Effects of fluoroquinolones and glucocorticoids on cultivated tendon cells in vitro

doi:10.1016/S0887-2333(96)00050-1

Toxicology in Vitro

Volume 10, Issue 6, December 1996, Pages 743-754

https://doi.org/10.1016/S0887-2333(96)00050-1 Get rights and content

Abstract

Achilles tendon rupture is known to occur after administration of various drugs to patients. It is also reported to occur after treatment with fluoroquinolone and glucocorticoids. To study potential cytotoxic effects of fluoroquinolones (ciprofloxacin, pefloxacin, sparfloxacin) and triamcinolonacetonide on tendons an in vitro model of cultivated tendon cells (human, dog, mini-pig, rat, marmoset) was established. The cells were characterized by their morphological appearance and by the synthesis of proteoglycans and collagen type I. The cytotoxicity of the tested drugs was determined by measurement of mitochondrial dehydrogenase activity (MTT assay) and other parameters (viability, proteoglycan content, proliferation). These investigations revealed the following: (1) no marked differences were found between various species after ciprofloxacin treatment, only rat tendon cells reacted slightly less sensitively at the highest concentration (100 μg/ml); (2) no age-dependent effects of ciprofloxacin and triamcinolonacetonide were found in cultivated human tendon cells from patients of different ages; (3) the simultaneous administration of fluoroquinolones and triamcinolonacetonide resulted in a significantly greater reduction of cell viability than when they were administered alone. This could indicate that the combined administration of fluoroquinolones and glucocorticoids can favour the occurrence of tendon rupture.

Reference (58)

AcarJ.F. et al.
The clinical problems of bacterial resistance to the new quinolones
Antimicrobial Chemotherapy
(1990)
AndrioleV.T.
Use of quinolones in treatment of prostatis and lower urinary tract infections
European Journal of Clinical Microbiology and Infectious Diseases
(1991)
AubierM. et al.
Treatment of suspected pneumococcal community-acquired pneumonia
BalasubramaniamP. et al.
The effect of injection of hydrocortisone into rabbit calcaneal tendons
Journal of Bone and Joint Surgery
(1972)
BaumgartenH.
ELISA zum Nachweis von Antigenen fixirter Zellen (Zell-ELISA)
BonmarchandG. et al.
Penetration of pefloxacin into bronchial secretions
Antimicrobial Agents and Chemotherapy
(1989)
BurkhardtJ.E. et al.
Histologic and histochemical changes in articular cartilages of immature beagle dogs dosed with difloxacin, a fluoroquinolone
Veterinary Pathology
(1990)
CampoR.D.
Effects of cations on cartilage structure: swelling of growth plate and degradation of proteoglycans induced by chelators of divalent cations
Calcified Tissue International
(1988)
CarmichaelJ. et al.
Chemosensitivity testing of human lung cancer cell lines using the MTT assay
British Journal of Cancer
(1985)
CarneyS.L. et al.
The structure and function of cartilage proteoglycans
Physiological Reviews
(1988)

ChaslerieA. et al.

Ruptures tendineuses et fluoroquinolones: un effet indésirable de classe

Revue du Rhumatisme et des Maladies Osteo-Articulaires

(1992)

ChevalierX. et al.

A case of destructive polyarthropathy in a 17-year-old youth following pefloxacin treatment

Drug Safety

(1992)

ChristW. et al.

Specific toxicologic aspects of the quinolones

Reviews of Infectious Disease

(1988)

CouchmanJ.R. et al.

Mapping by monoclonal antibody detection of glycosaminoglycans in connective tissue

Nature

(1984)

DehmP. et al.

Synthesis and extrusion of collagen by freshly isolated cells from chick embryo tendon

Biochimica et Biophysica Acta

(1971)

DrlicaK. et al.

Mode of action of quinolones: biochemical aspects

GachetC. et al.

α_libβ₃Integrin dissociation induced by EDTA results in morphological changes of the platelet surface-connected canalicular system with differential location of the two separate subunits

Journal of Cell Biology

(1993)

GaugerA. et al.

