Amino Acids

, Volume 44, Issue 1, pp 199–207 | Cite as

Transglutaminase 2 as a biomarker of osteoarthritis: an update

  • Umberto Tarantino
  • Amedeo Ferlosio
  • Gaetano Arcuri
  • Luigi Giusto Spagnoli
  • Augusto OrlandiEmail author
Invited Review


Osteoarthritis is a progressive joint disease characterized by cartilage degradation and bone remodelling. Under physiologic conditions, articular cartilage displays a stable chondrocyte phenotype, whereas in osteoarthritis a chondrocyte hypertrophy develops near the sites of cartilage surface damage and associates to the pathologic expression of type X collagen. Transglutaminases (TGs) include a family of Ca2+-dependent enzymes that catalyze the formation of γ-glutamyl cross-links. Their substrates include a variety of intracellular and extracellular macromolecular components. TGs are ubiquitously and abundantly expressed and implicated in a variety of physiopathological processes. TGs activity is modulated by inflammatory cytokines. TG2 (also known as tissue transglutaminase) mediates the hypertrophic differentiation of joint chondrocytes and interleukin-1-induced calcification. Histomorphometrical and biomolecular investigations document increased TG2 expression in human and experimental osteoarthritis. Consequently, the level of TG2 expression may represent an adjuvant additional marker to monitor tissue remodelling occurring in osteoarthritic joint tissue. Experimental induction of osteoarthritis in TG2 knockout mice is followed from reduced cartilage destruction and increased osteophyte formation compared to wild-type mice, suggesting a different influence on joint bone and cartilage remodelling. The capacity of transamidation by TG2 to regulate activation of latent TGF-β seems to have a potential impact on the regulation of inflammatory response in osteoarthritic tissues. Additional studies are needed to define TG2-regulated pathways that are differently modulated in osteoblasts and chondrocytes during osteoarthritis.


Osteoarthritis Transglutaminase 2 Joint tissue Transforming growth factor-beta 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. Aeschlimann D, Thomazy V (2000) Protein crosslinking in assembly and remodelling of extracellular matrices: the role of transglutaminases. Connect Tissue Res 41:1–27PubMedCrossRefGoogle Scholar
  2. Aeschlimann D, Wetterwald A, Fleisch H, Paulsson M (1993) Expression of tissue transglutaminase in skeletal tissues correlates with events of terminal differentiation of chondrocytes. J Cell Biol 120:1461–1470PubMedCrossRefGoogle Scholar
  3. Aeschlimann D, Kaupp O, Paulsson M (1995) Transglutaminase-catalyzed matrix cross-linking in differentiating cartilage: identification of osteonectin as a major glutaminyl substrate. J Cell Biol 129:881–892PubMedCrossRefGoogle Scholar
  4. Aeschlimann D, Mosher D, Paulsson M (1996) Tissue transglutaminase and factor XIII in cartilage and bone remodeling. Semin Thromb Hemost 22:437–443PubMedCrossRefGoogle Scholar
  5. Alini M, Kofsky Y, Wu W, Pidoux I, Poole AR (1996) In serum-free culture thyroid hormones can induce full expression of chondrocyte hypertrophy leading to matrix calcification. J Bone Miner Res 11:105–113PubMedCrossRefGoogle Scholar
  6. Attur MG, Patel IR, Patel RN, Abramson SB, Amin AR (1998) Autocrine production of IL-1 beta by human osteoarthritis-affected cartilage and differential regulation of endogenous nitric oxide, IL-6, prostaglandin E2, and IL-8. Proc Assoc Am Physicians 110:65–72PubMedGoogle Scholar
