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Published in: Clinical Rheumatology 8/2018

01-08-2018 | Original Article

Expression of circulating Semaphorin3A and its association with inflammation and bone destruction in rheumatoid arthritis

Authors: Hui Gao, Xiao-xu Ma, Qian Guo, Lin-feng Xie, Yu-chao Zhong, Xue-wu Zhang

Published in: Clinical Rheumatology | Issue 8/2018

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Abstract

To determine the expression of Semaphorin3A (Sema3A) in rheumatoid arthritis (RA) patients, and analyze the correlation between serum Sema3A and the pathogenesis of RA. The concentration of serum Sema3A and its mRNA expression level were detected in RA patients. The association of serum Sema3A level with clinical and laboratory features of RA were analyzed. Serum Sema3A of 130 RA patients (15.89 ± 8.58 ng/ml) was significantly higher than that of 150 HC (6.96 ± 2.62 ng/ml) and 215 patients with other rheumatic diseases (P < 0.05). Consistent with the serum level, the Sema3A mRNA level was also higher in RA patients’ PBMC than that in HC (1.8-fold increase, P < 0.01). The serum level of Sema3A was correlated with platelet counts (r = 0.229), ESR (r = 0.172), RF (r = 0.230), IgM (r = 0.254) and Sharp score (r = 0.254), and bone mineral density (BMD) of lumbar spine (r = 0.263). Serum Sema3A was also fundamentally higher in AKA-, APF-, anti-CCP-positive groups compared with negative groups (P < 0.05). The ROC curve showed that the optimum diagnostic cutoff value for Sema3A was 10.881 ng/ml. RF level and antibodies (anti-CCP, APF, AKA, and GPI) positive rates were significantly higher in Sema3A positive group. Sharp score was also higher, although without significance. The expression of Sema3A is significantly elevated in RA patients. The level of serum Sema3A is positively correlated with inflammatory factors (including ESR, IgM, and RF) and is associated with auto-antibody production and bone destruction.
Literature
1.
go back to reference Vadasz Z, Attias D, Kessel A, Toubi E (2010) Neuropilins and semaphorins—from angiogenesis to autoimmunity. Autoimmun Rev 9(12):825–829CrossRefPubMed Vadasz Z, Attias D, Kessel A, Toubi E (2010) Neuropilins and semaphorins—from angiogenesis to autoimmunity. Autoimmun Rev 9(12):825–829CrossRefPubMed
2.
go back to reference Takegahara N, Kumanogoh A (2009) [Immune semaphorins: involvement of semaphorins in various phases of immune responses]. Tanpakushitsu kakusan koso. Protein, Nucleic Acid, Enzyme 54(8 Suppl):1101–1107PubMed Takegahara N, Kumanogoh A (2009) [Immune semaphorins: involvement of semaphorins in various phases of immune responses]. Tanpakushitsu kakusan koso. Protein, Nucleic Acid, Enzyme 54(8 Suppl):1101–1107PubMed
4.
go back to reference Kolodkin AL, Matthes DJ, Goodman CS (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75(7):1389–1399CrossRefPubMed Kolodkin AL, Matthes DJ, Goodman CS (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75(7):1389–1399CrossRefPubMed
5.
go back to reference Luo Y, Raible D, Raper JA (1993) Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75(2):217–227CrossRefPubMed Luo Y, Raible D, Raper JA (1993) Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75(2):217–227CrossRefPubMed
6.
go back to reference Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Yabuki M, Harada K, Hori M, Kikutani H (2004) Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nat Cell Biol 6(12):1204–1211CrossRefPubMed Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Yabuki M, Harada K, Hori M, Kikutani H (2004) Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nat Cell Biol 6(12):1204–1211CrossRefPubMed
8.
go back to reference Acevedo LM, Barillas S, Weis SM, Gothert JR, Cheresh DA (2008) Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood 111(5):2674–2680CrossRefPubMedPubMedCentral Acevedo LM, Barillas S, Weis SM, Gothert JR, Cheresh DA (2008) Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood 111(5):2674–2680CrossRefPubMedPubMedCentral
9.
