Ciprofloxacin reduces tenocyte viability and proteoglycan synthesis in short-term explant cultures of equine tendon.
Abstract: Fluoroquinolones are an effective, broad-spectrum antibiotic used to treat an array of bacterial infections. However, they are associated with an increased risk of tendinopathy and tendon rupture even after discontinuation of treatment. This condition is known as fluoroquinolone-associated tendinopathy, the underlying mechanisms of which are poorly understood. While many factors may be involved in the pathophysiology of tendinopathies in general, changes in tenocyte metabolism and viability, as well as alteration of proteoglycan metabolism are prominent findings in the scientific literature. This study investigated the effects of ciprofloxacin, a common fluoroquinolone, on cell viability, proteoglycan synthesis, and proteoglycan RNA expression in equine superficial digital flexor tendon explants after 96 h treatment with between 1-300 µg/mL ciprofloxacin, and again after 8 days discontinuation of treatment. Ciprofloxacin caused significant reductions in cell viability by between 25-33% at all dosages except 10 µg/mL, and viability decreased further after 8 days discontinuation of treatment. Proteoglycan synthesis significantly decreased by approximately 50% in explants treated with 100 µg/mL and 300 µg/mL, however this effect reversed after 8 days in the absence of treatment. No significant RNA expression changes were observed after the treatment period with the exception of versican which was down-regulated at the highest concentration of ciprofloxacin. After the recovery period, aggrecan, biglycan and versican genes were all significantly downregulated in explants initially treated with 1-100 µg/mL. Results from this study corroborate previously reported findings of reduced cell viability and proteoglycan synthesis in a whole tissue explant model and provide further insight into the mechanisms underlying fluoroquinolone-associated tendinopathy and rupture. This study further demonstrates that certain ciprofloxacin induced cellular changes are not rapidly reversed upon cessation of treatment which is a novel finding in the literature.
© 2021 James et al.
Publication Date: 2021-08-30 PubMed ID: 34540363PubMed Central: PMC8411937DOI: 10.7717/peerj.12003Google Scholar: Lookup
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- Journal Article
Summary
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The research article discusses the effects of the antibiotic ciprofloxacin on equine tenocytes, specifically its impact on cell viability and proteoglycan synthesis. The study shows that ciprofloxacin significantly reduces cell viability and proteoglycan synthesis, and that these effects persist even after discontinuation of treatment.
Background
- The study builds upon scientific literature that associates fluoroquinolone antibiotics with an increased risk of tendinopathy and tendon rupture.
- Equine tendon cells, or tenocytes, are used as a model for studying the adverse effects of ciprofloxacin, a common fluoroquinolone.
Methodology
- Researchers studied the effects of ciprofloxacin on equine superficial digital flexor tendon explants with a dosage ranging between 1-300 µg/mL.
- The impact of the antibiotic on cell viability, proteoglycan synthesis, and proteoglycan RNA expression was studied immediately after the 96-hour treatment period and then again after 8 days of discontinuation of treatment.
Findings
- Ciprofloxacin was found to cause significant reductions in cell viability across all dosages except at 10 µg/mL. The viability further declined after the discontinuation of treatment.
- Explants treated with 100 µg/mL and 300 µg/mL of ciprofloxacin showed about a 50% drop in proteoglycan synthesis. This effect was, however, reversed after 8 days of non-treatment.
- There were no significant changes in RNA expression after treatment, except for the down-regulation of versican at the highest concentration of ciprofloxacin.
- After the recovery period, the aggrecan, biglycan, and versican genes showed significant downregulation in explants initially treated with 1-100 µg/mL ciprofloxacin.
Conclusion
- The findings of the study affirm the previous conclusions on ciprofloxacin’s side effects on tendons, giving further insights into the mechanisms of fluoroquinolone-associated tendinopathy and rupture.
- The study highlighted an important finding that certain cellular changes induced by ciprofloxacin did not reverse quickly after discontinuing the treatment.
Cite This Article
APA
James S, Schuijers J, Daffy J, Cook J, Samiric T.
(2021).
Ciprofloxacin reduces tenocyte viability and proteoglycan synthesis in short-term explant cultures of equine tendon.
PeerJ, 9, e12003.
https://doi.org/10.7717/peerj.12003 Publication
Researcher Affiliations
- Department of Physiology, Anatomy, and Microbiology, La Trobe University, Melbourne, Victoria, Australia.
- Department of Physiology, Anatomy, and Microbiology, La Trobe University, Melbourne, Victoria, Australia.
- Department of Infectious Diseases, St. Vincent's Hospital, Melbourne, Victoria, Australia.
- Sports and Exercise Medicine Research Centre, La Trobe University, Melbourne, Victoria, Australia.
- Department of Physiology, Anatomy, and Microbiology, La Trobe University, Melbourne, Victoria, Australia.
Conflict of Interest Statement
The authors declare that they have no competing interests.
References
This article includes 43 references
- Alves C, Mendes D, Marques FB. Fluoroquinolones and the risk of tendon injury: a systematic review and meta-analysis.. Eur J Clin Pharmacol 2019 Oct;75(10):1431-1443.
