Characterization of multinucleated giant cells in synovium and subchondral bone in knee osteoarthritis and rheumatoid arthritis

Iván Prieto-Potin, Raquel Largo, Jorge A Roman-Blas, Gabriel Herrero-Beaumont, David A Walsh, Iván Prieto-Potin, Raquel Largo, Jorge A Roman-Blas, Gabriel Herrero-Beaumont, David A Walsh

Abstract

Background: Multinucleated giant cells have been noticed in diverse arthritic conditions since their first description in rheumatoid synovium. However, their role in the pathogenesis of osteoarthritis (OA) or rheumatoid arthritis (RA) still remains broadly unknown. We aimed to study the presence and characteristics of multinucleated giant cells (MGC) both in synovium and in subchondral bone tissues of patients with OA or RA.

Methods: Knee synovial and subchondral bone samples were from age-matched patients undergoing total joint replacement for OA or RA, or non-arthritic post mortem (PM) controls. OA synovium was stratified by histological inflammation grade using index tissue sections. Synovitis was assessed by Krenn score. Histological studies employed specific antibodies against macrophage markers or cathepsin K, or TRAP enzymatic assay.

Results: Inflamed OA and RA synovia displayed more multinucleated giant cells than did non-inflamed OA and PM synovia. There was a significant association between MGC numbers and synovitis severity. A TRAP negative/cathepsin K negative Langhans-like subtype was predominant in OA, whereas both Langhans-like and TRAP-positive/cathepsin K-negative foreign-body-like subtypes were most commonly detected in RA. Plasma-like and foam-like subtypes also were observed in OA and RA synovia, and the latter was found surrounding adipocytes. TRAP positive/cathepsin K positive osteoclasts were only identified adjacent to subchondral bone surfaces. TRAP positive osteoclasts were significantly increased in subchondral bone in OA and RA compared to PM controls.

Conclusions: Multinucleated giant cells are associated with synovitis severity, and subchondral osteoclast numbers are increased in OA, as well as in RA. Further research targeting multinucleated giant cells is warranted to elucidate their contributions to the symptoms and joint damage associated with arthritis.

Figures

Fig. 1
Fig. 1
Characterization of MGC subtypes in OA and in RA. a. A greater proportion of inflamed OA (OAI) and RA cases displayed MGCs than did non-inflamed OA (OANI) or non-arthritic (post mortem, PM) controls. b. Increased MGC size in RA compared with OA cases. c and d. Relative abundance of morphological MGC subtypes observed in OA (c) and RA (d) synovia. Bars in b-d represent medians, with IQRs indicating between MGC heterogeneity
Fig. 2
Fig. 2
Morphological characterization of synovial MGC subtypes in OA and in RA. Foreign body giant cells were identified as MGCs with many nuclei diffusely distributed throughout the cytoplasm (a). Langhans giant cells were recognized by the multiple nuclei arranged in a horseshoe shape (b). Foam MGC subtype was characterized by numerous nuclei clustered together, surrounded by a foamy cytoplasm (c). Plasma MGC subtype was assessed by their eccentric nuclei with a dense distribution of chromatin (d). Overall MGC subtypes were identified in either OA or RA. Arrows indicate each different MGC subtype in synovium. Haematoxylin and eosin staining. Scale bars = 20 μm
Fig. 3
Fig. 3
TRAP and cathepsin K enzyme activity in synovium from OA and RA patients. a and b. Representative synovial TRAP-positive and TRAP-negative MGCs both in inflamed OAI (a) and RA (b) cases. c. Cathepsin K-immunoreactive MGC localized to synovial pannus adjacent to bone surface in RA and OA tibial plateaux. d and e. Cathepsin K-immunoreactive mononuclear synovial lining (d) and sublining (e) cells in OAI and in RA synovium. Filled arrows indicate TRAP-positive or cathepsin K-positive cells. Open arrows indicate TRAP-negative MGCs. P = pannus and B = bone, scale bars = 50 μm
Fig. 4
Fig. 4
Synovial inflammation in OA and RA. a-d. Representative sections of synovia from cases with median Krenn scores for each disease group stained with haematoxylin and eosin. Panels represent post-mortem, PM (a), non-inflamed OA, OANI (b), inflamed OA, OAI (c) and RA (d) cases. Scale bars = 100 μm. e. Synovitis, determined as total Krenn score was greatest in OAI and RA cases. f. Numbers of MGCs per area of synovium were positively correlated with synovitis scores both in OA and in RA cases
Fig. 5
Fig. 5
Subchondral bone TRAP positive osteoclast in OA and in RA. a-d. Representative sections from non-arthritic patients (a), with OANI (b), OAI (c) and RA (d) showing TRAP positive osteoclasts adjacent to bone surfaces. Scale bars = 20 μm. e. c. Absolute TRAP-positive osteoclast number adjusted for the area of mid-coronal tibial plateau fragments. Bars represent medians with IQRs