go back to reference Carmeliet P, Tessier-Lavigne M (2005) Common mechanisms of nerve and blood vessel wiring. Nature 436(7048):193–200CrossRefPubMed Carmeliet P, Tessier-Lavigne M (2005) Common mechanisms of nerve and blood vessel wiring. Nature 436(7048):193–200CrossRefPubMed
10.
go back to reference Guttmann-Raviv N, Shraga-Heled N, Varshavsky A, Guimaraes-Sternberg C, Kessler O, Neufeld G (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):26294–26305CrossRefPubMed Guttmann-Raviv N, Shraga-Heled N, Varshavsky A, Guimaraes-Sternberg C, Kessler O, Neufeld G (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):26294–26305CrossRefPubMed
11.
go back to reference Kaneko S, Iwanami A, Nakamura M, Kishino A, Kikuchi K, Shibata S, Okano HJ, Ikegami T, Moriya A, Konishi O, Nakayama C, Kumagai K, Kimura T, Sato Y, Goshima Y, Taniguchi M, Ito M, He Z, Toyama Y, Okano H (2006) A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord. Nat Med 12(12):1380–1389CrossRefPubMed Kaneko S, Iwanami A, Nakamura M, Kishino A, Kikuchi K, Shibata S, Okano HJ, Ikegami T, Moriya A, Konishi O, Nakayama C, Kumagai K, Kimura T, Sato Y, Goshima Y, Taniguchi M, Ito M, He Z, Toyama Y, Okano H (2006) A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord. Nat Med 12(12):1380–1389CrossRefPubMed
12.
go back to reference Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F, Zammataro L, Primo L, Tamagnone L, Logan M, Tessier-Lavigne M, Taniguchi M, Püschel AW, Bussolino F (2003) Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424(6947):391–397CrossRefPubMed Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F, Zammataro L, Primo L, Tamagnone L, Logan M, Tessier-Lavigne M, Taniguchi M, Püschel AW, Bussolino F (2003) Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424(6947):391–397CrossRefPubMed
13.
go back to reference Valdembri D, Caswell PT, Anderson KI, Schwarz JP, König I, Astanina E, Caccavari F, Norman JC, Humphries MJ, Bussolino F, Serini G (2009) Neuropilin-1/GIPC1 signaling regulates alpha5beta1 integrin traffic and function in endothelial cells. PLoS Biol 7(1):e25CrossRefPubMed Valdembri D, Caswell PT, Anderson KI, Schwarz JP, König I, Astanina E, Caccavari F, Norman JC, Humphries MJ, Bussolino F, Serini G (2009) Neuropilin-1/GIPC1 signaling regulates alpha5beta1 integrin traffic and function in endothelial cells. PLoS Biol 7(1):e25CrossRefPubMed
14.
go back to reference Futamura M, Kamino H, Miyamoto Y, Kitamura N, Nakamura Y, Ohnishi S, Masuda Y, Arakawa H (2007) Possible role of semaphorin 3F, a candidate tumor suppressor gene at 3p21.3, in p53-regulated tumor angiogenesis suppression. Cancer Res 67(4):1451–1460CrossRefPubMed Futamura M, Kamino H, Miyamoto Y, Kitamura N, Nakamura Y, Ohnishi S, Masuda Y, Arakawa H (2007) Possible role of semaphorin 3F, a candidate tumor suppressor gene at 3p21.3, in p53-regulated tumor angiogenesis suppression. Cancer Res 67(4):1451–1460CrossRefPubMed
15.
go back to reference Rolny C, Capparuccia L, Casazza A, Mazzone M, Vallario A, Cignetti A, Medico E, Carmeliet P, Comoglio PM, Tamagnone L (2008) The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment. J Exp Med 205(5):1155–1171CrossRefPubMedPubMedCentral Rolny C, Capparuccia L, Casazza A, Mazzone M, Vallario A, Cignetti A, Medico E, Carmeliet P, Comoglio PM, Tamagnone L (2008) The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment. J Exp Med 205(5):1155–1171CrossRefPubMedPubMedCentral
16.
go back to reference Sekido Y, Bader S, Latif F, Chen JY, Duh FM, Wei MH, Albanesi JP, Lee CC, Lerman MI, Minna JD (1996) Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. Proc Natl Acad Sci U S A 93(9):4120–4125CrossRefPubMedPubMedCentral Sekido Y, Bader S, Latif F, Chen JY, Duh FM, Wei MH, Albanesi JP, Lee CC, Lerman MI, Minna JD (1996) Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. Proc Natl Acad Sci U S A 93(9):4120–4125CrossRefPubMedPubMedCentral
17.
go back to reference Sierra JR, Corso S, Caione L, Cepero V, Conrotto P, Cignetti A, Piacibello W, Kumanogoh A, Kikutani H, Comoglio PM, Tamagnone L, Giordano S (2008) Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 205(7):1673–1685CrossRefPubMedPubMedCentral Sierra JR, Corso S, Caione L, Cepero V, Conrotto P, Cignetti A, Piacibello W, Kumanogoh A, Kikutani H, Comoglio PM, Tamagnone L, Giordano S (2008) Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 205(7):1673–1685CrossRefPubMedPubMedCentral