- Arnoczky SP, Tian T, Lavagnino M, Gardner K. Ex vivo static tensile loading inhibits MMP-1 expression in rat tail tendon cells through a cytoskeletally based mechanotransduction mechanism.. J Orthop Res 2004 Mar;22(2):328-33.
- Badal S, Her YF, Maher LJ 3rd. Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells.. J Biol Chem 2015 Sep 4;290(36):22287-97.
- Bank RA, TeKoppele JM, Oostingh G, Hazleman BL, Riley GP. Lysylhydroxylation and non-reducible crosslinking of human supraspinatus tendon collagen: changes with age and in chronic rotator cuff tendinitis.. Ann Rheum Dis 1999 Jan;58(1):35-41.
- Bendele AM, Hulman JF, Harvey AK, Hrubey PS, Chandrasekhar S. Passive role of articular chondrocytes in quinolone-induced arthropathy in guinea pigs.. Toxicol Pathol 1990;18(2):304-12.
- Beresford JN, Fedarko NS, Fisher LW, Midura RJ, Yanagishita M, Termine JD, Robey PG. Analysis of the proteoglycans synthesized by human bone cells in vitro.. J Biol Chem 1987 Dec 15;262(35):17164-72.
- Bernard-Beaubois K, Hecquet C, Hayem G, Rat P, Adolphe M. In vitro study of cytotoxicity of quinolones on rabbit tenocytes.. Cell Biol Toxicol 1998 Aug;14(4):283-92.
- Burkhardt JE, Hill MA, Carlton WW, Kesterson JW. Histologic and histochemical changes in articular cartilages of immature beagle dogs dosed with difloxacin, a fluoroquinolone.. Vet Pathol 1990 May;27(3):162-70.
- Burkhardt JE, Hill MA, Lamar CH, Smith GN Jr, Carlton WW. Effects of difloxacin on the metabolism of glycosaminoglycans and collagen in organ cultures of articular cartilage.. Fundam Appl Toxicol 1993 Feb;20(2):257-63.
- Cook JL, Rio E, Purdam CR, Docking SI. Revisiting the continuum model of tendon pathology: what is its merit in clinical practice and research?. Br J Sports Med 2016 Oct;50(19):1187-91.
- Corrao G, Zambon A, Bertù L, Mauri A, Paleari V, Rossi C, Venegoni M. Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study.. Drug Saf 2006;29(10):889-96.
- Csordás G, Santra M, Reed CC, Eichstetter I, McQuillan DJ, Gross D, Nugent MA, Hajnóczky G, Iozzo RV. Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo.. J Biol Chem 2000 Oct 20;275(42):32879-87.
- Danielson KG, Baribault H, Holmes DF, Graham H, Kadler KE, Iozzo RV. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility.. J Cell Biol 1997 Feb 10;136(3):729-43.
- Egerbacher M, Edinger J, Tschulenk W. Effects of enrofloxacin and ciprofloxacin hydrochloride on canine and equine chondrocytes in culture.. Am J Vet Res 2001 May;62(5):704-8.
- Farndale RW, Buttle DJ, Barrett AJ. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue.. Biochim Biophys Acta 1986 Sep 4;883(2):173-7.
- Fernández-Cuadros ME, Casique-Bocanegra LO, Albaladejo-Florín MJ, Gómez-Dueñas S, Ramos-Gonzalez C, Pérez-Moro OS. Bilateral Levofloxacin-Induced Achilles Tendon Rupture: An Uncommon Case Report and Review of the Literature.. Clin Med Insights Arthritis Musculoskelet Disord 2019;12:1179544119835222.
- Gillet P, Hestin D, Renoult E, Netter P, Kessler M. Fluoroquinolone-induced tenosynovitis of the wrist mimicking de Quervain's disease.. Br J Rheumatol 1995 Jun;34(6):583-4.
- Harrell RM. Fluoroquinolone-induced tendinopathy: what do we know?. South Med J 1999 Jun;92(6):622-5.
- Juras V, Winhofer Y, Szomolanyi P, Vosshenrich J, Hager B, Wolf P, Weber M, Luger A, Trattnig S. Multiparametric MR Imaging Depicts Glycosaminoglycan Change in the Achilles Tendon during Ciprofloxacin Administration in Healthy Men: Initial Observation.. Radiology 2015 Jun;275(3):763-71.
- Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical review of the literature.. Clin Infect Dis 2003 Jun 1;36(11):1404-10.
- Lawrence JW, Claire DC, Weissig V, Rowe TC. Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells.. Mol Pharmacol 1996 Nov;50(5):1178-88.
- Lewis T, Cook J. Fluoroquinolones and tendinopathy: a guide for athletes and sports clinicians and a systematic review of the literature.. J Athl Train 2014 May-Jun;49(3):422-7.
- Lim S, Hossain MA, Park J, Choi SH, Kim G. The effects of enrofloxacin on canine tendon cells and chondrocytes proliferation in vitro.. Vet Res Commun 2008 Mar;32(3):243-53.
- Lowes DA, Wallace C, Murphy MP, Webster NR, Galley HF. The mitochondria targeted antioxidant MitoQ protects against fluoroquinolone-induced oxidative stress and mitochondrial membrane damage in human Achilles tendon cells.. Free Radic Res 2009 Apr;43(4):323-8.
- Maffulli N, Sharma P, Luscombe KL. Achilles tendinopathy: aetiology and management.. J R Soc Med 2004 Oct;97(10):472-6.
- Pouzaud F, Bernard-Beaubois K, Thevenin M, Warnet JM, Hayem G, Rat P. In vitro discrimination of fluoroquinolones toxicity on tendon cells: involvement of oxidative stress.. J Pharmacol Exp Ther 2004 Jan;308(1):394-402.
- Ribard P, Audisio F, Kahn MF, De Bandt M, Jorgensen C, Hayem G, Meyer O, Palazzo E. Seven Achilles tendinitis including 3 complicated by rupture during fluoroquinolone therapy.. J Rheumatol 1992 Sep;19(9):1479-81.
- Riley G. Tendinopathy--from basic science to treatment.. Nat Clin Pract Rheumatol 2008 Feb;4(2):82-9.
- Ruoslahti E, Yamaguchi Y. Proteoglycans as modulators of growth factor activities.. Cell 1991 Mar 8;64(5):867-9.
- Ruoslahti E, Yamaguchi Y, Hildebrand A, Border WA. Extracellular matrix/growth factor interactions.. Cold Spring Harb Symp Quant Biol 1992;57:309-15.
- Samiric T, Ilic MZ, Handley CJ. Characterisation of proteoglycans and their catabolic products in tendon and explant cultures of tendon.. Matrix Biol 2004 May;23(2):127-40.
- Sendzik J, Shakibaei M, Schäfer-Korting M, Stahlmann R. Fluoroquinolones cause changes in extracellular matrix, signalling proteins, metalloproteinases and caspase-3 in cultured human tendon cells.. Toxicology 2005 Aug 15;212(1):24-36.
- Simonin MA, Gegout-Pottie P, Minn A, Gillet P, Netter P, Terlain B. Pefloxacin-induced achilles tendon toxicity in rodents: biochemical changes in proteoglycan synthesis and oxidative damage to collagen.. Antimicrob Agents Chemother 2000 Apr;44(4):867-72.
- Stahlmann R, Förster C, Shakibaei M, Vormann J, Günther T, Merker HJ. Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy.. Antimicrob Agents Chemother 1995 Sep;39(9):2013-8.
- Tsai WC, Hsu CC, Chen CP, Chang HN, Wong AM, Lin MS, Pang JH. Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type I collagen.. J Orthop Res 2011 Jan;29(1):67-73.
- Vogel KG, Hernandez DJ. The effects of transforming growth factor-beta and serum on proteoglycan synthesis by tendon fibrocartilage.. Eur J Cell Biol 1992 Dec;59(2):304-13.
- Williams RJ 3rd, Attia E, Wickiewicz TL, Hannafin JA. The effect of ciprofloxacin on tendon, paratenon, and capsular fibroblast metabolism.. Am J Sports Med 2000 May-Jun;28(3):364-9.
- Wilton LV, Pearce GL, Mann RD. A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies.. Br J Clin Pharmacol 1996 Apr;41(4):277-84.
- Yoon JH, Brooks RL Jr, Khan A, Pan H, Bryan J, Zhang J, Budsberg SC, Mueller PO, Halper J. The effect of enrofloxacin on cell proliferation and proteoglycans in horse tendon cells.. Cell Biol Toxicol 2004 Feb;20(1):41-54.
- Yoon JH, Brooks RL Jr, Zhao JZ, Isaacs D, Halper J. The effects of enrofloxacin on decorin and glycosaminoglycans in avian tendon cell cultures.. Arch Toxicol 2004 Oct;78(10):599-608.
- Yoshida K, Yabe K, Nishida S, Yamamoto N, Ohshima C, Sekiguchi M, Yamada K, Furuhama K. Pharmacokinetic disposition and arthropathic potential of oral ofloxacin in dogs.. J Vet Pharmacol Ther 1998 Apr;21(2):128-32.
- Zhanel GG, Noreddin AM. Pharmacokinetics and pharmacodynamics of the new fluoroquinolones: focus on respiratory infections.. Curr Opin Pharmacol 2001 Oct;1(5):459-63.
- Zhanel GG, Walters M, Laing N, Hoban DJ. In vitro pharmacodynamic modelling simulating free serum concentrations of fluoroquinolones against multidrug-resistant Streptococcus pneumoniae.. J Antimicrob Chemother 2001 Apr;47(4):435-40.
Citations
This article has been cited 2 times.- James S, Daffy J, Cook J, Samiric T. Short-Term Exposure to Ciprofloxacin Reduces Proteoglycan Loss in Tendon Explants.. Genes (Basel) 2022 Nov 25;13(12).
- Al-Neklawy AF, El-Nefiawy NE, Rady HY. Does oral ciprofloxacin affect the structure of thoracic aorta in adult and senile male albino rats? A clue to fluoroquinolones-induced risk of aortic dissection.. Anat Cell Biol 2022 Mar 31;55(1):79-91.
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