Advertisement

Amino Acids

, Volume 47, Issue 11, pp 2447–2455 | Cite as

Transglutaminase 2 up-regulation is associated with RANKL/OPG pathway in cultured HPDL cells and THP-1-differentiated macrophages

  • Giovanni Matarese
  • Monica Currò
  • Gaetano Isola
  • Daniela Caccamo
  • Mercurio Vecchio
  • Maria Laura Giunta
  • Luca Ramaglia
  • Giancarlo Cordasco
  • Ray C. Williams
  • Riccardo Ientile
Original Article

Abstract

Recent evidence emphasized that transglutaminase 2 (TG2), a protein cross-linking enzyme, may play a role in the early phase of inflammation. High levels of TG2 have been associated with the constitutive activation of nuclear factor-kappa B (NF-κB) that is considered the main regulator of inflammation. In this context, the receptor activator of NF-kappa B ligand (RANKL) and receptor activator of NF-κB have extensive functions in the regulation of cytokine secretion associated with different pathological conditions. The human periodontal ligament (HPDL) cells, which express and secrete osteoprotegerin (OPG) and RANKL, represent an useful “ex vivo” model for monitoring cell response in inflammatory microenvironments, such as periodontitis-dependent tissue response. Thus, we evaluated TG2 expression and alterations in RANKL/OPG ratio occurring in cultured HPDL cells. The HPDL cells were obtained from patients with chronic periodontitis (CP) and healthy subjects. We observed the up-regulation of some inflammatory markers, such as IL-6, TNF-α, and HMGB-1, and at the same time an increase in TG2 mRNA levels in HPDL cells from CP patients compared with healthy subjects. We found a positive correlation between RANKL/OPG ratio and TG2 mRNA levels in HPDL cells from CP patients. In the parallel experiments, we demonstrated that TG2 inhibition reduced RANKL expression in both HPDL cells from CP patients and monocytes differentiated to macrophages by tetradecanoyl phorbol acetate treatment. Given the RANKL key role in NF-κB pathway and the observed up-regulation of pro-inflammatory cytokines, our data suggest that TG2 may be involved in molecular mechanisms of inflammatory response occurring in periodontal disease.

Keywords

RANKL/OPG Chronic periodontitis Transglutaminase Monocytes/macrophages Inflammation Human periodontal fibroblasts 

Abbreviations

ALP

Alkaline phosphatase

BAPA

5-(Biotinamido)pentylamine

CP

Chronic periodontitis

FBS

Fetal bovine serum

FMOD

Fibromodulin

HPDL

Human periodontal ligament

HMGB1

High mobility group box 1

IL-6

Interleukin-6

LUM

Lumican

NF-κB

Nuclear factor-kappa B

RANKL

Receptor activator of nuclear factor-kappa B ligand

OPG

Osteoprotegerin

PDL

Periodontal ligament

TNF-α

Tumor necrosis factor-α

TG2

Tissue-type transglutaminase

TG

Transglutaminase

Notes

Conflict of interest

This work has been performed with Departmental funding only. The authors declare that they have no conflict of interest to declare.

