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Human Osteoclast Formation and Bone Resorption by Monocytes And 816 Ann Rheum Dis 1996;55:816-822 Human osteoclast formation and bone resorption Ann Rheum Dis: first published as 10.1136/ard.55.11.816 on 1 November 1996. Downloaded from by monocytes and synovial macrophages in rheumatoid arthritis Y Fujikawa, A Sabokbar, S Neale, N A Athanasou Abstract and macrophages.3'- Both intimal and subin- Objective-To determine whether syno- timal synovial macrophages in rheumatoid vial macrophages and monocytes isolated arthritis are derived from the circulation, blood from patients with rheumatoid arthritis monocytes passing through the tall endothe- patients are capable ofdifferentiating into lium ofpostcapillary venules to enter the syno- osteoclastic bone resorbing cells; and the vial tissues.'0 cellular and humoral conditions required Macrophages rather than T cells have been for this to occur. found to predominate at the articular margins Methods-Macrophages isolated from the where there is bone and cartilage destruc- synovium and monocytes from the tion." 1 A significant correlation has been peripheral blood of rheumatoid arthritis reported between the degree of joint erosion patients were cultured on bone slices and and the number of synovial macrophages." At coverslips, in the presence and absence of the site of marginal erosions, bone resorption, UMR 106 rat osteoblast-like cells, however, appears to be effected largely by rec- 1,25-dihydroxy vitamin D3 (1,25(0H)2D3) ognisable osteoclasts.'"' Various macrophage and macrophage colony stimulating factor derived cytokines are known to enhance osteo- (M-CSF), and assessed for cytochemical clastic bone resorption indirectly (through and functional evidence of osteoclast osteoblast stimulation)'5 and several of these differentiation. cytokines also promote the release of Results-Isolated calcitonin receptor collagenase, elastase, plasminogen activator, (CTR), tartrate resistant acid phos- and prostaglandins by resident cells of bone phatase (TRAP), and vitronectin receptor and joint,'617 factors which may play a role in (VNR) negative, CDllb and CD14 positive bone destruction in rheumatoid arthritis.'8 monocytes and macrophages differenti- Several recent animal studies have shown http://ard.bmj.com/ ated into CTR, TRAP, and VNR positive that monocytes and macrophages (including multinucleated cells capable of extensive those isolated from tumours and inflammatory lacunar bone resorption when co-cultured lesions) are capable of differentiating into for 14 d with UMR 106 cells in the presence osteoclastic bone resorbing cells when 1,25(OH)2D3 and M-CSF. co-cultured with bone derived stromal cells in Conclusions-Mononuclear phagocytes the presence of 1,25-dihydroxyvitamin D3 (monocytes and macrophages) from (1,25(OH)2D3)'9-22; the mononuclear and on September 28, 2021 by guest. Protected copyright. rheumatoid arthritis patients are capable multinucleated cells formed in these co- ofdifferentiating into multinucleated cells cultures show all the phenotypic characteristics Nuffield Department showing all the cytochemical and of osteoclasts, including expression of tartrate ofOrthopaedic functional criteria of mature osteoclasts. resistant acid phosphatase (TRAP), calcitonin Surgery, University of differen- receptors and most importantly, the Oxford, Oxford, Synovial macrophage-osteoclast (CTR), United Kingdom tiation may represent an important cellu- functional ability to produce resorption Y Fujikawa lar mechanism in the bone destruction lacunae in bone. In the context of an A Sabokbar associated with rheumatoid arthritis. inflammatory disease such as rheumatoid Department of (Ann Rheum Dis 1996;55:816-822) arthritis, where there is a heavy macrophage Orthopaedics and infiltrate in synovial tissues, osteoclast differen- Trauma, University of Rheumatoid arthritis is a chronic inflammatory tiation by monocytes and macrophages could Adelaide, Adelaide, Australia disease of unknown aetiology that results in represent an important mechanism for the S Neale progressive damage to joint tissues. There is pathogenesis of bone destruction. In this study extension ofexuberant inflamed synovial tissue we have sought to determine whether this cel- Department of (pannus) over the articular surface, leading to lular mechanism of osteoclast formation and Pathology, Nuffield Orthopaedic Centre, its destruction.' Rheumatoid pannus also pathological bone resorption operates in rheu- Oxford, United extends into juxta-articular bone, producing matoid arthritis. Peripheral blood monocytes Kingdom marginal erosions and cyst-like areas of bone and synovial macrophages from rheumatoid N A Athanasou destruction. In the inflamed synovium from arthritis patients were co-cultured with osteo- Correspondence to: which pannus develops, there