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01-01-2020 | Bisphosphonate | Original Article

Influence of clodronate and compressive force on IL-1ß-stimulated human periodontal ligament fibroblasts

Authors: Sarah Grimm, Eva Wolff, Christian Walter, Andreas M. Pabst, Ambili Mundethu, Cornelius Jacobs, Heiner Wehrbein, Collin Jacobs

Published in: Clinical Oral Investigations | Issue 1/2020

Abstract

Objectives

The aim of this study was to investigate in vitro the effect of clodronate on interleukin-1ß (IL-1ß)–stimulated human periodontal ligament fibroblasts (HPdLFs) with the focus on inflammatory factors of orthodontic tooth movement with and without compressive force.

Materials and methods

HPdLFs were incubated with 5 μM clodronate and 10 ng/mL IL-1ß. After 48 h, cells were exposed to 3 h of compressive force using a centrifuge. The gene expression of cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), matrix metalloproteinase 8 (MMP-8), and the tissue inhibitor of MMP (TIMP-1) was analyzed using RT-PCR. Prostaglandin E2 (PGE-2), IL-6, and TIMP-1 protein syntheses were quantified via ELISA.

Results

Compressive force and IL-1ß induced an overexpression of COX-2 gene expression (61.8-fold; p < 0.05 compared with control), diminished by clodronate (41.1-fold; p < 0.05 compared with control). Clodronate slowed down the compression and IL-1ß induced IL-6 gene expression (161-fold vs. 85.6-fold; p < 0.05 compared with control). TNF-α was only slightly affected without statistical significance. Clodronate reduced IL-1ß-stimulated MMP-8 expression with and without compressive force. TIMP-1 on gene and protein level was downregulated in all groups. Analyzing the MMP-8/TIMP-1 ratio, the highest ratio was detected in IL-1ß-stimulated HPdLFs with compressive force (21.2-fold; p < 0.05 compared with control). Clodronate diminished IL-1ß-induced upregulation of MMP-8/TIMP-1 ratio with (11.5-fold; p < 0.05 compared with control) and without (12.5-fold; p < 0.05 compared with control) compressive force.

Conclusion

Our study demonstrates a slightly anti-inflammatory effect by clodronate under compressive force in vitro. Additionally, the periodontal remodeling presented by the MMP-8/TIMP-1 ratio seems to be diminished by clodronate.

Clinical relevance

Reduction of pro-inflammatory factors and reduction of periodontal remodeling might explain reduced orthodontic tooth movement under clodronate intake.

Lekic PC, Rajshankar D, Chen H, Tenenbaum H, McCulloch CA (2001) Transplantation of labeled periodontal ligament cells promotes regeneration of alveolar bone. Anat Rec 262:193–202PubMed

Saito M, Saito S, Ngan PW, Shanfeld J, Davidovitch Z (1991) Interleukin 1 beta and prostaglandin E are involved in the response of periodontal cells to mechanical stress in vivo and in vitro. Am J Orthod Dentofac Orthop 99:226–240

Jager A, Zhang D, Kawarizadeh A, Tolba R, Braumann B, Lossdorfer S, Gotz W (2005) Soluble cytokine receptor treatment in experimental orthodontic tooth movement in the rat. Eur J Orthod 27:1–11PubMed

Nunes L, Quintanilha L, Perinetti G, Capelli JJ (2017) Effect of orthodontic force on expression levels of ten cytokines in gingival crevicular fluid. Arch Oral Biol 76:70–75PubMed

Surlin P, Rauten AM, Mogoanta L, Silosi I, Oprea B, Pirici D (2010) Correlations between the gingival crevicular fluid MMP8 levels and gingival overgrowth in patients with fixed orthodontic devices. Romanian J Morphol Embryol 51:515–519

Grieve WG 3rd, Johnson GK, Moore RN, Reinhardt RA, DuBois LM (1994) Prostaglandin E (PGE) and interleukin-1 beta (IL-1 beta) levels in gingival crevicular fluid during human orthodontic tooth movement. Am J Orthod Dentofac Orthop 105:369–374

Scott P, Fleming P, DiBiase A (2007) An update in adult orthodontics. Dent Update 34:427–428, 431-4, 436 passimPubMed

Rogers MJ (2003) New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 9:2643–2658PubMed

Schenk R, Merz WA, Muhlbauer R, Russell RG, Fleisch H (1973) Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl 2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calcif Tissue Res 11:196–214PubMed

10.

Jacobs C, Walter C, Ziebart T, Dirks I, Schramm S, Grimm S, Krieger E, Wehrbein H (2014) Mechanical loading influences the effects of bisphosphonates on human periodontal ligament fibroblasts. Clin Oral Investig 19:699–708PubMed

11.