18.
go back to reference Vacca A, Scavelli C, Serini G, di Pietro G, Cirulli T, Merchionne F, Ribatti D, Bussolino F, Guidolin D, Piaggio G, Bacigalupo A, Dammacco F (2006) Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma. Blood 108(5):1661–1667CrossRefPubMed Vacca A, Scavelli C, Serini G, di Pietro G, Cirulli T, Merchionne F, Ribatti D, Bussolino F, Guidolin D, Piaggio G, Bacigalupo A, Dammacco F (2006) Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma. Blood 108(5):1661–1667CrossRefPubMed
19.
go back to reference Catalano A (2010) The neuroimmune semaphorin-3A reduces inflammation and progression of experimental autoimmune arthritis. J Immunol 185(10):6373–6383CrossRefPubMed Catalano A (2010) The neuroimmune semaphorin-3A reduces inflammation and progression of experimental autoimmune arthritis. J Immunol 185(10):6373–6383CrossRefPubMed
20.
go back to reference Hayashi M, Nakashima T, Taniguchi M, Kodama T, Kumanogoh A, Takayanagi H (2012) Osteoprotection by semaphorin 3A. Nature 485(7396):69–74CrossRefPubMed Hayashi M, Nakashima T, Taniguchi M, Kodama T, Kumanogoh A, Takayanagi H (2012) Osteoprotection by semaphorin 3A. Nature 485(7396):69–74CrossRefPubMed
21.
go back to reference Catalano A, Caprari P, Moretti S, Faronato M, Tamagnone L, Procopio A (2006) Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function. Blood 107(8):3321–3329CrossRefPubMed Catalano A, Caprari P, Moretti S, Faronato M, Tamagnone L, Procopio A (2006) Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function. Blood 107(8):3321–3329CrossRefPubMed
22.
go back to reference Garcia F, Lepelletier Y, Smaniotto S, Hadj-Slimane R, Dardenne M, Hermine O, Savino W (2012) Inhibitory effect of semaphorin-3A, a known axon guidance molecule, in the human thymocyte migration induced by CXCL12. J Leukoc Biol 91(1):7–13CrossRefPubMed Garcia F, Lepelletier Y, Smaniotto S, Hadj-Slimane R, Dardenne M, Hermine O, Savino W (2012) Inhibitory effect of semaphorin-3A, a known axon guidance molecule, in the human thymocyte migration induced by CXCL12. J Leukoc Biol 91(1):7–13CrossRefPubMed
23.
go back to reference Lepelletier Y, Lecourt S, Renand A, Arnulf B, Vanneaux V, Fermand JP, Menasché P, Domet T, Marolleau JP, Hermine O, Larghero J (2010) Galectin-1 and semaphorin-3A are two soluble factors conferring T-cell immunosuppression to bone marrow mesenchymal stem cell. Stem Cells Dev 19(7):1075–1079CrossRefPubMed Lepelletier Y, Lecourt S, Renand A, Arnulf B, Vanneaux V, Fermand JP, Menasché P, Domet T, Marolleau JP, Hermine O, Larghero J (2010) Galectin-1 and semaphorin-3A are two soluble factors conferring T-cell immunosuppression to bone marrow mesenchymal stem cell. Stem Cells Dev 19(7):1075–1079CrossRefPubMed
24.
go back to reference Takagawa S, Nakamura F, Kumagai K, Nagashima Y, Goshima Y, Saito T (2013) Decreased semaphorin3A expression correlates with disease activity and histological features of rheumatoid arthritis. BMC Musculoskelet Disord 14:40CrossRefPubMedPubMedCentral Takagawa S, Nakamura F, Kumagai K, Nagashima Y, Goshima Y, Saito T (2013) Decreased semaphorin3A expression correlates with disease activity and histological features of rheumatoid arthritis. BMC Musculoskelet Disord 14:40CrossRefPubMedPubMedCentral
25.
go back to reference Vadasz Z, Haj T, Halasz K, Rosner I, Slobodin G, Attias D, Kessel A, Kessler O, Neufeld G, Toubi E (2012) Semaphorin 3A is a marker for disease activity and a potential immunoregulator in systemic lupus erythematosus. Arthritis Res Ther 14(3):R146CrossRefPubMedPubMedCentral Vadasz Z, Haj T, Halasz K, Rosner I, Slobodin G, Attias D, Kessel A, Kessler O, Neufeld G, Toubi E (2012) Semaphorin 3A is a marker for disease activity and a potential immunoregulator in systemic lupus erythematosus. Arthritis Res Ther 14(3):R146CrossRefPubMedPubMedCentral
26.
go back to reference Eixarch H, Gutierrez-Franco A, Montalban X, Espejo C (2013) Semaphorins 3A and 7A: potential immune and neuroregenerative targets in multiple sclerosis. Trends Mol Med 19(3):157–164CrossRefPubMed Eixarch H, Gutierrez-Franco A, Montalban X, Espejo C (2013) Semaphorins 3A and 7A: potential immune and neuroregenerative targets in multiple sclerosis. Trends Mol Med 19(3):157–164CrossRefPubMed