References

  1. Al-Jallad HF, Nakano Y, Chen JL, McMillan E, Lefebvre C, Kaartinen MT (2006) Transglutaminase activity regulates osteoblast differentiation and matrix mineralization in MC3T3-E1 osteoblast cultures. Matrix Biol 25:135–148CrossRefPubMedGoogle Scholar
  2. Belibasakis GN, Bostanci N (2012) The RANKL-OPG system in clinical periodontology. J Clin Periodontol 39:239–248CrossRefPubMedGoogle Scholar
  3. Belibasakis GN, Johansson A, Wang Y, Chen C, Lagergård T, Kalfas S, Lerner UH (2005) Cytokine responses of human gingival fibroblasts to Actinobacillus actinomycetemcomitans cytolethal distending toxin. Cytokine 30:56–63CrossRefPubMedGoogle Scholar
  4. Bostanci N, Ilgenli T, Emingil G, Afacan B, Han B, Toz H, Berdeli A, Atilla G, McKay IJ, Hughes FJ, Belibasakis GN (2007) Differential expression of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin mRNA in periodontal diseases. J Periodontal Res 42:287–293CrossRefPubMedGoogle Scholar
  5. Caccamo D, Campisi A, Currò M, Bramanti V, Tringali M, Li Volti G, Vanella A, Ientile R (2005) Antioxidant treatment inhibited glutamate-evoked NF-kappaB activation in primary astroglial cell cultures. Neurotoxicology 26:915–921CrossRefPubMedGoogle Scholar
  6. Crotti T, Smith MD, Hirsch R, Soukoulis S, Weedon H, Capone M, Ahern MJ, Haynes D (2003) Receptor activator NF kappaB ligand (RANKL) and osteoprotegerin (OPG) protein expression in periodontitis. J Periodontal Res 38:380–387CrossRefPubMedGoogle Scholar
  7. Currò M, Ferlazzo N, Risitano R, Condello S, Vecchio M, Caccamo D, Ientile R (2014a) Transglutaminase 2 and phospholipase A(2) interactions in the inflammatory response in human THP-1 monocytes. Amino Acids 46:759–766CrossRefPubMedGoogle Scholar
  8. Currò M, Matarese G, Isola G, Caccamo D, Ventura V, Cornelius C, Lentini M, Cordasco G, Ientile R (2014b) Differential expression of transglutaminase genes in patients with chronic periodontitis. Oral Dis 20:616–623CrossRefPubMedGoogle Scholar
  9. Dzink JL, Tanner AC, Haffajee AD, Socransky SS (1985) Gram negative species associated with active destructive periodontal lesions. J Clin Periodontol 12:648–659CrossRefPubMedGoogle Scholar
  10. El-Awady AR, Messer RLW, Gamal AY, Sharawy MM, Wenger KH, Lapp CA (2010) Periodontal ligament fibroblasts sustain destructive immune modulators of chronic periodontitis. J Periodontol 81:1324–1335CrossRefPubMedGoogle Scholar
  11. Griffin M, Casadio R, Bergamini CM (2002) Transglutaminases: nature’s biological glues. Biochem J 368:377–396PubMedCentralCrossRefPubMedGoogle Scholar
  12. Gross SR, Balklava Z, Griffin M (2003) Importance of tissue transglutaminase in repair of extracellular matrices and cell death of dermal fibroblasts after exposure to a solarium ultraviolet A source. J Invest Dermatol 121:412–423CrossRefPubMedGoogle Scholar
  13. Ientile R, Caccamo D, Griffin M (2007) Tissue transglutaminase and the stress response. Amino Acids 33:385–394CrossRefPubMedGoogle Scholar
  14. Jin Q, Cirelli JA, Park CH, Sugai JV, Taba M Jr, Kostenuik PJ, Giannobile WV (2007) RANKL inhibition through osteoprotegerin blocks bone loss in experimental periodontitis. J Periodontol 78:1300–1308PubMedCentralCrossRefPubMedGoogle Scholar
  15. Kim SY (2006) Transglutaminase 2 in inflammation. Front Biosci J Virtual Libr 11:3026–3035CrossRefGoogle Scholar
  16. Kuncio GS, Tsyganskaya M, Zhu J, Liu SL, Nagy L, Thomazy V, Davies PJ, Zern MA (1998) TNF-alpha modulates expression of the tissue transglutaminase gene in liver cells. Am J Physiol 274:G240–G245PubMedGoogle Scholar
  17. Lallier TE, Spencer A, Fowler MM (2005) Transcript profiling of periodontal fibroblasts and osteoblasts. J Periodontol 76:1044–1055CrossRefPubMedGoogle Scholar
  18. Lee HJ, Pi SH, Kim Y, Kim HS, Kim SJ, Kim YS, Lee SK, Kim EC (2009) Effects of nicotine on antioxidant defense enzymes and RANKL expression in human periodontal ligament cells. J Periodontol 80:1281–1288CrossRefPubMedGoogle Scholar
  19. Li X, Kim KW, Cho ML, Ju JH, Kang CM, Oh HJ, Min JK, Lee SH, Park SH, Kim HY (2010) IL-23 induces receptor activator of NF-kappaB ligand expression in fibroblast-like synoviocytes via STAT3 and NF-kappaB signal pathways. Immunol Lett 127:100–107CrossRefPubMedGoogle Scholar
