Clinical Rheumatology

, Volume 37, Issue 8, pp 2073–2080 | Cite as

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

  • Hui Gao
  • Xiao-xu Ma
  • Qian Guo
  • Lin-feng Xie
  • Yu-chao Zhong
  • Xue-wu ZhangEmail author
Original Article


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.


Auto-antibody Bone destruction Inflammation Rheumatoid arthritis Semaphorin3A 



We are grateful to doctor Qi-zhi Zhu and Xia Liu from Radiology Department, Peking University People’s Hospital, who scored radiographs of hands and wrists from RA patients.


This study was supported by grants from the National Natural Science Foundation of China (Nos. 31530030 and 2101000218).

Compliance with ethical standards




  1. 1.
    Vadasz Z, Attias D, Kessel A, Toubi E (2010) Neuropilins and semaphorins—from angiogenesis to autoimmunity. Autoimmun Rev 9(12):825–829CrossRefPubMedGoogle Scholar
  2. 2.
    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):1101–1107PubMedGoogle Scholar
  3. 3.
    Yazdani U, Terman JR (2006) The semaphorins. Genome Biol 7(3):211CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Kolodkin AL, Matthes DJ, Goodman CS (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75(7):1389–1399CrossRefPubMedGoogle Scholar
  5. 5.
    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):217–227CrossRefPubMedGoogle Scholar
  6. 6.
    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):1204–1211CrossRefPubMedGoogle Scholar
  7. 7.
    Tamagnone L, Comoglio PM (2004) To move or not to move? Semaphorin signalling in cell migration. EMBO Rep 5(4):356–361CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    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):2674–2680CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Carmeliet P, Tessier-Lavigne M (2005) Common mechanisms of nerve and blood vessel wiring. Nature 436(7048):193–200CrossRefPubMedGoogle Scholar
  10. 10.
    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):26294–26305CrossRefPubMedGoogle Scholar
  11. 11.
    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):1380–1389CrossRefPubMedGoogle Scholar
  12. 12.
    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):391–397CrossRefPubMedGoogle Scholar
  13. 13.
    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):e25CrossRefPubMedGoogle Scholar
  14. 14.
    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):1451–1460CrossRefPubMedGoogle Scholar
  15. 15.
    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):1155–1171CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    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):4120–4125CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    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):1673–1685CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    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):1661–1667CrossRefPubMedGoogle Scholar
  19. 19.
    Catalano A (2010) The neuroimmune semaphorin-3A reduces inflammation and progression of experimental autoimmune arthritis. J Immunol 185(10):6373–6383CrossRefPubMedGoogle Scholar
  20. 20.
    Hayashi M, Nakashima T, Taniguchi M, Kodama T, Kumanogoh A, Takayanagi H (2012) Osteoprotection by semaphorin 3A. Nature 485(7396):69–74CrossRefPubMedGoogle Scholar
  21. 21.
    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):3321–3329CrossRefPubMedGoogle Scholar
  22. 22.
    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):7–13CrossRefPubMedGoogle Scholar
  23. 23.
    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):1075–1079CrossRefPubMedGoogle Scholar
  24. 24.
    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 14:40CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    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):R146CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    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):157–164CrossRefPubMedGoogle Scholar
  27. 27.
    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):370–374PubMedGoogle Scholar
  28. 28.
    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):521–528CrossRefPubMedGoogle Scholar
  29. 29.
    Okuno T, Nakatsuji Y, Kumanogoh A (2011) The role of immune semaphorins in multiple sclerosis. FEBS Lett 585(23):3829–3835CrossRefPubMedGoogle Scholar
  30. 30.
    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):34–44CrossRefPubMedGoogle Scholar
  31. 31.
    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):1466–1473CrossRefPubMedGoogle Scholar
  32. 32.
    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):71–80CrossRefPubMedGoogle Scholar
  33. 33.
    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):1782–1793CrossRefPubMedGoogle Scholar
  34. 34.
    Elefteriou F (2008) Regulation of bone remodeling by the central and peripheral nervous system. Arch Biochem Biophys 473(2):231–236CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7(4):292–304CrossRefPubMedGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  • Hui Gao
    • 1
    • 2
  • Xiao-xu Ma
    • 1
  • Qian Guo
    • 1
    • 2
  • Lin-feng Xie
    • 1
  • Yu-chao Zhong
    • 1
  • Xue-wu Zhang
    • 1
    • 2
    Email author
  1. 1.Department of Rheumatology and ImmunologyPeking University People’s HospitalBeijingChina
  2. 2.Department of Rheumatology and ImmunologyPeking University International HospitalBeijingChina

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