Full Text:   <680>

Summary:  <194>

Suppl. Mater.: 

CLC number: 

On-line Access: 2024-01-02

Received: 2023-03-16

Revision Accepted: 2023-05-17

Crosschecked: 2024-01-02

Cited: 0

Clicked: 861

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2024 Vol.25 No.1 P.38-50

http://doi.org/10.1631/jzus.B2300180


Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model


Author(s):  Dongfang ZHANG, Hao XU, Chi QIN, Kangming CAI, Jing ZHANG, Xinqiu XIA, Jingwen BI, Li ZHANG, Lianping XING, Qianqian LIANG, Wensheng WANG

Affiliation(s):  Laboratory of Molecular Medicine, College of Life Science and State Key Laboratory of Cell Differentiation and Regulation, Henan Normal University, Xinxiang 453007, China; more

Corresponding email(s):   wangwensheng2019@htu.edu.cn, liangqianqian@shutcm.edu.cn

Key Words:  Semaphorin 3A, Gorham-Stout disease, Osteoclast, Osteolysis, Lymphatic endothelial cell


Dongfang ZHANG, Hao XU, Chi QIN, Kangming CAI, Jing ZHANG, Xinqiu XIA, Jingwen BI, Li ZHANG, Lianping XING, Qianqian LIANG, Wensheng WANG. 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, 2024, 25(1): 38-50.

@article{title="Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model",
author="Dongfang ZHANG, Hao XU, Chi QIN, Kangming CAI, Jing ZHANG, Xinqiu XIA, Jingwen BI, Li ZHANG, Lianping XING, Qianqian LIANG, Wensheng WANG",
journal="Journal of Zhejiang University Science B",
volume="25",
number="1",
pages="38-50",
year="2024",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2300180"
}

%0 Journal Article
%T Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model
%A Dongfang ZHANG
%A Hao XU
%A Chi QIN
%A Kangming CAI
%A Jing ZHANG
%A Xinqiu XIA
%A Jingwen BI
%A Li ZHANG
%A Lianping XING
%A Qianqian LIANG
%A Wensheng WANG
%J Journal of Zhejiang University SCIENCE B
%V 25
%N 1
%P 38-50
%@ 1673-1581
%D 2024
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2300180

TY - JOUR
T1 - Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model
A1 - Dongfang ZHANG
A1 - Hao XU
A1 - Chi QIN
A1 - Kangming CAI
A1 - Jing ZHANG
A1 - Xinqiu XIA
A1 - Jingwen BI
A1 - Li ZHANG
A1 - Lianping XING
A1 - Qianqian LIANG
A1 - Wensheng WANG
J0 - Journal of Zhejiang University Science B
VL - 25
IS - 1
SP - 38
EP - 50
%@ 1673-1581
Y1 - 2024
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2300180


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.

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

张东芳1,徐浩2,3,秦驰1,蔡康明1,张靖1,夏鑫秋1,毕静雯1,张莉1,邢联平4,梁倩倩2,3,王文晟1
1河南师范大学细胞分化与调控国家重点实验室,生命科学学院分子医学实验室,中国新乡市,453007
2上海中医药大学附属龙华医院脊柱研究所,中国上海市,200032
3上海中医药大学教育部筋骨理论与治疗重点实验室,中国上海市,200032
4罗切斯特大学医学中心病理与医学检验系,美国罗切斯特市,14642
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。

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

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]al BaroudiS, JabreNA, DunnE, et al., 2020. A 15-year-old boy with dyspnea and vanishing bones. Am J Respir Crit Care Med, 202(3):451-452.

[2]BernatchezPN, RollinS, SokerS, et al., 2002. Relative effects of VEGF-A and VEGF-C on endothelial cell proliferation, migration and PAF synthesis: role of neuropilin-1. J Cell Biochem, 85(3):629-639.

[3]BiswasL, ChenJY, de AngelisJ, et al., 2023. Lymphatic vessels in bone support regeneration after injury. Cell, 186(2):382-397.e24.

[4]Bruch-GerharzD, GerharzCD, StegeH, et al., 2007. Cutaneous lymphatic malformations in disappearing bone (Gorham-Stout) disease: a novel clue to the pathogenesis of a rare syndrome. J Am Acad Dermatol, 56(S2):S21-S25.