  7. Bakker EN, Buus CL, Spaan JA, Perree J, Ganga A, Rolf TM, Sorop O, Bramsen LH, Mulvany MJ, Vanbavel E (2005) Small artery remodeling depends on tissue-type transglutaminase. Circ Res 96:119–126PubMedCrossRefGoogle Scholar
  8. Ballestar E, Abad C, Franco L (1996) Core histones are glutaminyl substrates for tissue transglutaminase. J Biol Chem 271:18817–18824PubMedCrossRefGoogle Scholar
  9. Bauer DC, Hunter DJ, Abramson SB, Attur M, Corr M, Felson D, Heinegård D, Jordan JM, Kepler TB, Lane NE, Saxne T, Tyree B, Kraus VB, Osteoarthritis Biomarkers Network (2006) Classification of osteoarthritis biomarkers: a proposed approach. Osteoarthr Cartil 14:723–727PubMedCrossRefGoogle Scholar
  10. Beninati S, Senger DR, Cordella-Miele E, Mukherjee AB, Chackalaparampil I, Shanmugam V, Singh K, Mukherjee BB (1994) Osteopontin: its transglutaminase-catalyzed posttranslational modifications and cross-linking to fibronectin. J Biochem 115:675–682PubMedGoogle Scholar
  11. Bini A, Itoh Y, Kudryk BJ, Nagase H (1996) Degradation of crosslinked fibrin by matrix metalloproteinase 3 (stromelysin 1): hydrolysis of the gamma Gly 404-Ala 405 peptide bond. Biochemistry 35:13056–13063PubMedCrossRefGoogle Scholar
  12. Blaney Davidson EN, van der Kraan PM, van den Berg WB (2007) TGF-beta and osteoarthritis. Osteoarthr Cartil 15:597–604PubMedCrossRefGoogle Scholar
  13. Borge L, Demignot S, Adolphe M (1996) Type II transglutaminase expression in rabbit articular chondrocytes in culture: relation with cell differentiation, cell growth, cell adhesion and cell apoptosis. Biochim Biophys Acta 1312:117–124PubMedCrossRefGoogle Scholar
  14. Cecil DL, Terkeltaub R (2008) Transamidation by transglutaminase 2 transforms S100A11 calgranulin into a procatabolic cytokine for chondrocytes. J Immunol 180:8378–8385PubMedGoogle Scholar
  15. Chen JS, Mehta K (1999) Tissue transglutaminase: an enzyme with a split personality. Int J Biochem Cell Biol 31:817–836PubMedCrossRefGoogle Scholar
  16. Collighan RJ, Griffin M (2009) Transglutaminase 2 cross-linking of matrix proteins: biological significance and medical applications. Amino Acids 36:659–670PubMedCrossRefGoogle Scholar
  17. Cummings M (1996) Apoptosis of epithelial cells in vivo involves tissue transglutaminase upregulation. J Pathol 179:288–293PubMedCrossRefGoogle Scholar
  18. De Laurenzi V, Melino G (2001) Gene disruption of tissue transglutaminase. Mol Cell Biol 21:148–155PubMedCrossRefGoogle Scholar
  19. Erlebacher A, Filvaroff EH, Gitelman SE, Derynck R (1995) Toward a molecular understanding of skeletal development. Cell 80:371–378PubMedCrossRefGoogle Scholar
  20. Eyre DR (2004) Collagens and cartilage matrix homeostasis. Clin Orthop Rel Res 427:S118–S122CrossRefGoogle Scholar
  21. Facchiano A, Facchiano F (2009) Transglutaminases and their substrates in biology and human diseases: 50 years of growing. Amino Acids 36:599–614PubMedCrossRefGoogle Scholar
  22. Fesus L, Piacentini M (2002) Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci 27:534–539PubMedCrossRefGoogle Scholar
  23. Fésüs L, Szondy Z (2005) Transglutaminase 2 in the balance of cell death and survival. FEBS Lett 579:3297–3302PubMedCrossRefGoogle Scholar
  24. Fesus L, Madi A, Balajthy Z, Nemes Z, Szondy Z (1996) Transglutaminase induction by various cell death and apoptosis pathways. Experientia (Basel) 52:942–949CrossRefGoogle Scholar
