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Formation of Osteoclast-Like Cells from Peripheral Blood of Periodontitis Patients Occurs Without Supplementation of Macrophage Colony-Stimulating Factor

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Formation of Osteoclast-Like Cells from Peripheral Blood of Periodontitis Patients Occurs Without Supplementation of Macrophage Colony-Stimulating Factor J Clin Periodontol 2008; 35: 568–575 doi: 10.1111/j.1600-051X.2008.01241.x Stanley T. S. Tjoa1, Teun J. de Formation of osteoclast-like cells Vries1,2, Ton Schoenmaker1,2, Angele Kelder3, Bruno G. Loos1 and Vincent Everts2 from peripheral blood of 1Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), Universiteit van Amsterdam and Vrije periodontitis patients occurs Universteit, Amsterdam, The Netherlands; 2Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), without supplementation of Universiteit van Amsterdam and Vrije Universteit, Amsterdam, Research Institute MOVE, The Netherlands; 3Department of Hematology, VUMC, Vrije Universiteit, macrophage colony-stimulating Amsterdam, The Netherlands factor Tjoa STS, de Vries TJ, Schoenmaker T, Kelder A, Loos BG, Everts V. Formation of osteoclast-like cells from peripheral blood of periodontitis patients occurs without supplementation of macrophage colony-stimulating factor. J Clin Periodontol 2008; 35: 568–575. doi: 10.1111/j.1600-051X.2008.01241.x. Abstract Aim: To determine whether peripheral blood mononuclear cells (PBMCs) from chronic periodontitis patients differ from PBMCs from matched control patients in their capacity to form osteoclast-like cells. Material and Methods: PBMCs from 10 subjects with severe chronic periodontitis and their matched controls were cultured on plastic or on bone slices without or with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kB ligand (RANKL). The number of tartrate-resistant acid phosphatase-positive (TRACP1) multinucleated cells (MNCs) and bone resorption were assessed. Results: TRACP1 MNCs were formed under all culture conditions, in patient and control cultures. In periodontitis patients, the formation of TRACP1 MNC was similar for all three culture conditions; thus supplementation of the cytokines was not needed to induce MNC formation. In control cultures, however, M-CSF or M-CSF/RANKL resulted in higher numbers compared with cultures without cytokines. Upregulations of osteoclast marker mRNA cathepsin K and carbonic anhydrase II confirmed the osteoclastic character. Bone resorption was only observed when PBMCs were cultured in the presence of M-CSF and RANKL. Key words: osteoclast formation; periodontitis; Conclusion: Our data indicate that PBMCs from periodontitis patients do not need peripheral blood priming by M-CSF to become osteoclast-like cells, suggesting that PBMCs from periodontitis patients are present in the circulation in a different state of activity. Accepted for publication 20 March 2008 Conflict of interest and source of Chronic periodontitis is a multi-factorial primary aetiological factor of periodontal funding statement disease characterized by inflammation of disease is bacterial plaque (Kinane 1999), The authors declare that they have no the periodontium, leading to loss of soft studies have shown that not everyone is conflict of interests. tissue attachment and alveolar bone (Page equally susceptible to periodontal disease The funding for this study was received et al. 1997). If left untreated, this condition (Loe et al. 1986). The host response has from the Royal Netherlands Academy of may ultimately lead to tooth exfoliation. been considered as an important disease- Arts and Sciences (T. J. de V.). Although it is generally accepted that the modifying factor (Page et al. 1997). 568 r 2008 Blackwell Munksgaard No claim to original US government works Osteoclast formation in periodontitis 569 Osteoclasts are the cells ultimately significant increase in osteoclast formation Table 1. Characteristics of controls and responsible for alveolar bone resorp- and bone resorption activity compared patients tion. They are multinucleated giant with non-osteoporotic postmenopausal Pair C/P Age Gender Ethnicity Smoking cells (Roodman 1996) originating from and healthy controls, respectively. the monocyte/macrophage lineages Spontaneous osteoclastogenesis, for 1 C 41 M Caucasian 1 (Udagawa et al. 1990, Fujikawa et al. example osteoclast formation without P 40 M Caucasian 1 1996). Human osteoclast precursor cells addition of cytokines such as M-CSF 2 C 27 M North African À have been found in the mononuclear and RANKL, was higher in osteoporotic P 26 M North African À fraction of peripheral blood (PBMCs), women and arthritis patients (Ritchlin 3 C 29 M African black 1 P 29 M African black 1 and in vitro these cells differentiate into et al. 2003, D’Amelio et al. 2005). 