Walter C, Klein MO, Pabst A, Al-Nawas B, Duschner H, Ziebart T (2010) Influence of bisphosphonates on endothelial cells, fibroblasts, and osteogenic cells. Clin Oral Investig 14:35–41PubMed

12.

Saviola G, Abdi-Ali L, Campostrini L, Sacco S, Baiardi P, Manfredi M, Mannoni A, Benucci M (2012) Clodronate and hydroxychloroquine in erosive osteoarthritis: a 24-month open randomized pilot study. Mod Rheumatol 22:256–263PubMed

13.

Zhang JX, Dang SC, Yin K, Jiang DL (2011) Protective effect of clodronate-containing liposomes on intestinal mucosal injury in rats with severe acute pancreatitis. Hepatobiliary Pancreat Dis Int 10:544–551PubMed

14.

Llavaneras A, Ramamurthy NS, Heikkila P, Teronen O, Salo T, Rifkin BR, Ryan ME, Golub LM, Sorsa T (2001) A combination of a chemically modified doxycycline and a bisphosphonate synergistically inhibits endotoxin-induced periodontal breakdown in rats. J Periodontol 72:1069–1077PubMed

15.

Dombrecht EJ, Schuerwegh AJ, Bridts CH, Ebo DG, Van Offel JF, Stevens WJ, De Clerck LS (2007) Effect of bisphosphonates on nitric oxide production by inflammatory activated chondrocytes. Clin Exp Rheumatol 25:817–822PubMed

16.

Ozdemir SP, Kurtis B, Tuter G, Bozkurt S, Gultekin SE, Senguven B, Watanabe K, Aydin S (2012) Effects of low-dose doxycycline and bisphosphonate clodronate on alveolar bone loss and gingival levels of matrix metalloproteinase-9 and interleukin-1beta in rats with diabetes: a histomorphometric and immunohistochemical study. J Periodontol 83:1172–1182PubMed

17.

Dehghani F, Conrad A, Kohl A, Korf HW, Hailer NP (2004) Clodronate inhibits the secretion of proinflammatory cytokines and NO by isolated microglial cells and reduces the number of proliferating glial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp Neurol 189:241–251PubMed

18.

Choi J, Baek SH, Lee JI, Chang YI (2010) Effects of clodronate on early alveolar bone remodeling and root resorption related to orthodontic forces: a histomorphometric analysis. Am J Orthod Dentofac Orthop 138:548 e1–548 e8 discussion 548-9

19.

Liu L, Igarashi K, Haruyama N, Saeki S, Shinoda H, Mitani H (2004) Effects of local administration of clodronate on orthodontic tooth movement and root resorption in rats. Eur J Orthod 26:469–473PubMed

20.

Lotwala RB, Greenlee GM, Ott SM, Hall SH, Huang GJ (2012) Bisphosphonates as a risk factor for adverse orthodontic outcomes: a retrospective cohort study. Am J Orthod Dentofac Orthop 142:625–634 e3

21.

Liu L, Igarashi K, Kanzaki H, Chiba M, Shinoda H, Mitani H (2006) Clodronate inhibits PGE(2) production in compressed periodontal ligament cells. J Dent Res 85:757–760PubMed

22.

Proff P, Reicheneder C, Faltermeier A, Kubein-Meesenburg D, Romer P (2014) Effects of mechanical and bacterial stressors on cytokine and growth-factor expression in periodontal ligament cells. J Orofac Orthop 75:191–202PubMed

23.

Nokhbehsaim M, Winter J, Rath B, Jager A, Jepsen S, Deschner J (2011) Effects of enamel matrix derivative on periodontal wound healing in an inflammatory environment in vitro. J Clin Periodontol 38:479–490PubMed

24.

Jacobs C, Schramm S, Dirks I, Walter C, Pabst A, Meila D, Jacobs C, Wehrbein H (2018) Mechanical loading increases pro-inflammatory effects of nitrogen-containing bisphosphonate in human periodontal fibroblasts. Clin Oral Investig 22:901–907PubMed

25.

Long P, Liu F, Piesco NP, Kapur R, Agarwal S (2002) Signaling by mechanical strain involves transcriptional regulation of proinflammatory genes in human periodontal ligament cells in vitro. Bone 30:547–552PubMedPubMedCentral

26.

Walter C, Pabst A, Ziebart T, Klein M, Al-Nawas B (2011) Bisphosphonates affect migration ability and cell viability of HUVEC, fibroblasts and osteoblasts in vitro. Oral Dis 17:194–199PubMed

27.