  25. Garvican ER, Vaughan-Thomas A, Innes JF, Clegg PD (2010) Biomarkers of cartilage turnover. Part 1: markers of collagen degradation and synthesis. Vet J 185:36–42PubMedCrossRefGoogle Scholar
  26. Gerstenfeld LC, Shapiro FD (1996) Expression of bone-specific genes by hypertrophic chondrocytes: implication of the complex functions of the hypertrophic chondrocyte during endochondral bone development. J Cell Biochem 62:1–9PubMedCrossRefGoogle Scholar
  27. Goldenberg DL, Cohen AS (1978) Synovial membrane histopathology in the differential diagnosis of rheumatoid arthritis, gout, pseudogout, systemic lupus erythematosus, infectious arthritis and degenerative joint disease. Medicine (Baltimore) 57:239–252Google Scholar
  28. Goldring MB (2000) The role of the chondrocyte in osteoarthritis. Arthr Rheum 43:1916–1926CrossRefGoogle Scholar
  29. Goldring MB, Goldring SR (2010) Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci 1192:230–237Google Scholar
  30. Gray ML, Burstein D, Kim YJ, Maroudas A (2008) 2007 Elizabeth Winston Lanier Award Winner. Magnetic resonance imaging of cartilage glycosaminoglycan: basic principles, imaging technique, and clinical applications. J Orthop Res 26:281–291Google Scholar
  31. Greenberg CS, Birckbichler PJ, Rice RH (1991) Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. FASEB J 5:3071–3077PubMedGoogle Scholar
  32. Hang J, Zemskov EA, Lorand L, Belkin AM (2005) Identification of a novel recognition sequence for fibronectin within the NH2-terminal beta-sandwich domain of tissue transglutaminase. J Biol Chem 280:23675–23683PubMedCrossRefGoogle Scholar
  33. Harmey D, Hessle L, Narisawa S, Johnson KA, Terkeltaub R, Millán JL (2004) Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders. Am J Pathol 164:1199–1209Google Scholar
  34. Hasegawa G, Suwa M, Ichikawa Y, Ohtsuka T, Kumagai S, Kikuchi M, Sato Y, Saito Y (2003) A novel function of tissue-type transglutaminase: protein disulphide isomerase. Biochem J 373:793–803PubMedCrossRefGoogle Scholar
  35. Heinkel D, Gohr CM, Uzuki M, Rosenthal AK (2004) Transglutaminase contributes to CPPD crystal formation in osteoarthritis. Front Biosci 19:3257–3261CrossRefGoogle Scholar
  36. Ientile R, Caccamo D, Griffin M (2007) Tissue transglutaminase and the stress response. Amino Acids 33:385–394PubMedCrossRefGoogle Scholar
  37. Ishikawa K, Masuda I, Ohira T, Yokoyama M (1989) A histological study of calcium pyrophosphate dihydrate crystal-deposition disease. J Bone Jt Surg Am 71:875–886Google Scholar
  38. Janiak A, Zemskov EA, Belkin AM (2006) Cell surface transglutaminase promotes RhoA activation via integrin clustering and suppression of the Src-p190RhoGAP signaling pathway. Mol Biol Cell 17:1606–1619PubMedCrossRefGoogle Scholar
  39. Janssens K, ten Dijke P, Janssens S, Van Hul W (2005) Transforming growth factor-beta1 to the bone. Endocr Rev 26:743–774PubMedCrossRefGoogle Scholar
  40. Johnson KA, Terkeltaub RA (2005) External GTP-bound transglutaminase 2 is a molecular switch for chondrocyte hypertrophic differentiation and calcification. J Biol Chem 280:15004–15012PubMedCrossRefGoogle Scholar
  41. Johnson K, Hashimoto S, Lotz M, Pritzker K, Terkeltaub R (2001) Interleukin-1 induces pro-mineralizing activity of cartilage tissue transglutaminase and factor XIIIa. Am J Pathol 159:149–163PubMedCrossRefGoogle Scholar
  42. Johnson KA, van Etten D, Nanda N, Graham RM, Terkeltaub RA (2003) Distinct transglutaminase 2-independent and transglutaminase 2-dependent pathways mediate articular chondrocyte hypertrophy. J Biol Chem 278:18824–18832PubMedCrossRefGoogle Scholar
  43. Johnson K, Svensson CI, Etten DV, Ghosh SS, Murphy AN, Powell HC, Terkeltaub R (2004) Mediation of spontaneous knee osteoarthritis by progressive chondrocyte ATP depletion in Hartley guinea pigs. Arthr Rheum 50:1216–1225CrossRefGoogle Scholar
  44. Johnson KA, Rose DM, Terkeltaub RA (2008) Factor XIIIA mobilizes transglutaminase 2 to induce chondrocyte hypertrophic differentiation. J Cell Sci 121:2256–2264PubMedCrossRefGoogle Scholar
  45. Kaartinen MT, El-Maadawy S, Rasanen NH, McKee MD (2002) Tissue transglutaminase and its substrates in bone. J Bone Miner Res 17:2161–2173PubMedCrossRefGoogle Scholar
  46. Kamekura S, Kawasaki Y, Hoshi K, Shimoaka T, Chikuda H, Maruyama Z, Komori T, Sato S, Takeda S, Karsenty G, Nakamura K, Chung UI, Kawaguchi H (2006) Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthr Rheum 54:2462–2470CrossRefGoogle Scholar
  47. Katoh S, Nakagawa N, Yano Y, Satoh K, Kohno H, Ohkubo Y, Suzuki T, Kitani K (1996) Hepatocyte growth factor induces transglutaminase activity that negatively regulates the growth signal in primary cultured hepatocytes. Exp Cell Res 222:255–261PubMedCrossRefGoogle Scholar
  48. Kim DS, Park KS, Jeong KC, Lee BI, Lee CH, Kim SY (2009) Glucosamine is an effective chemo-sensitizer via transglutaminase 2 inhibition. Cancer Lett 273:243–249PubMedCrossRefGoogle Scholar
  49. Krane SM (2001) Petulant cellular acts: destroying the ECM rather than creating it. J Clin Invest 107:31–32PubMedCrossRefGoogle Scholar
  50. Lohmander LS, Eyre DR (2005) From biomarker to surrogate outcome to osteoarthritis—what are the challenges? J Rheumatol 32:1142–1143PubMedGoogle Scholar
  51. Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Natl Rev Mol Cell Biol 4:140–156CrossRefGoogle Scholar
  52. McCarthy GM (1999) Crystal-induced inflammation and cartilage degradation. Curr Rheumatol Rep 1:101–106PubMedCrossRefGoogle Scholar
  53. Merz D, Liu R, Johnson K, Terkeltaub R (2003) IL-8/CXCL8 and growth-related oncogeneα/CXCL1induce chondrocyte hypertrophic differentiation. Immunology 171:4406–4415Google Scholar
  54. Mishra S, Murphy LJ (2004) Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase. J Biol Chem 279:23863–23868PubMedCrossRefGoogle Scholar
  55. Mosher DF, Proctor RA (1980) Binding and factor XIIIa-mediated cross-linking of a 27 kilodalton fragment of fibronectin to Staphylococcus aureus. Science 209:927–929PubMedCrossRefGoogle Scholar
  56. Nakaoka H, Perez DM, Baek KJ, Das T, Husain A, Misono K, Im MJ, Graham RM (1994) Gh: a GTP-binding protein with transglutaminase activity and receptor signaling function. Science 264:1593–1596PubMedCrossRefGoogle Scholar
  57. Nemes Z Jr, Adány R, Balázs M, Boross P, Fésüs L (1997) Identification of cytoplasmic actin as an abundant glutaminyl substrate for tissue transglutaminase in HL-60 and U937 cells undergoing apoptosis. J Biol Chem 272:20577–20583PubMedCrossRefGoogle Scholar
  58. Nunes I, Gleizes PE, Metz CN, Rifkin DB (1997) Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J Cell Biol 136:1151–1163PubMedCrossRefGoogle Scholar
  59. Nurminskaya M, Kaartinen MT (2006) Transglutaminases in mineralized tissues. Front Biosci 11:1591–1606PubMedCrossRefGoogle Scholar
  60. Nurminskaya M, Linsenmayer TF (1996) Identification and characterization of up-regulated genes during chondrocyte hypertrophy. Dev Dyn 206:260–271PubMedCrossRefGoogle Scholar