  20. Liu D, Xu JK, Figliomeni L, Huang L, Pavlos NJ, Rogers M, Tan A, Price P, Zheng MH (2003) Expression of RANKL and OPG mRNA in periodontal disease: possible involvement in bone destruction. Int J Mol Med 11:17–21PubMedGoogle Scholar
  21. Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4:140–156CrossRefPubMedGoogle Scholar
  22. Matarese G, Picerno I, Caccamo D, Spataro P, Cordasco G, Ientile R (2006) Increased transglutaminase activity was associated with IL-6 release in cultured human gingival fibroblasts exposed to dental cast alloys. Amino Acids 30:267–271CrossRefPubMedGoogle Scholar
  23. Matarese G, Isola G, Anastasi GP, Favaloro A, Milardi D, Vermiglio G, Vita G, Cordasco G, Cutroneo G (2012) Immunohistochemical analysis of TGF-β1 and VEGF in gingival and periodontal tissues: a role of these biomarkers in the pathogenesis of scleroderma and periodontal disease. Int J Mol Med 30:502–508PubMedGoogle Scholar
  24. Matarese G, Isola G, Anastasi GP, Cutroneo G, Cordasco G, Favaloro A, Vita G, Vermiglio G, Milardi D, Zizzari VL, Tetè S, Perillo L (2013) Effects of the transforming growth factor beta 1 and vascular endothelial growth factor expressions in the pathogenesis of periodontal disease. Eur J Inflamm 11:479–488Google Scholar
  25. McKee MD, Sodek J (2000) Bone matrix proteins. In: Henderson JE, Goltzman D (eds) The Osteoporosis Primer. Cambridge University Press, Cambridge, pp 46–63CrossRefGoogle Scholar
  26. Mehta K, Kumar A, Kim HI (2010) Transglutaminase 2: a multi-tasking protein in the complex circuitry of inflammation and cancer. Biochem Pharmacol 80:1921–1929CrossRefPubMedGoogle Scholar
  27. Nagasawa T, Kiji M, Yashiro R, Hormdee D, Lu H, Kunze M, Suda T, Koshy G, Kobayashi H, Oda S, Nitta S, Ishikawa I (2007) Roles of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin in periodontal health and disease. Periodontol 2000 43:65–84CrossRefPubMedGoogle Scholar
  28. Oeckinghaus A, Ghosh S (2009) The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 1:a000034PubMedCentralCrossRefPubMedGoogle Scholar
  29. Page RC, Eke PI (2007) Case definitions for use in population-based surveillance of periodontitis. J Periodontol 78:1387–1399CrossRefPubMedGoogle Scholar
  30. Parlar A, Bosshardt DD, Unsal B, Cetiner D, Haytaç C, Lang NP (2005) New formation of periodontal tissues around titanium implants in a novel dentin chamber model. Clin Oral Implants Res 16:259–267CrossRefPubMedGoogle Scholar
  31. Taubman MA, Kawai T (2001) Involvement of T-lymphocytes in periodontal disease and in direct and indirect induction of bone resorption. Crit Revie Oral Biol Med 12:125–135CrossRefGoogle Scholar
  32. Telci D, Griffin M (2006) Tissue transglutaminase (TG2)–a wound response enzyme. Front Biosci 11:867–882CrossRefPubMedGoogle Scholar
  33. Vardar-Sengul S, Arora S, Baylas H, Mercola D (2009) Expression profile of human gingival fibroblasts induced by interleukin-1beta reveals central role of nuclear factor-kappa B in stabilizing human gingival fibroblasts during inflammation. J Periodontol 80:833–849PubMedCentralCrossRefPubMedGoogle Scholar
  34. Verdrengh M, Bokarewa M, Ohlsson C, Stolina M, Tarkowski A (2010) RANKL-targeted therapy inhibits bone resorption in experimental Staphylococcus aureus-induced arthritis. Bone 46:752–758CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Giovanni Matarese
    • 1
  • Monica Currò
    • 2
  • Gaetano Isola
    • 1
    • 3
  • Daniela Caccamo
    • 2
  • Mercurio Vecchio
    • 2
  • Maria Laura Giunta
    • 2
  • Luca Ramaglia
    • 3
  • Giancarlo Cordasco
    • 1
  • Ray C. Williams
    • 4
  • Riccardo Ientile
    • 2
  1. 1.Department of Specialist Medical-Surgical Experimental Sciences and OdontostomatologyUniversity of MessinaMessinaItaly
  2. 2.Department of Biomedical Sciences and Morpho-Functional ImagingUniversity of Messina, Polyclinic Hospital UniversityMessinaItaly
  3. 3.Department of Neurosciences, Reproductive and Odontostomatological SciencesSchool of Medicine University “Federico II”NaplesItaly
  4. 4.Dean, School of Dental MedicineStony Brook UniversityStony BrookUSA

Personalised recommendations