is marked thick- blastic cells in the presence and absence of Dr N A Athanasou, ening of the synovial intima, which is humoral factors which are known to be impor- Department ofPathology, Nuffield Orthopaedic composed largely of lining cells of macrophage tant in mouse osteoclast formation, in order to Centre, Oxford OX3 7LD. phenotype2-5; there is also a heavy subintimal determine the cellular and humoral conditions Accepted for publication chronic inflammatory cells infiltrate which for mononuclear phagocyte-osteoclast differ- 12 August 1996 includes numerous lymphocytes, plasma cells, entiation in rheumatoid arthritis.2'25 Fujikawa, Sabokbar, Neale, Athanasou 817 Methods to bone slices and to glass coverslips, half of Synovial tissue was obtained fresh from six which had been preseeded with UMR 106 cells Ann Rheum Dis: first published as 10.1136/ard.55.11.816 on 1 November 1996. Downloaded from patients with seropositive rheumatoid arthri- as described above. tis,26 all ofwhom were undergoing knee arthro- The monocyte-UMR 106 and macrophage- plasty operations. The synovial samples were UMR 106 co-cultures were maintained in obtained from five women and one man (age 24-well plates, in 1 ml MEM/FCS for up to 14 range 51 to 82 years). days, both in the presence and absence of 10-' Monocytes were isolated from the peripheral M 1,25(OH)2D3 (Solvay Duphar, The blood of eight patients with seropositive Netherlands), 25 ng ml-' human macrophage rheumatoid arthritis; seven women and one colony stimulating factor (M-CSF) (R & D man were studied (age range 46 to 74 years). Systems, UK), and 10' M dexamethasone. In all cultures, the medium (with added factors) ISOLATION AND CULTURE OF MONOCYTES AND was entirely replaced every 3 days. SYNOVIAL MACROPHAGES As controls, cultures of monocytes and For isolation of monocytes, blood was diluted synovial macrophages were also set up with 1:1 in Hanks 's balanced salt solution (HBSS) and without UMR 106 cells, and in the (Gibco, UK), layered over Ficoll Hypaque presence or absence of 1,25(OH)2D3, M-CSF, (Pharmacia), centrifuged, washed, and then and dexamethasone. resuspended in 5 ml of a minimal essential medium (MEM) (Gibco, UK) with 10% fetal CYTOCHEMICAL AND IMMUNOCYTOCHEMICAL catf serum (Gibco, UK) containing glutamine, CHARACTERISATION OF ISOLATED AND CULTURED benzylpenicillin, and streptomycin (MEM/ CELLS FCS). The number of cells in the resultant Isolated monocytes and macrophages which suspension was counted in a haemocytometer. had been cultured on coverslips for 24 hours Peripheral blood mononuclear cells (5 x 10' and 7 days were fixed in citrate acetone and were then added to 7 mm diameter wells of stained for tartrate resistant acid phosphatase 96-well plates containing human cortical bone (TRAP), an osteoclast associated enzyme,29 slices (5 mm2), prepared as previously using a kit from Sigma. For immunocytochem- described,27 or 6 mm diameter glass coverslips, istry, cell cultures on coverslips were fixed in on half of which 4 x 104 osteoblast-like UMR cold acetone and stained by an indirect immu- 106 cells-a rat osteosarcoma cell line28-had noperoxidase technique30 for the detection of previously been cultured for 24 h in CD5 1, the vitronectin receptor (VNR), a MEMIFCS. highly osteoclast associated antigen, using Specimen radiography was carried out on all monoclonal antibody 23C6 (a kind gift of Pro- samples of rheumatoid arthritis synovium to fessor M Horton, London)." Cultures on cov- determine whether any bone particles were erslips were also stained immunohistochemi- present in the synovial membrane; blocks were cally for the presence of CD1lb and CD14, also taken for routine histology. The remainder monocyte/macrophage antigens known not to of the synovial specimen was then cut into be expressed by human osteoclasts," with the small pieces (approximately 1 mm') and monoclonal antibodies TMG6-5 and http://ard.bmj.com/ washed thoroughly in HBSS. The synovial MEM-18 respectively. These monoclonal anti- fragments were digested in HBSS containing 1 bodies were derived from the 5th International mg ml-' collagenase type I (Sigma, UK) and Workshop on Human Leucocyte Differentia- 0.25% trypsin for 90 min at 37°C. The tion Antigens." suspension was filtered through a 70 gm cell DETECTION OF CALCITONIN RECEPTORS ON strainer (Falcon, UK) before being centrifuged MONOCYTE CULTURES at 680 g for 10 min. The cell pellet was resus- Peripheral blood mononuclear cells isolated and on September 28, 2021 by guest. Protected copyright. pended in 5 ml MEM/FCS and the cell cultured on glass coverslips in the presence and suspension (1 x 10' cells/well) was then added absence of UMR 106 cells, 1,25(OH)2D3, and M-CSF were assessed after incubation for 24 hours and 14 days for the presence of calcitonin receptors
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