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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

[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.