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Clinical Oral Investigations

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01.03.2015 | Original Article

Macrophages and bisphosphonate-related osteonecrosis of the jaw (BRONJ): evidence of local immunosuppression of macrophages in contrast to other infectious jaw diseases

verfasst von: Sebastian Hoefert, Inge Schmitz, Frank Weichert, Marcel Gaspar, Harald Eufinger

Erschienen in: Clinical Oral Investigations | Ausgabe 2/2015

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Abstract

Objectives

Bisphosphonates (BIP) are well established in bone diseases. A serious side effect is the bisphosphonate-related osteonecrosis of the jaw (BRONJ). Among different aetiology factors, local suppression of immune functions is gaining interest. The aim of this study was to analyze the function of macrophages in BRONJ in contrast to patients with osteoradionecrosis (ORN) and secondary chronic osteomyelitis (OM) of the jaws. Samples were also taken from patients with bisphosphonate medication (BP) without signs of infection, radiation therapy (RA), and osteoporosis (OP) as controls.

Material and methods

One hundred five patients with surgery to the jaw were included in this study: 33 patients with BRONJ, 17 with ORN, 11 with secondary chronic OM, 8 with RA, 25 with BP medication and 11 with OP. Samples were histologically analysed and monocytes/macrophages stained using CD14 and CD68. The number of positively marked cells was counted per view (pv), and the CD68/CD14 ratio was calculated. Statistically, the Naïve-Bayes and decision-tree classifier were used.

Results

The number of CD14 positive cells was 10.3 cells/pv in the BRONJ-group in as compared to 5 in the ORN- and 3.8 in the OM-group respectively. The number of CD68 positive cells was 11.4/pv (BRONJ-group) as compared to 14/pv (ORN-group) and 12.7/pv (OM-group). With 0.89, the BRONJ-group showed a statistically different CD68/CD14 ratio than ORN-group with 3.39 and OM-group with 3.03.

Conclusions

Our results indicate a different expression of CD14 and CD68 markers of monocytes/macrophages in BRONJ as compared to other jaw infections. This could be a sign of macrophage immunosuppression by BPs. In contrast, patients receiving BP medication without BRONJ showed no differences to other controls.

Clinical relevance

This is the first study that clinically indicates a compromised macrophage function at BRONJ sites in contrast to ORN or secondary OM sites. The BRONJ itself could be forwarded by this effect.

Dunstan C, Felsenberg D, Seibel MJ (2007) Therapy insight: the risks and benefits of bisphosphonates for the treatment of tumor induced bone disease. Nat Clin Prct Oncol 4:42–55CrossRef

Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 66:2356–2363CrossRef

Crass MF (1941) A history of match industry. J Chem Educ 18:428–431CrossRef

Pazianas M (2011) Osteonecrosis of the jaw and the role of macrophages. J Natl Cancer 103:1–9CrossRef

Moreau MF, Guillet C, Massin P, Chevalier S, Gascan H, Basle MF, Chappard D (2007) Comparative effects of five bisphosphonates on apoptosis of macrophage cells in vitro. Biochem Phamacol 73:718–723CrossRef

Farina C, Theil D, Semlinger B, Hohlfeld R, Meinl E (2004) Distinct responses of monocytes to toll-like receptors ligands and infammatory cytokines. Int Imunology 16:799–809CrossRef

Muratsu D, Yoshiga D, Taketomi T, Onimura T, Seki Y, Matsumoto A, Nakamura S (2013) Zoledronic acid enhances lipopolysaccharide-stimulated proinflammatory reactions through controlled expression of SOCS1 in macrophages. PLoS One 8:e67906CrossRefPubMedCentralPubMed

Marx RE (1983) Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 41:283–288CrossRefPubMed

Pietschmann P, Stohlawetz P, Brosch S, Steiner G, Smolen JS, Peterlik M (1998) The effect of alendronate on cytokine production, adhesion molecule expression, and transendothelial migration of human peripheral blood mononuclear cells. Calcify Tissue Int 63:325–330CrossRef

10.

Reid IR, Bolland MJ, Grey AB (2007) Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 41:318–320CrossRefPubMed

11.

Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, Taguchi A, Toyosawa S, Nagata T, Urade M (2010) Bisphosphonate-related osteonecrosis of the jaw: position paper from the allied task force committee of japanese society for bone and mineral research, japan osteoporosis society, japanese society of periodontology, japanese society for oral and maxillofacial radiology, and japanese society of oral and maxillofacial surgeons. J Bone Miner Metab 28:365–383CrossRefPubMed

12.

Hoefert S, Eufinger H (2011) Relevance of a prolonged preoperative antibiotic regime in the treatment of bisphosphonate-related osteonecrosis of the jaw. J Oral Maxillofac Surg 69:362–380CrossRefPubMed

13.

Ohe JY, Kwon YD, Lee HW (2012) Bisphosphonates modulate the expression of OPG and M-CSF in hMSC-derived osteoblasts. Clin Oral Invest 16:1153–1159CrossRef

14.

Sato M, Gasser W (1990) Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. J Bone Miner Res 5:31–40CrossRefPubMed

15.

Allen MR, Burr DB (2009) The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg 67(5 suppl):61–70CrossRefPubMed

16.

Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehotra B (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 76:2–12

17.

Kumar V, Sinha RK (2013) Evolution and etiopathogenesis of bisphosphonate induced osteonecrosis of the jaw. North Am J Med Sci 5:260–265CrossRef

18.

Peris P, Atkinson EJ, Gössl M, Kane TL, Mc Cready LK, Lerman A, Khosala S, McGregor UI (2012) Effects of bisphosphonate treatment on circulating osteogenic endothelial progenitor cells in postmenopausal women. Mayo Clin Proc 88:46–55CrossRefPubMedCentralPubMed

19.

Ziebart T, Pabst A, Klein MO, Kämmerer P, Gauss L, Brüllmann D, Al-Nawas B, Walter C (2011) Bisphosphonates: restriction for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro. Clin Oral Invest 15:105–111CrossRef

20.

Nabil S, Samman N (2012) Risk factors for osteoradionecrosis after head and neck radiation: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol 113:54–69CrossRefPubMed

21.

Jereczek-Fossa BA, Orecchia R (2002) Radiotherapy-induced mandibular bone complications. Cancer Treat Rev 28:65–74CrossRefPubMed

22.

Morrish RB, Chan E, Silverman S, Meyer J, Fu KK, Greenspan D (1981) Osteonecrosis in patients irradiated for head and neck carcinoma. Cancer 47:1980–1983CrossRefPubMed

23.

Chracanovic BR, Reher P, Sousa AA, Harris M (2010) Osteoradionecrosis of the jaws—a current overview—part 1: physiopathology and risk and predisposing factors. Oral Maxillofac Surg 14:3–16CrossRef

24.

Marx RE, Tursun R (2012) Suppurative osteomyelitis, bisphosphonate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implication for the mechanism of each disease. Int J Oral Maxillofac Surg 41:283–289CrossRefPubMed

25.

Baltensperger MM, Eyrich GK (2009) Osteomyelitis of the jaws: definition and classification. In: Baltensperger MM, Eyrich GK (eds) Osteomyelitis of jaws, 1st edn. Springer, Berlin, Heidelberg, pp 11–56CrossRef

26.

Abbas AK, Lichtman AH, Pillai S (2007) Innate immunity. In: Abbas AK (ed) Cellular and molecular immunology, 6th edn. Saunders Elsevier, Philadelphia, pp 24–26

27.

Dobrovolskaia MA, Vogel SN (2002) Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect 4:903–914CrossRefPubMed

28.

Vega VL, De Maio A (2003) Geldanamycin treatment ameliorates the response to LPS in murine macrophages by decreasing CD14 surface expression. Mol Biol Cell 14:764–773CrossRefPubMedCentralPubMed

29.

Amanzada A, Malik IA, Blaschke M, Khan S, Ramadori G, Moriconi F (2013) Identification of CD68(+) neutrophil granulocytes in in vitro model of acute inflammation and inflammatory bowel disease. Int J Clin Exp Pathol 6:561–570PubMedCentralPubMed

30.

Ji X, Pushalkar S, Li Y, Glickman R, Fleischer K, Saxena D (2011) Antibiotic effects on bacterial profile in osteonecrosis of the jaw. Oral Dis 18:85–95CrossRefPubMedCentralPubMed

31.

Russel RGG (2011) Bisphosphonates: the first 40 years. Bone 49:2–19CrossRef

32.

