Top

Published in:

01-11-2016 | Original Article

In vitro comparison of new bisphosphonic acids and zoledronate effects on human gingival fibroblasts viability, inflammation and matrix turnover

Authors: Marianna De Colli, Paolo Tortorella, Guya Diletta Marconi, Mariangela Agamennone, Cristina Campestre, Marilena Tauro, Amelia Cataldi, Susi Zara

Published in: Clinical Oral Investigations | Issue 8/2016

Abstract

Objectives

Bisphosphonates (BPs) are drugs clinically used in resorptive diseases. It was already proved that some clinically relevant BPs can inhibit a class of enzymes called matrix metalloproteinases (MMPs), required during tissue remodelling. Combining the arylsulfonamide function with the bisphosphonic group, several compounds were synthesized to obtain selective inhibitors of MMPs. The aim of the present study was to compare the effect of zoledronic acid (ZA), the most potent bisphosphonate available as therapy, with new sulfonamide containing BPs in an in vitro model of human gingival fibroblasts (HGFs).

Materials and methods

Western blot was used to measure procollagen I, β1 integrin MMP-8 and MMP-9, phase contrast and MTT for cell viability; L-lactate-dehydrogenase (LDH) measurement was performed for toxicity evaluation and ELISA for prostaglandin E₂ (PGE₂) secretion assessment.

Results

When compared with ZA, the treatment with the newly synthesized compounds shows increasing viability, procollagen I expression and decreased expression of β1 integrin in HGFs. Higher levels of released LDH, PGE₂ and MMP-9 expression are recorded in ZA-treated HGFs. Increased levels of MMP-8 are recorded in newly synthesized compounds-treated samples.

Conclusions

These findings allowed to conclude that new tested BPs did not affect HGFs viability and adhesion, did not induce cellular toxicity, were not responsible for inflammatory event induction and could preserve the physiological matrix turnover.

Clinical Relevance

It could be hypothesized that the new molecules were better tolerated by soft tissues, resulting in lesser side effects.

Clezardin P, Fournier P, Boissier S, Peyruchaud O (2003) In vitro and in vivo antitumor effects of bisphosphonates. Curr Med Chem 10:173–180CrossRefPubMed

Fernandez D, Polla G, Vega D, Ellena JA (2004) The Zn²⁺ salt of pamidronate: a role for water in the metal-cation binding properties of bisphosphonates. Acta Crystallogr C 60:m73–m75CrossRefPubMed

Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA, Blumenstein BA, Albain KS, Lipton A, Brown S (2004) American Society of Clinical Oncology American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003 (21):4042–4057 Erratum in: J Clin Oncol. 22: 1351

Hansen PJ, Knitschke M, Draenert FG, Irle S, Neff A (2013) Incidence of bisphosphonate-related osteonecrosis of the jaws (BRONJ) in patients taking bisphosphonates for osteoporosis treatment - a grossly underestimated risk? Clin Oral Investig 17:1829–1837CrossRefPubMed

Rustemeyer J, Bremerich A (2010) Bisphosphonate-associated osteonecrosis of the jaw: what do we currently know? A survey of knowledge given in the recent literature. Clin Oral Investig 14:59–64CrossRefPubMed

Kyrgidis A, Triardis S, Antoniades K (2009) Effects of bisphosphonates on keratinocytes and fibroblasts having a role in the development of osteonecrosis of the jaw. Byosciences Hypotheses 2:153–159CrossRef

De Colli M, Zara S, di Giacomo V, Patruno A, Marconi GD, Gallorini M, Zizzari VL, Tetè G, Cataldi A (2015) Nitric oxide-mediated cytotoxic effect induced by zoledronic acid treatment on human gingival fibroblasts. Clin Oral Investig 19:1269–1277CrossRefPubMed

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 14:35–41CrossRefPubMed

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 16:87–93CrossRefPubMed

10.

Nemeth JA, Yousif R, Herzog M, Che M, Upadhyay J, Shekarriz B, Bhagat S, Mullins C, Fridman R, Cher ML (2002) Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis. J Natl Cancer Inst 94:17–25CrossRefPubMed

11.

Clezardin P, Teti A (2007) A bone metastasis: pathogenesis and therapeutic implications. Clin Exp Metastasis 24:599–608CrossRefPubMed

12.