References

    1. Stoppiello LA, Mapp PI, Wilson D, Scammell BE, Orth F, Walsh DA. Structural associations of symptomatic knee osteoarthritis. Arthritis Rheum. 2014;66:3018–27. doi: 10.1002/art.38778.
    1. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64:1697–707. doi: 10.1002/art.34453.
    1. Woolley DE, Tetlow LC. Observations on the microenvironmental nature of cartilage degradation in rheumatoid arthritis. Ann Rheum Dis. 1997;56:151–161. doi: 10.1136/ard.56.3.151.
    1. Benito M, Veale D, FitzGerald O, Van den Berg W, Bresnihan B. Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005;64:1263–1267. doi: 10.1136/ard.2004.025270.
    1. Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis -- results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage. 2005;13:361–7. doi: 10.1016/j.joca.2005.01.005.
    1. Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51:249–57. doi: 10.1016/j.bone.2012.02.012.
    1. Walsh DA, McWilliams DF, Turley MJ, Dixon MR, Fransès RE, Mapp PI, Wilson D. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatology (Oxford) 2010;49:1852–61. doi: 10.1093/rheumatology/keq188.
    1. Mulherin D, Fitzgerald O, Bresnihan B. Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum. 1996;39:115–124. doi: 10.1002/art.1780390116.
    1. Anderson JM. Multinucleated giant cells. Curr Opin Hematol. 2000;7:40–7. doi: 10.1097/00062752-200001000-00008.
    1. Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol. 2008;20:86–100. doi: 10.1016/j.smim.2007.11.004.
    1. Cowan RW, Singh G. Giant cell tumor of bone: A basic science perspective. Bone. 2012;52:238–246. doi: 10.1016/j.bone.2012.10.002.
    1. Khan UA, Hashimi SM, Khan S, Quan J, Bakr MM, Forwood MR, Morrison NM. Differential expression of chemokines, chemokine receptors and proteinases by foreign body giant cells (FBGCs) and osteoclasts. J Cell Biochem. 2014;115:1290–8. doi: 10.1002/jcb.24781.
    1. Maggiani F, Forsyth R, Hogendoorn PCW, Krenacs T, Athanasou NA. The immunophenotype of osteoclasts and macrophage polykaryons. J Clin Pathol. 2011;64:701–5. doi: 10.1136/jcp.2011.090852.
    1. Quinn MT, Schepetkin IA. Role of NADPH oxidase in formation and function of multinucleated giant cells. J Innate Immun. 2009;1:509–26. doi: 10.1159/000228158.
    1. Lay G, Poquet Y, Puissegur M, Botanch C, Bon H, Levillain F, Duteyrat J, Emile J. Langhans giant cells from M. tuberculosis -induced human granulomas cannot mediate mycobacterial uptake. J Pathol. 2007;211:76–85. doi: 10.1002/path.2092.
    1. Brodbeck WG, Anderson JM. Giant cell formation and function. Curr Opin Hematol. 2009;16:53–57. doi: 10.1097/MOH.0b013e32831ac52e.
    1. Gómez-Mateo MDC, Monteagudo C. Nonepithelial skin tumors with multinucleated giant cells. Semin Diagn Pathol. 2013;30:58–72. doi: 10.1053/j.semdp.2012.01.004.
    1. Schett G. Cells of the synovium in rheumatoid arthritis. Osteoclasts. Arthritis Res Ther. 2007;9:203. doi: 10.1186/ar2110.