Thomas CJ, Kapoor M, Sharma S, Bausinger H, Zyilan U, Lipsker D, Hanau D, Surolia A (2002) Evidence of a trimolecular complex involving LPS, binding protein and soluble CD14 as an effector of LPS responds. FEBS Lett 531:184–188CrossRefPubMed

33.

Thompson K, Rogers MJ, Coxon FP, Crockett JC (2006) Cytosolic entry of bisphosphonate drugs requires acidification of vesicles after fluid-phase endocytosis. Mol Pharmacol 69:1624–1832CrossRefPubMed

34.

Roelofs AJ, Jauhiainen M, Mönkkönen H, Rogers MJ, Mönkkönen J, Thompson K (2009) Peripheral blood monocytes are responsible for gammadelta T cell activation induced by zoledronic acid through accumulation of IIP/DMAPP. Br J Haemotol 144:245–250CrossRef

35.

Favia G, Pilolli GP, Maiorano E (2009) Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: an analysis of 31 cases with confocal laser scanning microscopy. Bone 45:406–413CrossRefPubMed

36.

Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964CrossRefPubMed

37.

Zhang Q, Atsuta I, Liu S, Chen C, Shi S, Shi S, Le AD (2013) IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws. Clin Cancer Res 19:3176–3188CrossRefPubMed

38.

Stevenson PH, Stevenson JR (1986) Cytotoxic and migration inhibitory effects of bisphosphonates on macrophages. Calcif Tissue 38:227–233CrossRef

39.

Tsurushima H, Kokuryo S, Sakaguchi O, Tanaka J, Tominaga K (2013) Bacterial promotion of bisphosphonate-induced osteonecrosis in Wistar rats. Int J Oral Maxillofac Surg 42:1481–1487CrossRefPubMed

40.

Roelofs AJ, Coxon FP, Ebetino FH, Lundy MW, Henneman ZJ, Nancollas GH, Sun S, Blazewska KM, Bala JLF, Kashemirov BA, Khalid AB, McKenna CE, Rogers MJ (2010) Fluorescent risedronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivo. J Bone Mineral Res 25:606–616CrossRef

41.

Moser B, Eberl M (2001) γδ T-APCs: a novel tool for immunotherapy? Cell Mol Life Sci 68:2443–2452CrossRef

42.

Egan PJ, Carding SR (2000) Downmodulation of the inflammatory response to bacterial infection by gammadelta T cells cytotoxic for activated macrophages. J Exp Med 191:2145–2158CrossRefPubMedCentralPubMed

43.

Kalyan S, Quabius ES, Wiltfang J, Mönig H, Kabelitz D (2013) Can peripheral blood γδ T cells predict osteonecrosis of the jaw? An immunological perspective on the adverse drug effects of aminobisphosphonate therapy. J Bone Miner Res 28:723–727CrossRef

44.

Hansen T, Kunkel M, Weber M, Kirkpatrick CJ (2006) Osteonecrosis of the jaws in patients treated with bisphosphonates-histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 35:155–160CrossRefPubMed

45.

Wei X, Pushalkar S, Estilo C, Wong C, Farooki A, Fornier M, Bohle G, Huryn J, Li Y, Doty S, Saxena D (2012) Molecular profiling of oral microbiota in jawbone samples of bisphosphonate-related osteonecrosis of the jaw. Oral Dis 18:602–612CrossRefPubMed

46.

Sedghizadeh P, Kumar S, Gorur A, Schaudinn C, Shuler C, Costerton J (2009) Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw secondary to bisphosphonate therapy. J Am Dent Assoc 140:1259–1265CrossRefPubMed

Titel: Macrophages and bisphosphonate-related osteonecrosis of the jaw (BRONJ): evidence of local immunosuppression of macrophages in contrast to other infectious jaw diseases
verfasst von: Sebastian Hoefert
Inge Schmitz
Frank Weichert
Marcel Gaspar
Harald Eufinger
Publikationsdatum: 01.03.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Clinical Oral Investigations / Ausgabe 2/2015
Print ISSN: 1432-6981
Elektronische ISSN: 1436-3771
DOI: https://doi.org/10.1007/s00784-014-1273-7

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Abstract

Objectives

Material and methods

Results

Conclusions

Clinical relevance

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