[5]BussolinoF, GiraudoE, SeriniG, 2013. Class 3 semaphorin in angiogenesis and lymphangiogenesis. In: S. Karger AG (Ed.), Angiogenesis, Lymphangiogenesis and Clinical Implications. Karger, Basel, p.71-88.

[6]CasazzaA, FuX, JohanssonI, et al., 2011. Systemic and targeted delivery of semaphorin 3A inhibits tumor angiogenesis and progression in mouse tumor models. Arterioscler Thromb Vasc Biol, 31(4):741-749.

[7]DellingerMT, McCormackFX, 2020. The emergence of targetable MEKanisms in sporadic lymphatic disorders. EMBO Mol Med, 12(10):e12822.

[8]DellingerMT, GargN, OlsenBR, 2014. Viewpoints on vessels and vanishing bones in Gorham-Stout disease. Bone, 63:47-52.

[9]EdwardsJR, WilliamsK, KindblomLG, et al., 2008. Lymphatics and bone. Hum Pathol, 39(1):49-55.

[10]FavierB, AlamA, BarronP, et al., 2006. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood, 108(4):1243-1250.

[11]Franco-BarreraMJ, Zavala-CernaMG, Aguilar-PortilloG, et al., 2017. Gorham-Stout disease: a clinical case report and immunological mechanisms in bone erosion. Clin Rev Allergy Immunol, 52:125-132.

[12]FukudaT, TakedaS, XuR, et al., 2013. Sema3A regulates bone-mass accrual through sensory innervations. Nature, 497(7450):490-493.

[13]GorhamLW, StoutAP, 1955. Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone): its relation to hemangiomatosis. J Bone Joint Surg Am, 37-A(5):985-1004.

[14]GuCH, RodriguezER, ReimertDV, et al., 2003. Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev Cell, 5(1):‍45-57.

[15]Guttmann-RavivN, Shraga-HeledN, VarshavskyA, et al., 2007. Semaphorin-3A and semaphorin-3F work together to repel endothelial cells and to inhibit their survival by induction of apoptosis. J Biol Chem, 282(36):26294-26305.

[16]HayashiM, NakashimaT, TaniguchiM, et al., 2012. Osteoprotection by semaphorin 3A. Nature, 485(7396):69-74.

[17]HayashiM, NakashimaT, YoshimuraN, et al., 2019. Autoregulation of osteocyte Sema3A orchestrates estrogen action and counteracts bone aging. Cell Metab, 29(3):627-637.e5.

[18]HuLH, WuW, ZouJ, 2022. Circular RNAs: typical biomarkers for bone-related diseases. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 23(12):975-988.

[19]HirayamaT, SabokbarA, ItonagaI, et al., 2001. Cellular and humoral mechanisms of osteoclast formation and bone resorption in Gorham-Stout disease. J Pathol, 195(5):624-630.

[20]Homayun-SepehrN, MccarterAL, HelaersR, et al., 2021. KRAS-driven model of Gorham-Stout disease effectively treated with trametinib. JCI Insight, 6(15):e149831.

[21]HominickD, SilvaA, KhuranaN, et al., 2018. VEGF-C promotes the development of lymphatics in bone and bone loss. Elife, 7:e34323.

[22]JiaoB, LiuSY, TanX, et al., 2021. Class-3 semaphorins: potent multifunctional modulators for angiogenesis-associated diseases. Biomed Pharmacother, 137:111329.

[23]JoyalJS, SitarasN, BinetF, et al., 2011. Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A. Blood, 117(22):6024-6035.

[24]JurisicG, Maby-El HajjamiH, KaramanS, et al., 2012. An unexpected role of semaphorin3A‍–‍neuropilin-1 signaling in lymphatic vessel maturation and valve formation. Circ Res, 111(4):426-436.

[25]KimJM, LinCJ, StavreZ, et al., 2020. Osteoblast-osteoclast communication and bone homeostasis. Cells, 9(9):2073.

[26]LeeH, MacphersonLJ, ParadaCA, et al., 2017. Rewiring the taste system. Nature, 548(7667):330-333.

[27]LiTT, ZhangSH, YangYX, et al., 2022. Co-regulation of circadian clock genes and microRNAs in bone metabolism. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 23(7):529-546.

[28]LiuSZ, ZhouX, SongA, et al., 2018a. A rare case of Gorham-Stout syndrome of femur treated with cement augmentation. Chin Med J (Engl), 131(13):1628-1629.

