Skip to main content

Advertisement

Log in

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

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Vadasz Z, Attias D, Kessel A, Toubi E (2010) Neuropilins and semaphorins—from angiogenesis to autoimmunity. Autoimmun Rev 9(12):825–829

    Article  PubMed  CAS  Google Scholar 

  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):1101–1107

    PubMed  CAS  Google Scholar 

  3. Yazdani U, Terman JR (2006) The semaphorins. Genome Biol 7(3):211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):1389–1399

    Article  PubMed  CAS  Google Scholar 

  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):217–227

    Article  PubMed  CAS  Google Scholar 

  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):1204–1211

    Article  PubMed  CAS  Google Scholar 

  7. Tamagnone L, Comoglio PM (2004) To move or not to move? Semaphorin signalling in cell migration. EMBO Rep 5(4):356–361

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):2674–2680

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Carmeliet P, Tessier-Lavigne M (2005) Common mechanisms of nerve and blood vessel wiring. Nature 436(7048):193–200

    Article  PubMed  CAS  Google Scholar 

  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):26294–26305

    Article  PubMed  CAS  Google Scholar 

  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):1380–1389

    Article  PubMed  CAS  Google Scholar 

  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):391–397

    Article  PubMed  CAS  Google Scholar 

  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):e25

    Article  PubMed  CAS  Google Scholar 

  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):1451–1460

    Article  PubMed  CAS  Google Scholar 

  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):1155–1171

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):4120–4125

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):1673–1685

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):1661–1667

    Article  PubMed  CAS  Google Scholar 

  19. Catalano A (2010) The neuroimmune semaphorin-3A reduces inflammation and progression of experimental autoimmune arthritis. J Immunol 185(10):6373–6383

    Article  PubMed  CAS  Google Scholar 

  20. Hayashi M, Nakashima T, Taniguchi M, Kodama T, Kumanogoh A, Takayanagi H (2012) Osteoprotection by semaphorin 3A. Nature 485(7396):69–74

    Article  PubMed  CAS  Google Scholar 

  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):3321–3329

    Article  PubMed  CAS  Google Scholar 

  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):7–13

    Article  PubMed  CAS  Google Scholar 

  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):1075–1079

    Article  PubMed  CAS  Google Scholar 

  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 14:40

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):R146

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):157–164

    Article  PubMed  CAS  Google Scholar 

  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):370–374

    PubMed  CAS  Google Scholar 

  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):521–528

    Article  PubMed  CAS  Google Scholar 

  29. Okuno T, Nakatsuji Y, Kumanogoh A (2011) The role of immune semaphorins in multiple sclerosis. FEBS Lett 585(23):3829–3835

    Article  PubMed  CAS  Google Scholar 

  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):34–44

    Article  PubMed  CAS  Google Scholar 

  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):1466–1473

    Article  PubMed  CAS  Google Scholar 

  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):71–80

    Article  PubMed  CAS  Google Scholar 

  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):1782–1793

    Article  PubMed  CAS  Google Scholar 

  34. Elefteriou F (2008) Regulation of bone remodeling by the central and peripheral nervous system. Arch Biochem Biophys 473(2):231–236

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7(4):292–304

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

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.

Funding

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

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xue-wu Zhang.

Ethics declarations

Disclosures

None.

Additional information

Xiao-xu Ma contribute equally to the first author

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, H., Ma, Xx., Guo, Q. et al. Expression of circulating Semaphorin3A and its association with inflammation and bone destruction in rheumatoid arthritis. Clin Rheumatol 37, 2073–2080 (2018). https://doi.org/10.1007/s10067-018-4070-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-018-4070-x

Keywords

Navigation