Heikkila P, Teronen O, Moilanen M, Konttinen YT, Hanemaaijer R, Laitinen M, Maisi P, van der Pluijm G, Bartlett JD, Salo T, Sorsa T (2002) Bisphosphonates inhibit stromelysin-1 (MMP-3), matrix metalloelastase (MMP-12), collagenase-3 (MMP-13) and enamelysin (MMP-20), but not urokinase-type plasminogen activator, and diminish invasion and migration of human malignant and endothelial cell lines. Anti-Cancer Drugs 13:245–254CrossRefPubMed

13.

Woodward JK, Holen I, Coleman RE, Buttle DJ (2007) The roles of proteolytic enzymes in the development of tumour-induced bone disease in breast and prostate cancer. Bone 41:912–927CrossRefPubMed

14.

Varghese S (2006) Matrix metalloproteinases and their inhibitors in bone: an overview of regulation and functions. Front Biosci 11:2949–2966CrossRefPubMed

15.

Paiva KB, Granjeiro JM (2014) Bone tissue remodeling and development: focus on matrix metalloproteinase functions. Arch Biochem Biophys 1(561):74–87CrossRef

16.

Vincenti MP, Brinckerhoff CE (2002) Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res 4:157–164CrossRefPubMed

17.

Sorsa T, Tjäderhane L, Salo T (2004) Matrix metalloproteinases (MMPs) in oral diseases. Oral Dis 10:311–318CrossRefPubMed

18.

Rao BG (2005) Recent developments in the design of specific matrix metalloproteinase inhibitors aided by structural and computational studies. Curr Pharm Des 11:295–322CrossRefPubMed

19.

Pochetti G, Gavuzzo E, Campestre C, Agamennone M, Tortorella P, Consalvi V, Gallina C, Hiller O, Tschesche H, Tucker PA, Mazza F (2006) Structural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates. J Med Chem 49:923–931CrossRefPubMed

20.

Biasone A, Tortorella P, Campestre C, Agamennone M, Preziuso S, Chiappini M, Nuti E, Carelli P, Rossello A, Mazza F, Gallina C (2007) Alpha-biphenylsulfonylamino 2-methylpropyl phosphonates: enantioselective synthesis and selective inhibition of MMPs. Bioorg Med Chem 15:791–799CrossRefPubMed

21.

Rubino MT, Agamennone M, Campestre C, Campiglia P, Cremasco V, Faccio R, Laghezza A, Loiodice F, Maggi D, Panza E, Rossello A, Tortorella P (2011) Biphenyl sulfonylamino methyl bisphosphonic acids as inhibitors of matrix metalloproteinases and bone resorption. Chem Med Chem 6:1258–1268CrossRefPubMed

22.

Tauro M, Loiodice F, Ceruso M, Supuran CT, Tortorella P (2014) Dual carbonic anhydrase/matrix metalloproteinase inhibitors incorporating bisphosphonic acid moieties targeting bone tumors. Bmcl 24:2617–2620

23.

Tauro M, Laghezza A, Loiodice F, Agamennone M, Campestre C, Tortorella P (2013) Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors. Bioorg Med Chem 21:6456–6465CrossRefPubMed

24.

Sawatari Y, Marx RE (2007) Bisphosphonates and bisphosphonate induced osteonecrosis. Oral Maxillofac Surg Clin North Am 19:487–498CrossRefPubMed

25.

Cheng XC, Wang Q, Fang H, Xu WF (2008) Role of sulfonamide group in matrix metalloproteinase inhibitors. Curr Med Chem 15:368–373CrossRefPubMed

26.

Jain P, Saravanan C, Singh SK (2013) Sulphonamides: deserving class as MMP inhibitors? Eur J Med Chem 60:89–100CrossRefPubMed

27.

Kraft-Neumärker M, Lorenz K, Koch R, Hoffmann T, Mäntylä P, Sorsa T, Netuschil L (2012) Full-mouth profile of active MMP-8 in periodontitis patients. J Periodontal Res 47:121–128CrossRefPubMed

28.