    1. Bhan AK, Roy S. Synovial giant cells in rheumatoid arthritis and other joint diseases. Ann Rheum Dis. 1971;30:294–298. doi: 10.1136/ard.30.3.294.
    1. Soren A, Waugh TR. The giant cells in the synovial membrane. Ann Rheum Dis. 1981;40:496–500. doi: 10.1136/ard.40.5.496.
    1. Grimley P, Sokoloff L. Synovial giant cells in rheumatoid arthritis. Am J Pathol. 1966;49:931–54.
    1. Ogawa K, Mawatari M, Komine M, Shigematsu M, Kitajima M, Kukita A, Hotokebuchi T. Mature and activated osteoclasts exist in the synovium of rapidly destructive coxarthrosis. J Bone Miner Metab. 2007;25:354–60. doi: 10.1007/s00774-007-0761-0.
    1. Seitz S, Zustin J, Amling M, Rüther W, Niemeier A. Massive accumulation of osteoclastic giant cells in rapid destructive hip disease. J Orthop Res. 2014;32:702–8. doi: 10.1002/jor.22573.
    1. Ashton BA, Ashton IK, Marshall MJ, Butler RC. Localisation of vitronectin receptor immunoreactivity and tartrate resistant acid phosphatase activity in synovium from patients with inflammatory or degenerative arthritis. Ann Rheum Dis. 1993;52:133–7. doi: 10.1136/ard.52.2.133.
    1. Wilkinson LS, Pitsillides AA, Edwards JC. Giant cells in arthritic synovium. Ann Rheum Dis. 1993;52:182–4. doi: 10.1136/ard.52.3.182.
    1. Rousseau JC, Garnero P. Biological markers in osteoarthritis. Bone. 2012;51:265–77. doi: 10.1016/j.bone.2012.04.001.
    1. Woloszynski T, Podsiadlo P, Stachowiak GW, Kurzynski M, Lohmander LS, Englund M. Prediction of progression of radiographic knee osteoarthritis using tibial trabecular bone texture. Arthritis Rheum. 2012;64:688–695. doi: 10.1002/art.33410.
    1. Hunter DJ. Insights from Imaging on the Epidemiology and Pathophysiology of Osteoarthritis. Radiol Clin North Am. 2009;47(4):539–551. doi: 10.1016/j.rcl.2009.03.004.
    1. Roman-Blas JA, Castañeda S, Largo R, Lems WF, Herrero-Beaumont G. An OA phenotype may obtain major benefit from bone-acting agents. Semin Arthritis Rheum. 2014;43:421–8. doi: 10.1016/j.semarthrit.2013.07.012.
    1. Bucklandwright C. Subchondral bone changes in hand and knee osteoarthritis detected by radiography. Osteoarthr Cartil. 2004;12:10–19. doi: 10.1016/j.joca.2003.09.007.
    1. Sagar DR, Ashraf S, Xu L, Burston JJ, Menhinick MR, Poulter CL, Bennett AJ, Walsh DA, Chapman V: Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis. Ann rheum Dis 2013 [Epub ahead of print].
    1. Bugatti S, Caporali R, Manzo A, Vitolo B, Pitzalis C, Montecucco C. Involvement of subchondral bone marrow in rheumatoid arthritis: lymphoid neogenesis and in situ relationship to subchondral bone marrow osteoclast recruitment. Arthritis Rheum. 2005;52:3448–59. doi: 10.1002/art.21377.
    1. Schett G, Stolina M, Bolon B, Middleton S, Adlam M, Brown H, Zhu L, Feige U, Zack DJ. Analysis of the kinetics of osteoclastogenesis in arthritic rats. Arthritis Rheum. 2005;52:3192–201. doi: 10.1002/art.21343.