[29]LiuSZ, ZhouX, SongA, et al., 2018b. Successful treatment of Gorham-Stout syndrome in the spine by vertebroplasty with cement augmentation: a case report and literature review. Medicine (Baltimore), 97(29):e11555.

[30]MaioneF, MollaF, MedaC, et al., 2009. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J Clin Invest, 119(11):3356-3372.

[31]MaoTJ, XuL, YuYM, et al., 2018. Use of zoledronic acid combined with thalidomide in the treatment of Gorham-Stout disease. Rheumatology (Oxford), 57(6):1122-1124.

[32]MöllerG, PriemelM, AmlingM, et al., 1999. The Gorham-Stout syndrome (Gorham’s massive osteolysis). A report of six cases with histopathological findings. J Bone Joint Surg Br, 81(3):501-506.

[33]MonroyM, MccarterAL, HominickD, et al., 2020. Lymphatics in bone arise from pre-existing lymphatics. Development, 147(21):dev184291.

[34]NozawaA, OzekiM, NiihoriT, et al., 2020. A somatic activating KRAS variant identified in an affected lesion of a patient with Gorham-Stout disease. J Hum Genet, 65(11):995-1001.

[35]OchsenbeinAM, KaramanS, JurisicG, et al., 2014. The role of neuropilin-1/semaphorin 3A signaling in lymphatic vessel development and maturation. In: Kiefer F, Schulte-Merker S (Eds.), Developmental Aspects of the Lymphatic Vascular System. Springer, Vienna, p.143-152.

[36]OchsenbeinAM, KaramanS, ProulxST, et al., 2016. Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells. Development, 143(4):589-594.

[37]Páez CodesoFM, Morillo DomínguezMC, Dorado GalindoA, 2017. A rare case of chylothorax. Gorham-Stout syndrome. Arch Bronconeumol, 53(11):640.

[38]QuLY, CaiXY, WangBL, 2018. Diagnosis and treatment of Gorham-Stout disease in maxillofacial regions. J Craniofac Surg, 29(2):460-461.

[39]RaimondiC, RuhrbergC, 2013. Neuropilin signalling in vessels, neurons and tumours. Semin Cell Dev Biol, 24(3):172-178.

[40]RicciKW, HammillAM, Mobberley-SchumanP, et al., 2019. Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease. Pediatr Blood Cancer, 66(5):e27614.

[41]SakuraiA, DoçiCL, GutkindJS, 2012. Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer. Cell Res, 22:23-32.

[42]SeriniG, ValdembriD, ZanivanS, et al., 2003. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature, 424(6947):391-397.

[43]StatonCA, 2011. Class 3 semaphorins and their receptors in physiological and pathological angiogenesis. Biochem Soc Trans, 39(6):1565-1570.

[44]ToledanoS, Nir-ZviI, EngelmanR, et al., 2019. Class-3 semaphorins and their receptors: potent multifunctional modulators of tumor progression. Int J Mol Sci, 20(3):556.

[45]van der KlaauwAA, CroizierS, de OliveiraEM, et al., 2019. Human semaphorin 3 variants link melanocortin circuit development and energy balance. Cell, 176(4):‍729-742.e18.

[46]WangWS, WangH, ZhouXC, et al., 2017. Lymphatic endothelial cells produce M-CSF, causing massive bone loss in mice. J Bone Miner Res, 32(5):939-950.

[47]WilkinsonMF, 2019. Genetic paradox explained by nonsense. Nature, 568(7751):179-180.

[48]WuJH, ZhouYF, HongCD, et al., 2019. Semaphorin-3A protects against neointimal hyperplasia after vascular injury. EBioMedicine, 39:95-108.

[49]YamashitaY, HayashiM, SaitoM, et al., 2022. Osteoblast lineage cell-derived Sema3A regulates bone homeostasis independently of androgens. Endocrinology, 163(10):bqac126.

[50]YangK, MironRJ, BianZ, et al., 2018. A bone-targeting drug-delivery system based on semaphorin 3A gene therapy ameliorates bone loss in osteoporotic ovariectomized mice. Bone, 114:40-49.

[51]ZhangQ, GuoRL, LuY, et al., 2008. VEGF-C, a lymphatic growth factor, is a RANKL target gene in osteoclasts that enhances osteoclastic bone resorption through an autocrine mechanism. J Biol Chem, 283(19):‍13491-13499.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE