Background Tissue-infiltrating multinucleated giant cells (MNGs) within geographic necrosis are pathologic hallmarks of granulomatosis with polyangiitis (GPA). However, the origin, phenotype, and function of these cells in GPA remain undefined. Methodology/Principal Findings MNG phenotype in GPA lung tissue was examined by immunohistochemistry using antibody directed against cathepsin K and calcitonin-receptor. Tartrate-resistant-acid-phosphatase (TRAP) expression was assessed using enzymatic color reaction. Peripheral blood mononuclear cells (PBMCs) from 13 GPA patients (5 with localized and 8 with systemic disease) and 11 healthy controls were cultured in the presence of RANKL and M-CSF for 9 days, and TRAP+ MNGs containing 3 or more nuclei were identified. GPA lung granulomata contained numerous MNGs that expressed osteoclastic TRAP and cathepsin K but not calcitonin receptors. In the presence of RANKL and M-CSF, PBMCs of GPA patients formed significantly more MNGs than healthy controls (114±29 MNG/well vs. 22±9 MNG/well, P = 0.02). In a subgroup analysis, patients with systemic disease generated significantly more MNGs than patients with localized disease (161±35 MNG/well vs. 39±27 MNG/well, P<0.01) or healthy controls (P<0.01). MNG production did not differ between localized GPA and control subjects (P = 0.96). Conclusions/Significance MNGs in granulomata in the GPA lung express osteoclastic enzymes TRAP and cathepsin K. GPA patients have a higher propensity to form TRAP+ MNGs from peripheral blood than healthy controls. These data suggest that (i) the tendency to form MNGs is a component of the GPA phenotype itself, and (ii) that lesional MNGs might participate in the destructive process through their proteolytic enzymes.
References
[1]
Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, et al. (1992) Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 116: 488–498.
[2]
Sullivan EJ, Hoffman GS (1998) Pulmonary vasculitis. Clin Chest Med 19: 759–776, ix.
[3]
Falk RJ, Gross WL, Guillevin L, Hoffman GS, Jayne DR, et al. (2011) Granulomatosis with polyangiitis (Wegener’s): an alternative name for Wegener’s granulomatosis. Arthritis Rheum 63: 863–864.
[4]
Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, et al. (1994) Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 120: 12–17.
[5]
Popa ER, Stegeman CA, Abdulahad WH, van der Meer B, Arends J, et al. (2007) Staphylococcal toxic-shock-syndrome-toxin-1 as a risk factor for disease relapse in Wegener’s granulomatosis. Rheumatology (Oxford) 46: 1029–1033.
[6]
da Costa CE, Annels NE, Faaij CM, Forsyth RG, Hogendoorn PC, et al. (2005) Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis. J Exp Med 201: 687–693.
[7]
Burstone MS (1959) Histochemical demonstration of acid phosphatase activity in osteoclasts. J Histochem Cytochem 7: 39–41.
[8]
Bossard MJ, Tomaszek TA, Thompson SK, Amegadzie BY, Hanning CR, et al. (1996) Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem 271: 12517–12524.
[9]
Teitelbaum SL, Ross FP (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4: 638–649.
[10]
Hayman AR, Macary P, Lehner PJ, Cox TM (2001) Tartrate-resistant acid phosphatase (Acp 5): identification in diverse human tissues and dendritic cells. J Histochem Cytochem 49: 675–684.
[11]
Helming L, Gordon S (2007) The molecular basis of macrophage fusion. Immunobiology 212: 785–793.
[12]
Stone JH (2003) Limited versus severe Wegener’s granulomatosis: baseline data on patients in the Wegener’s granulomatosis etanercept trial. Arthritis Rheum 48: 2299–2309.
[13]
Quinn JM, Morfis M, Lam MH, Elliott J, Kartsogiannis V, et al. (1999) Calcitonin receptor antibodies in the identification of osteoclasts. Bone 25: 1–8.
[14]
Devaney KO, Travis WD, Hoffman G, Leavitt R, Lebovics R, et al. (1990) Interpretation of head and neck biopsies in Wegener’s granulomatosis. A pathologic study of 126 biopsies in 70 patients. Am J Surg Pathol 14: 555–564.
[15]
Holle JU, Gross WL, Latza U, Nolle B, Ambrosch P, et al. (2011) Improved outcome in 445 patients with Wegener’s granulomatosis in a German vasculitis center over four decades. Arthritis Rheum 63: 257–266.
[16]
Cheadle C, Berger AE, Andrade F, James R, Johnson K, et al. (2010) Transcription of proteinase 3 and related myelopoiesis genes in peripheral blood mononuclear cells of patients with active Wegener’s granulomatosis. Arthritis Rheum 62: 1744–1754.
[17]
Ritchlin CT, Haas-Smith SA, Li P, Hicks DG, Schwarz EM (2003) Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 111: 821–831.
[18]
Gravallese EM, Manning C, Tsay A, Naito A, Pan C, et al. (2000) Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 43: 250–258.
[19]
Shen Z, Crotti TN, McHugh KP, Matsuzaki K, Gravallese EM, et al. (2006) The role played by cell-substrate interactions in the pathogenesis of osteoclast-mediated peri-implant osteolysis. Arthritis Res Ther 8: R70.
[20]
Chiu YG, Shao T, Feng C, Mensah KA, Thullen M, et al. (2010) CD16 (FcRgammaIII) as a potential marker of osteoclast precursors in psoriatic arthritis. Arthritis Res Ther 12: R14.
[21]
Mensah KA, Ritchlin CT, Schwarz EM (2010) RANKL induces heterogeneous DC-STAMP(lo) and DC-STAMP(hi) osteoclast precursors of which the DC-STAMP(lo) precursors are the master fusogens. J Cell Physiol 223: 76–83.
[22]
Muto A, Mizoguchi T, Udagawa N, Ito S, Kawahara I, et al. (2011) Lineage-committed osteoclast precursors circulate in blood and settle down into bone. J Bone Miner Res 26: 2978–2990.
[23]
Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, et al. (1994) Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 37: 187–192.