Conway JG, Trexler SJ, Wakefield JA, Marron BE, Emerson DL, Bickett DM, et al. (1996) Effect of matrix metalloproteinase inhibitors on tumor growth and spontaneous metastasis. Clin Exp Metastasis 14:115–124CrossRefPubMed

29.

Jotwani R, Eswaran SV, Moonga S, Cutler CW (2010) MMP-9/TIMP-1 imbalance induced in human dendritic cells by Porphyromonas gingivalis. FEMS Immunol Med Microbiol 58:314–321CrossRefPubMedPubMedCentral

30.

Basi DL, Hughes PJ, Thumbigere-Math V, Sabino M, Mariash A, Lunos SA, Jensen E, Gopalakrishnan R (2011) Matrix metalloproteinase-9 expression in alveolar extraction sockets of zoledronic acid-treated rats. J Oral Maxillofac Surg 69:2698–2707CrossRefPubMed

31.

Surazyński A, Sienkiewicz P, Wołczyński S, Pałka J (2005) Differential effects of echistatin and thrombin on collagen production and prolidase activity in human dermal fibroblasts and their possible implication in beta1-integrinmediatedsignaling. Pharmacol Res 51:217–221CrossRefPubMed

32.

Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687CrossRefPubMed

33.

Dickeson SK, Mathis NL, Rahman M, Bergelson JM, Santoro SA (1999) Determinants of ligand binding specificity of the alpha(1)beta(1) and alpha(2)beta(1) integrins. J Biol Chem 274:32182–32191CrossRefPubMed

34.

Pivodova V, Frankova J, Ulrichova J (2011) Osteoblast and gingival fibroblast markers in dental implant studies. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 155:109–116CrossRefPubMed

35.

Liu S, Leask A (2013) Integrin β1 is required for dermal homeostasis. J Invest Dermatol 133:899–906CrossRefPubMed

36.

Oizumi T, Funayama H, Yamaguchi K, Yokoyama M, Takahashi H, Yamamoto M, Kuroishi T, Kumamoto H, Sasaki K, Kawamura H, Sugawara S, Endo Y (2010) Inhibition of necrotic actions of nitrogen-containing bisphosphonates (NBPs) and their elimination from bone by etidronate (a non-NBP): a proposal for possible utilization of etidronate as a substitution drug for NBPs. J Oral Maxillofac Surg 68:1043–1054CrossRefPubMed

37.

Deng X, Yu Z, Funayama H, Yamaguchi K, Sasano T, Sugawara S, Endo Y (2007) Histidine decarboxylase-stimulating and inflammatory effects of alendronate in mice: involvement of mevalonate pathway, TNF, macrophages, and T-cells. Int Immunopharmacol 7:152–161CrossRefPubMed

Title: In vitro comparison of new bisphosphonic acids and zoledronate effects on human gingival fibroblasts viability, inflammation and matrix turnover
Authors: Marianna De Colli
Paolo Tortorella
Guya Diletta Marconi
Mariangela Agamennone
Cristina Campestre
Marilena Tauro
Amelia Cataldi
Susi Zara
Publication date: 01-11-2016
Publisher: Springer Berlin Heidelberg
Published in: Clinical Oral Investigations / Issue 8/2016
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI: https://doi.org/10.1007/s00784-015-1690-2

At a glance: The STEP trials

Springer Medicine

In vitro comparison of new bisphosphonic acids and zoledronate effects on human gingival fibroblasts viability, inflammation and matrix turnover

Abstract

Objectives

Materials and methods

Results

Conclusions

Clinical Relevance

At a glance: The STEP trials

Springer Medicine

Abstract

Objectives

Materials and methods

Results

Conclusions

Clinical Relevance

Please log in to get access to this content

Other articles of this Issue 8/2016

Effect of ultrasonic tip and root-end filling material on bond strength

Assessment of postoperative pain after reciprocating or rotary NiTi instrumentation of root canals: a randomized, controlled clinical trial

Stain removal effect of novel papain- and bromelain-containing gels applied to enamel

Influence of ultrasonic and sonic activation of epoxy-amine resin-based sealer on penetration of sealer into lateral canals

An ex vivo comparison of working length determination by three electronic root canal length measurement devices integrated into endodontic rotary motors

Influence of metabolic-linked early life factors on the eruption timing of the first primary tooth