  61. Nurminskaya M, Magee C, Nurminsky D, Linsenmayer TF (1998) Plasma transglutaminase in hypertrophic chondrocytes: expression and cell-specific intracellular activation produce cell death and externalization. J Cell Biol 142:1135–1144PubMedCrossRefGoogle Scholar
  62. Nurminskaya M, Magee C, Faverman L, Linsenmayer TF (2003) Chondrocyte-derived transglutaminase promotes maturation of preosteoblasts in periosteal bone. Dev Biol 263:139–152PubMedCrossRefGoogle Scholar
  63. Orlandi A, Oliva F, Taurisano G, Candi E, Di Lascio A, Melino G, Spagnoli LG, Tarantino U (2009) Transglutaminase-2 differently regulates cartilage destruction and osteophyte formation in a surgical model of osteoarthritis. Amino Acids 36:755–763PubMedCrossRefGoogle Scholar
  64. Petersson IF, Jacobsson LT (2002) Osteoarthritis of the peripheral joints. Best Pract Res Clin Rheumatol 16:741–760PubMedCrossRefGoogle Scholar
  65. Poole AR (1996) Pathologic manifestations of joint disease in the athletic horse. In: McIllwraith CW, Trotter GW (eds) Joint disease in the horse. WB Saunders Co, Philadelphia, pp 87–104Google Scholar
  66. Poole AR (2003) Biochemical/immunochemical biomarkers of osteoarthritis: utility for prediction of incident or progressive osteoarthritis. Rheum Dis Clin North Am 29:803–818PubMedCrossRefGoogle Scholar
  67. Poole AR, Matsui Y, Hinek A, Lee ER (1989) Cartilage macromolecules and the calcification of cartilage matrix. Anat Rec 224:167–179PubMedCrossRefGoogle Scholar
  68. Prince CW, Dickie D, Krumdieck CL (1991) Osteopontin, a substrate for transglutaminase and factor XIII activity. Biochem Biophys Res Commun 177:1205–1210PubMedCrossRefGoogle Scholar
  69. Rosenthal AK, Derfus BA, Henry LA (1997) Transglutaminase activity in aging articular chondrocytes and articular cartilage vesicles. Arthr Rheum 40:966–970CrossRefGoogle Scholar
  70. Rosenthal AK, Mosesson MW, Gohr CM, Masuda I, Heinkel D, Seibenlist KR (2004) Regulation of transglutaminase activity in articular chondrocytes through thrombin receptor-mediated factor XIII synthesis. Thromb Haemost 91:558–568PubMedGoogle Scholar
  71. Ryan LM, McCarty DJ (1997) Calcium pyrophosphate crystal deposition disease, pseudogout, and articular chondrocalcinosis. In: Koopman W (ed) Arthritis and allied conditions: a textbook of rheumatology, 13th edn. Williams and Wilkins, Baltimore, pp 2103–2126Google Scholar
  72. Sanchez C, Deberg MA, Bellahcène A, Castronovo V, Msika P, Delcour JP, Crielaard JM, Henrotin YE (2008) Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone. Arthr Rheum 58:442–455CrossRefGoogle Scholar
  73. Sarang Z, Tóth B, Balajthy Z, Köröskényi K, Garabuczi E, Fésüs L, Szondy Z (2009) Some lessons from the tissue transglutaminase knockout mouse. Amino Acids 36:625–631PubMedCrossRefGoogle Scholar
  74. Sawitzke AD, Shi H, Finco MF, Dunlop DD, Bingham CO 3rd, Harris CL, Singer NG, Bradley JD, Silver D, Jackson CG, Lane NE, Oddis CV, Wolfe F, Lisse J, Furst DE, Reda DJ, Moskowitz RW, Williams HJ, Clegg DO (2008) The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthr Rheum 58:3183–3191CrossRefGoogle Scholar
  75. Scharstuhl A, Glansbeek HL, van Beuningen HM, Vitters EL, van der Kraan PM, van den Berg WB (2002) Inhibition of endogenous TGF-beta during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J Immunol 169:507–514PubMedGoogle Scholar
  76. Soder S, Hakimiyan A, Rueger DC, Kuettner KE, Aigner T, Chubinskaya S (2005) Antisense inhibition of osteogenic protein 1 disturbs human articular cartilage integrity. Arthr Rheum 52:468–478 B.TCrossRefGoogle Scholar