    1. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M, Howell D, Kaplan D, Koopman W, Longley S, Mankin H, Mcshane DJ, Medsger T, Meenan R, Mikkelsen W, Mqskowitz R, Murphy W, Rothschild B, Segal M, Sokoloff L, Wolfe F. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Arthritis Rheum. 1986;29:1039–1049. doi: 10.1002/art.1780290816.
    1. Arnett F, Edworthy S, Bloch D. The american rheumatism association 1987 revised criteria for the classification of the rheumatoid arthritis. Arthritis Rheum. 1988;31:315–324. doi: 10.1002/art.1780310302.
    1. Fransen J, van Riel PLCM. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol. 2005;23(5 Suppl 39):S93–S99.
    1. Haywood L, McWilliams DF, Pearson CI, Gill SE, Ganesan A, Wilson D, Walsh DA. Inflammation and angiogenesis in osteoarthritis. Arthritis Rheum. 2003;48:2173–7. doi: 10.1002/art.11094.
    1. Krenn V, Morawietz L, Häupl T, Neidel J, Petersen I, König A. Grading of chronic synovitis--a histopathological grading system for molecular and diagnostic pathology. Pathol Res Pract. 2002;198:317–25. doi: 10.1078/0344-0338-5710261.
    1. Perry M, Mustafa Y, Wood S, Cawley M. Binucleated and multinucleated forms of plasma cells in synovia from patients with rheumatoid arthritis. Rheumatol Int. 1997;17:169–174. doi: 10.1007/s002960050029.
    1. Shu SY, Ju G, Fan LZ. The glucose oxidase-DAB-nickel method in peroxidase histochemistry of the nervous system. Neurosci Lett. 1988;85:169–71. doi: 10.1016/0304-3940(88)90346-1.
    1. Park JK, Rosen A, Saffitz JE, Asimaki A, Litovsky SH, Mackey-Bojack SM, Halushka MK. Expression of cathepsin K and tartrate-resistant acid phosphatase is not confined to osteoclasts but is a general feature of multinucleated giant cells: systematic analysis. Rheumatology (Oxford) 2013;52:1529–33. doi: 10.1093/rheumatology/ket184.
    1. Wenham CYJ, Conaghan PG. The role of synovitis in osteoarthritis. Ther Adv Musculoskelet Dis. 2010;2:349–59. doi: 10.1177/1759720X10378373.
    1. Walsh DA, Yousef A, McWilliams DF, Hill R, Hargin E, Wilson D. Evaluation of a Photographic Chondropathy Score (PCS) for pathological samples in a study of inflammation in tibiofemoral osteoarthritis. Osteoarthritis Cartilage. 2009;17:304–12. doi: 10.1016/j.joca.2008.07.016.
    1. Koizumi F, Matsuno H, Wakaki K, Ishii Y, Kurashige Y, Nakamura H. Synovitis in rheumatoid arthritis: scoring of characteristic histopathological features. Pathol Int. 1999;49:298–304. doi: 10.1046/j.1440-1827.1999.00863.x.
    1. Scanzello CR, Plaas A, Crow MK. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Curr Opin Rheumatol. 2008;20(5):565–72. doi: 10.1097/BOR.0b013e32830aba34.
    1. Gómez R, Villalvilla A, Largo R, Gualillo O, Herrero-Beaumont G: TLR4 signalling in osteoarthritis-finding targets for candidate DMOADs. Nat Rev Rheumatol 2015;11(3):159-70.
    1. De Lange-Brokaar BJE, Ioan-Facsinay A, van Osch GJVM, Zuurmond A, Schoones J, Toes REM, Huizinga TWJ, Kloppenburg M. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage. 2012;20:1484–99. doi: 10.1016/j.joca.2012.08.027.
