50(2024) DOI： 10.1631/jzus.B2300180.
摘要
戈勒姆综合征（Gorham-Stout disease, GSD）是一种罕见的散发性慢性骨科疾病，以进行性骨溶解、吸收和消失为特征，伴骨髓腔淋巴管浸润。虽然GSD的溶骨机制已被广泛研究，但其骨中淋巴管增生的原因却很少被触及。本研究通过RNA测序，比较破骨细胞（OCs）和破骨细胞前体（OCPs）的RNA表达谱，发现了具有骨保护作用的因子信号素3A（Sema3A）在OCs中的表达显著降低了。并且与OCPs相比，OCs促进了淋巴管内皮细胞（LECs）的生长、迁移和体外淋巴管管状形成。同时体外研究发现，重组Sema3A能抑制LECs的生长、迁移和体外淋巴管管状形成，证实了Sema3A对LECs的抑制作用。采用LECs诱导的GSD小鼠模型，通过在胫骨内注射表达Sema3A的慢病毒，我们进一步检测Sema3A在体内的作用。结果表明，在胫骨中过表达Sema3A可抑制LECs的扩张，减少骨丢失。而在胫骨中注射表达Sema3A shRNA的慢病毒以敲低Sema3A的表达可引发小鼠胫骨GSD样表型。组织学染色分析表明，与对照组相比，Sema3A慢病毒治疗后OCs减少，骨钙素增加。基于以上结果，我们认为OCs中Sema3A的减少是GSD的发病机制之一，表达Sema3A代表了一种治疗GSD的新方案。
Abstract
Gorham-Stout disease (GSD) is a sporadic chronic disease characterized by progressive bone dissolution, absorption, and disappearance along with lymphatic vessel infiltration in bone-marrow cavities. Although the osteolytic mechanism of GSD has been widely studied, the cause of lymphatic hyperplasia in GSD is rarely investigated. In this study, by comparing the RNA expression profile of osteoclasts (OCs) with that of OC precursors (OCPs) by RNA sequencing, we identified a new factor, semaphorin 3A (Sema3A), which is an osteoprotective factor involved in the lymphatic expansion of GSD. Compared to OCPs, OCs enhanced the growth, migration, and tube formation of lymphatic endothelial cells (LECs), in which the expression of Sema3A is low compared to that in OCPs. In the presence of recombinant Sema3A, the growth, migration, and tube formation of LECs were inhibited, further confirming the inhibitory effect of Sema3A on LECs in vitro. Using an LEC-induced GSD mouse model, the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in vivo. We found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss, whereas the injection of lentivirus expressing Sema3A short hairpin RNA (shRNA) into the tibiae caused GSD-like phenotypes. Histological staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment, compared with the control. Based on the above results, we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.
关键词
信号素3A戈勒姆综合征破骨细胞骨溶解淋巴管内皮细胞
Keywords
Semaphorin 3AGorham-Stout diseaseOsteoclastOsteolysisLymphatic endothelial cell
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