  77. Summey BT Jr, Graff RD, Lai TS, Greenberg CS, Lee GM (2002) Tissue transglutaminase localization and activity regulation in the extracellular matrix of articular cartilage. J Orthop Res 20:76–82PubMedCrossRefGoogle Scholar
  78. Takeuchi Y, Ohashi H, Birckbichler PJ, Ikejima T (1998) Nuclear translocation of tissue type transglutaminase during sphingosine-induced cell death: a novel aspect of the enzyme with DNA hydrolytic activity. Z Naturforsch C 53:352–358PubMedGoogle Scholar
  79. Tanaka K, Yokosaki Y, Higashikawa F, Saito Y, Eboshida A, Ochi M (2007) The integrin alpha5beta1 regulates chondrocyte hypertrophic differentiation induced by GTP-bound transglutaminase 2. Matrix Biol 26:409–418PubMedCrossRefGoogle Scholar
  80. Tarantino U, Oliva F, Taurisano G, Orlandi A, Pietroni V, Candi E, Melino G, Maffulli N (2009) FXIIIA and TGF-beta over-expression produces normal musculo-skeletal phenotype in TG2−/− mice. Amino Acids 36:679–684PubMedCrossRefGoogle Scholar
  81. Telci D, Wang Z, Li X, Verderio EA, Humphries MJ, Baccarini M, Basaga H, Griffin M (2008) Fibronectin-tissue transglutaminase matrix rescues RGD-impaired cell adhesion through syndecan-4 and beta1 integrin co-signaling. J Biol Chem 283:20937–20947PubMedCrossRefGoogle Scholar
  82. Terkeltaub RA (2002) What does cartilage calcification tell us about osteoarthritis? J Rheumatol 29:411–415PubMedGoogle Scholar
  83. Thacher SM (1989) Purification of keratinocyte transglutaminase and its expression during squamous differentiation. J Invest Dermatol 92:578–584PubMedGoogle Scholar
  84. Todhunter RJ (1996) Anatomy and physiology of synovial joints. In: McIllwraith CW, Trotter GW (eds) Joint disease in the horse. WB Saunders Co, Philadelphia, pp 1–28Google Scholar
  85. Ueki S, Takagi J, Saito Y (1996) Dual functions of transglutaminase in novel cell adhesion. J Cell Sci 109:2727–2735PubMedGoogle Scholar
  86. Verderio EA, Griffin TS, Johnson M (2005) Transglutaminases in wound healing and inflammation. Prog Exp Tumor Res 38:89–114PubMedCrossRefGoogle Scholar
  87. Vignon E, Arlot M, Hartmann D, Moyen B, Ville G (1983) Hypertrophic repair of articular cartilage in experimental osteoarthrosis. Ann Rheum Dis 42:82–88PubMedCrossRefGoogle Scholar
  88. von der Mark K, Kirsch T, Nerlich A, Kuss A, Weseloh G, Gluckert K, Stöss H (1992) Type X collagen synthesis in human osteoarthritic cartilage, Indication of chondrocyte hypertrophy. Arthr Rheum 35:806–811CrossRefGoogle Scholar
  89. Zemmyo M, Meharra EJ, Kühn K, Creighton-Achermann L, Lotz M (2003) Accelerated, aging-dependent development of osteoarthritis in alpha1 integrin-deficient mice. Arthr Rheum 48:2873–2880CrossRefGoogle Scholar
  90. Zhu Y, Tassi L, Lane W, Mendelsohn ME (1994) Specific binding of the transglutaminase, platelet factor XIII, to HSP27. J Biol Chem 269:22379–22384PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Umberto Tarantino
    • 1
  • Amedeo Ferlosio
    • 2
  • Gaetano Arcuri
    • 3
  • Luigi Giusto Spagnoli
    • 2
  • Augusto Orlandi
    • 2
    Email author
  1. 1.Orthopaedics and TraumatologyUniversity of Rome “Tor Vergata”RomeItaly
  2. 2.Anatomy Pathology, Department of Biopathology and Image Diagnostics, School of MedicineUniversity of Rome “Tor Vergata”RomeItaly
  3. 3.Experimental Medicine and Biochemical SciencesTor Vergata University of RomeRomeItaly

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