27.
go back to reference Gao H, Ma XX, Guo Q, Zou YD, Zhong YC, Xie LF, Shao M, Zhang XW (2017) Expression and clinical significance of Semaphorin 3A in serum and mononuclear cells in patients with systemic lupus erythematosus. Zhonghua Yi Xue Za Zhi 97(5):370–374PubMed Gao H, Ma XX, Guo Q, Zou YD, Zhong YC, Xie LF, Shao M, Zhang XW (2017) Expression and clinical significance of Semaphorin 3A in serum and mononuclear cells in patients with systemic lupus erythematosus. Zhonghua Yi Xue Za Zhi 97(5):370–374PubMed
28.
go back to reference Kou K, Nakamura F, Aihara M, Chen H, Seto K, Komori-Yamaguchi J, Kambara T, Nagashima Y, Goshima Y, Ikezawa Z (2012) Decreased expression of semaphorin-3A, a neurite-collapsing factor, is associated with itch in psoriatic skin. Acta Derm Venereol 92(5):521–528CrossRefPubMed Kou K, Nakamura F, Aihara M, Chen H, Seto K, Komori-Yamaguchi J, Kambara T, Nagashima Y, Goshima Y, Ikezawa Z (2012) Decreased expression of semaphorin-3A, a neurite-collapsing factor, is associated with itch in psoriatic skin. Acta Derm Venereol 92(5):521–528CrossRefPubMed
29.
go back to reference Okuno T, Nakatsuji Y, Kumanogoh A (2011) The role of immune semaphorins in multiple sclerosis. FEBS Lett 585(23):3829–3835CrossRefPubMed Okuno T, Nakatsuji Y, Kumanogoh A (2011) The role of immune semaphorins in multiple sclerosis. FEBS Lett 585(23):3829–3835CrossRefPubMed
30.
go back to reference Sawaki H, Nakamura F, Aihara M, Nagashima Y, Komori-Yamaguchi J, Yamashita N, Nakazawa M, Goshima Y, Ikezawa Z (2011) Intranasal administration of semaphorin-3A alleviates sneezing and nasal rubbing in a murine model of allergic rhinitis. J Pharmacol Sci 117(1):34–44CrossRefPubMed Sawaki H, Nakamura F, Aihara M, Nagashima Y, Komori-Yamaguchi J, Yamashita N, Nakazawa M, Goshima Y, Ikezawa Z (2011) Intranasal administration of semaphorin-3A alleviates sneezing and nasal rubbing in a murine model of allergic rhinitis. J Pharmacol Sci 117(1):34–44CrossRefPubMed
31.
go back to reference Vadasz Z, Ben-Izhak O, Bejar J, Sabo E, Kessel A, Storch S, Toubi E (2011) The involvement of immune semaphorins and neuropilin-1 in lupus nephritis. Lupus 20(14):1466–1473CrossRefPubMed Vadasz Z, Ben-Izhak O, Bejar J, Sabo E, Kessel A, Storch S, Toubi E (2011) The involvement of immune semaphorins and neuropilin-1 in lupus nephritis. Lupus 20(14):1466–1473CrossRefPubMed
32.
go back to reference Tamagnone L, Artigiani S, Chen H, He Z, Ming GL, Song HJ, Chedotal A, Winberg ML, Goodman CS, Poo MM, Tessier-Lavigne M, Comoglio PM (1999) Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99(1):71–80CrossRefPubMed Tamagnone L, Artigiani S, Chen H, He Z, Ming GL, Song HJ, Chedotal A, Winberg ML, Goodman CS, Poo MM, Tessier-Lavigne M, Comoglio PM (1999) Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99(1):71–80CrossRefPubMed
33.
go back to reference Lepelletier Y, Moura IC, Hadj-Slimane R et al (2006) Immunosuppressive role of semaphorin-3A on T cell proliferation is mediated by inhibition of actin cytoskeleton reorganization. Eur J Immunol 36(7):1782–1793CrossRefPubMed Lepelletier Y, Moura IC, Hadj-Slimane R et al (2006) Immunosuppressive role of semaphorin-3A on T cell proliferation is mediated by inhibition of actin cytoskeleton reorganization. Eur J Immunol 36(7):1782–1793CrossRefPubMed
35.
go back to reference Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7(4):292–304CrossRefPubMed Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7(4):292–304CrossRefPubMed
Metadata
Title
Expression of circulating Semaphorin3A and its association with inflammation and bone destruction in rheumatoid arthritis
Authors
Hui Gao
Xiao-xu Ma
Qian Guo
Lin-feng Xie
Yu-chao Zhong
Xue-wu Zhang
Publication date
01-08-2018
Publisher
Springer London
Published in
Clinical Rheumatology / Issue 8/2018
Print ISSN: 0770-3198
Electronic ISSN: 1434-9949
DOI
https://doi.org/10.1007/s10067-018-4070-x

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