4 C 45 F African black À osteoclasts (Faust et al. 1999, Shalhoub Similarly, increased spontaneous osteo- P 44 F African black À et al. 1999). clastogenesis was found in cancer 5 C 35 M Caucasian 1 Key regulators of osteoclast differen- patients with bone metastases compared P 35 M Caucasian 1 tiation are macrophage colony-stimulating with healthy controls or cancer patients 6 C 32 F North African À factor (M-CSF), receptor activator of without bone metastases (Roato et al. P 31 F North African À nuclear factor-kB (RANK) ligand 2005). This increase in osteoclast 7 C 48 M Caucasian 1 (RANKL) and osteoprotegerin (OPG). formation and osteoclast activity was P 49 M Caucasian 1 8 C 40 F Indian À In a mouse model, it was shown that also suggested to occur in PBMCs P 41 F Indian À the growth factor M-CSF is indispensa- from periodontitis patients compared 9 C 40 M Indian 1 ble to the proliferation of osteoclast with non-periodontitis patients (Brunetti P 43 M Indian 1 progenitors and their differentiation et al. 2005). However, it is not clear from 10 C 37 F African black À into mature osteoclasts (Tanaka et al. the latter study whether the increased P 37 F African black À 1993). However, M-CSF alone could osteoclast formation was due to the high- C, control; P, patient; M, male; F, female; 1, not induce osteoclasts to form resorption er average age of the patients (mean smoker; À , no smoker. pits on dentine slices (Jimi et al. 1999). 42.8 Æ 15.2 years) compared with the Differentiation and activation of osteo- controls (mean 30.5 Æ 5.2 years), clasts is triggered by RANKL, which is because it is known that osteoclast ACTA who received restorative dental a member of the tumor necrosis factor formation from human PBMCs may treatments and regular dental check-ups, (TNF)-related cytokines, and this cyto- increase with age (Cheleuitte et al. or were subjects from private dental kine has a direct involvement in the 1998, Jevon et al. 2002). clinics. A control subject was selected differentiation, activation and survival In the current study, we further in- on basis of the following criteria: max- of osteoclasts and their precursors vestigated whether PBMCs from perio- imum of one missing tooth per quadrant (Lacey et al. 1998). Binding of RANKL dontitis patients have an increased (third molars excluded), a radiographic to its receptor RANK stimulates osteo- capacity to form osteoclasts by analys- distance of o3 mm between the cemen- clast precursors to differentiate into ing the dependency of M-CSF and toenamel junction (CEJ) and the alveo- osteoclasts and activates mature osteo- RANKL. Osteoclastogenesis was eval- lar bone crest on all teeth on recent clasts to resorb bone. OPG is a decoy uated in PBMC cultures from perio- (not older than 1 year) bite-wings radio- receptor for RANKL, it competes with dontitis patients and controls who were graphs. The control subjects were matched RANK for binding of RANKL, thereby matched for age, sex, ethnicity and and paired with the patient group for age, acting as an inhibitor of osteoclast smoking. gender, ethnicity and smoking habits maturation and activity (Simonet et al. (Table 1), because these parameters are 1997, Lacey et al. 1998). Although the established risk determinants for perio- importance of the RANK–RANKL–OPG Material and Methods dontitis (Borrell & Papapanou 2005) and system in osteoclast biology was mainly could possibly influence osteoclasto- Subjects explored in mice, it is believed that the genesis (Jevon et al. 2002). regulatory mechanisms of human osteo- The patient group consisted of 10 un- An extensive medical history of each clast differentiation are similar (Suda treated patients diagnosed with general- participant was taken by a written ques- et al. 1999). ized severe chronic periodontitis. These tionnaire and by an interview. Each Various studies were undertaken to patients were referred to the Department subject was free from systemic diseases understand the cellular mechanisms of Periodontology at the Academic Cen- and had no clinical symptoms of bacter- underlying bone breakdown in people tre for Dentistry Amsterdam (ACTA) ial, viral or parasitic infections at the with osteopenic diseases, such as auto- for diagnosis and/or treatment of perio- time of the study, except for perio- immune arthritis (Ritchlin et al. 2003), dontitis. Generalized severe chronic dontitis in the patient group. None of post-menopausal osteoporosis (D’Amelio periodontitis patients were defined as the subjects in the study had taken any et al. 2005) and bone tumours (Roato patients who never had periodontal ther- form of medication that could affect et al. 2005). From these studies, it apy or at least not in the last 10 years their periodontal status, such as anti- appeared that differences in osteoclast and who presented with alveolar bone biotics, anti-inflammatory agents and recruitment exist at the level of periph- loss X50% of the root length on at least immune suppressants during the preced- eral blood. Peripheral blood mono- seven teeth on a set of full mouth dental ing 6 months. Women older than 46 years nuclear cells (PBMCs) from patients radiographs (Bizzarro et al. 2007). were excluded from the study to prevent with postmenopausal osteoporosis Patients were carefully matched with skewing of the data due to the possible (D’Amelio et al. 2005) and psoriatic healthy controls. Control subjects were onset of menopause-related osteoporo- arthritis (Ritchlin et al. 2003) exhibit a recruited among dental patients at sis. All subjects received both verbal r 2008 Blackwell Munksgaard No claim to original US government works 570 Tjoa et al.
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