Pabst AM, Ziebart T, Koch FP, Taylor KY, Al-Nawas B, Walter C (2012) The influence of bisphosphonates on viability, migration, and apoptosis of human oral keratinocytes--in vitro study. Clin Oral Investig 16:87–93PubMed

28.

Grimm S, Walter C, Pabst A, Goldschmitt J, Wehrbein H, Jacobs C (2015) Effect of compressive loading and incubation with clodronate on the RANKL/OPG system of human osteoblasts. J Orofac Orthop 76:531–542PubMed

29.

Diercke K, Zingler S, Kohl A, Lux CJ, Erber R (2014) Gene expression profile of compressed primary human cementoblasts before and after IL-1beta stimulation. Clin Oral Investig 18:1925–1939PubMed

30.

Redlich M, Roos H, Reichenberg E, Zaks B, Grosskop A, Bar Kana I, Pitaru S, Palmon A (2004) The effect of centrifugal force on mRNA levels of collagenase, collagen type-I, tissue inhibitors of metalloproteinases and beta-actin in cultured human periodontal ligament fibroblasts. J Periodontal Res 39:27–32PubMed

31.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408

32.

Meeran NA (2013) Cellular response within the periodontal ligament on application of orthodontic forces. J Indian Soc Periodontol 17:16–20PubMedPubMedCentral

33.

Mitsui N, Suzuki N, Maeno M, Yanagisawa M, Koyama Y, Otsuka K, Shimizu N (2006) Optimal compressive force induces bone formation via increasing bone morphogenetic proteins production and decreasing their antagonists production by Saos-2 cells. Life Sci 78:2697–2706PubMed

34.

Bartzela T, Turp JC, Motschall E, Maltha JC (2009) Medication effects on the rate of orthodontic tooth movement: a systematic literature review. Am J Orthod Dentofac Orthop 135:16–26

35.

Shima K, Nemoto W, Tsuchiya M, Tan-No K, Takano-Yamamoto T, Sugawara S, Endo Y (2016) The bisphosphonates clodronate and etidronate exert analgesic effects by acting on glutamate- and/or ATP-related pain transmission pathways. Biol Pharm Bull 39:770–777PubMed

36.

Jiang L, Tang Z (2018) Expression and regulation of the ERK1/2 and p38 MAPK signaling pathways in periodontal tissue remodeling of orthodontic tooth movement. Mol Med Rep 17:1499–1506PubMed

37.

Ren Y, Hazemeijer H, de Haan B, Qu N, de Vos P (2007) Cytokine profiles in crevicular fluid during orthodontic tooth movement of short and long durations. J Periodontol 78:453–458PubMed

38.

Garlet TP, Coelho U, Silva JS, Garlet GP (2007) Cytokine expression pattern in compression and tension sides of the periodontal ligament during orthodontic tooth movement in humans. Eur J Oral Sci 115:355–362PubMed

39.

Alhashimi N, Frithiof L, Brudvik P, Bakhiet M (2001) Orthodontic tooth movement and de novo synthesis of proinflammatory cytokines. Am J Orthod Dentofac Orthop 119:307–312

40.

Taddei SR, Moura AP, Andrade I Jr, Garlet GP, Garlet TP, Teixeira MM, da Silva TA (2012) Experimental model of tooth movement in mice: a standardized protocol for studying bone remodeling under compression and tensile strains. J Biomech 45:2729–2735PubMed

41.

Apajalahti S, Sorsa T, Railavo S, Ingman T (2003) The in vivo levels of matrix metalloproteinase-1 and -8 in gingival crevicular fluid during initial orthodontic tooth movement. J Dent Res 82:1018–1022PubMed

42.

Jacobs C, Walter C, Ziebart T, Grimm S, Meila D, Krieger E, Wehrbein H (2013) Induction of IL-6 and MMP-8 in human periodontal fibroblasts by static tensile strain. Clin Oral Investig 18:901–908PubMed

Title: Influence of clodronate and compressive force on IL-1ß-stimulated human periodontal ligament fibroblasts
Authors: Sarah Grimm
Eva Wolff
Christian Walter
Andreas M. Pabst
Ambili Mundethu
Cornelius Jacobs
Heiner Wehrbein
Collin Jacobs
Publication date: 01-01-2020
Publisher: Springer Berlin Heidelberg
Keyword: Bisphosphonate
Published in: Clinical Oral Investigations / Issue 1/2020
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI: https://doi.org/10.1007/s00784-019-02930-z

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Influence of clodronate and compressive force on IL-1ß-stimulated human periodontal ligament fibroblasts

Abstract

Objectives

Materials and methods

Results

Conclusion

Clinical relevance

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Objectives

Materials and methods

Results

Conclusion

Clinical relevance

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