    1. Consolaro A, Sant’Ana E, Lawall MA, Consolaro MFMO, Bacchi CE. Gingival juvenile xanthogranuloma in an adult patient: case report with immunohistochemical analysis and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107:246–52. doi: 10.1016/j.tripleo.2008.09.032.
    1. Aterman K, Remmele W, Smith M. Karl Touton and His “Xanthelasmatic Giant Cell” A Selective Review of Multinucleated Giants Cells. Am J Dermatopathol. 1988;10:257–269. doi: 10.1097/00000372-198806000-00012.
    1. Ferraz-Amaro I, González-Juanatey C, López-Mejias R, Riancho-Zarrabeitia L, González-Gay MA. Metabolic syndrome in rheumatoid arthritis. Mediators Inflamm. 2013;2013:11. doi: 10.1155/2013/710928.
    1. Prieto-Potin I, Roman-Blas JA, Martinez-Calatrava MJ, Gomez R, Largo R, Herrero-Beaumont G. Hypercholesterolemia boosts joint destruction in chronic arthritis. An experimental model aggravated by foam macrophage infiltration. Arthritis Res Ther. 2013;15:R81. doi: 10.1186/ar4261.
    1. Connor JR, Dodds RA, James IE, Gowen M. Human osteoclast and giant cell differentiation: the apparent switch from nonspecific esterase to tartrate resistant acid phosphatase activity coincides with the in situ expression of osteopontin mRNA. J Histochem Cytochem. 1995;43:1193–1201. doi: 10.1177/43.12.8537635.
    1. Jösten M, Rudolph R. Methods for the differentiation of giant cells in canine and feline neoplasias in paraffin sections. Zentralbl Vet A. 1997;44:630. doi: 10.1111/j.1439-0442.1997.tb01151.x.
    1. Park JK, Askin F, Giles JT, Halushka MK, Rosen A, Levine SM. Increased generation of TRAP expressing multinucleated giant cells in patients with granulomatosis with polyangiitis. PLoS One. 2012;7:e42659. doi: 10.1371/journal.pone.0042659.
    1. Nordborg E, Bengtsson B, Petursdottir V, Nordborg C. Morphological aspects of giant cells in giant cell arteritis: an electron-microscopic and immunocytochemical study. Clin Exp Rheumatol. 1997;15:129–34.
    1. Shibakawa A, Yudoh K, Masuko-Hongo K, Kato T, Nishioka K, Nakamura H. The role of subchondral bone resorption pits in osteoarthritis: MMP production by cells derived from bone marrow. Osteoarthr Cartil. 2005;13:679–87. doi: 10.1016/j.joca.2005.04.010.
    1. Knowles HJ, Moskovsky L, Thompson MS, Grunhen J, Cheng X, Kashima TG, Athanasou NA. Chondroclasts are mature osteoclasts which are capable of cartilage matrix resorption. Virchows Arch. 2012;461:205–10. doi: 10.1007/s00428-012-1274-3.
    1. Karsdal MA, Bay-Jensen AC, Lories RJ, Abramson S, Spector T, Pastoureau P, Christiansen C, Attur M, Henriksen K, Goldring SR, Kraus V. The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments? Ann Rheum Dis. 2014;73:336–48. doi: 10.1136/annrheumdis-2013-204111.
    1. Botter SM, van Osch GJVM, Clockaerts S, Waarsing JH, Weinans H, van Leeuwen JPTM. Osteoarthritis induction leads to early and temporal subchondral plate porosity in the tibial plateau of mice: An in vivo micro CT study. Arthritis Rheum. 2011;63:2690–2699. doi: 10.1002/art.30307.

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