A low-serum medium for tendon cells: effects of growth factors on tendon cell growth and collagen production

In Vitro Cellular and Developmental Biology

(1985)

GoughA.W. et al.

Quinolone arthropathy—acute toxicity to immature articular cartilage

Toxicologic Pathology

(1992)

HaynesworthS.E. et al.

Comparison of the cartilage proteoglycan core protein synthesized by chondrocytes of different ages

Connective Tissue Research

(1991)

HildebrandH. et al.

Chondrotoxicity of quinolones in vivo and in vitro

Archives of Toxicology

(1993)

HirataC.A. et al.

Steady-state pharmacokinetics of intravenous and oral ciprofloxacin in elderly patients

Antimicrobial Agents and Chemotherapy

(1989)

HustonK.A.

Achilles tendinitis and tendon rupture due to fluoroquinolone antibiotics

New England Journal of Medicine

(1994)

JorgensenC. et al.

Arthropathies et tendinopathie Achilléenne induites par la pefloxacine

Revue du Rhumatisme

(1991)

JozsaL. et al.

Amianthoid Fibres in Ruptured Human Tendons

Pathology, Research and Practice

(1993)

KaoW.W.-Y. et al.

Kinetics for the secretion of procollagen by fresh isolated tendon cells

Journal of Biological Chemistry

(1977)

KarpmanR.R. et al.

Tendon rupture following local steroid injection

Post-graduate Medicine

(1980)

KennedyJ.C. et al.

The effects of local steroid injection on tendon: a biomechanical and microscopic correlative study

American Journal of Sports Medicine

(1976)

KoegerA.-C. et al.

Tendon complications during treatment with fluoroquinolones evaluated by MR imaging

Arthritis Rheumatism

(1993)

Cited by (18)

The risks and benefits of glucocorticoid treatment for tendinopathy: A systematic review of the effects of local glucocorticoid on tendon
2014, Seminars in Arthritis and Rheumatism
Our primary objective was to summarise the known effects of locally administered glucocorticoid on tendon tissue and tendon cells.
We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. The search yielded 50 articles, which consisted of 13 human studies, 36 animal studies and one combined human/animal study.
Histologically, there was a loss of collagen organisation (6 studies) and an increase in collagen necrosis (3 studies). The proliferation (8 studies) and viability (9 studies) of fibroblasts was reduced. Collagen synthesis was decreased in 17 studies. An increased inflammatory cell infiltrate was shown in 4 studies. Increased cellular toxicity was demonstrated by 3 studies.
The mechanical properties of tendon were investigated by 18 studies. Descriptively, 6 of these studies showed a decrease in mechanical properties, 3 showed an increase, while the remaining 9 showed no significant change. A meta-analysis of the mechanical data revealed a significant deterioration in mechanical properties, with an overall effect size of −0.67 (95% CI = 0.01 to −1.33) (data from 9 studies).
Overall it is clear that the local administration of glucocorticoid has significant negative effects on tendon cells in vitro, including reduced cell viability, cell proliferation and collagen synthesis. There is increased collagen disorganisation and necrosis as shown by in vivo studies. The mechanical properties of tendon are also significantly reduced. This review supports the emerging clinical evidence that shows significant long-term harms to tendon tissue and cells associated with glucocorticoid injections.
Synergistic effects of dexamethasone and quinolones on human-derived tendon cells
2010, International Journal of Antimicrobial Agents
Citation Excerpt :
Data from in vivo and in vitro studies or clinical trials are scarce. An in vitro study with triamcinolone acetonide (100 μg/mL) combined with ciprofloxacin (100 μg/mL), pefloxacin or sparfloxacin showed enhanced cytotoxicity (mitochondrial dehydrogenase activity; MTT test) in comparison with incubation with the quinolone alone [48]. However, triamcinolone acetonide alone was more cytotoxic than ciprofloxacin in this model [48].
Quinolones and glucocorticoids are frequently used drugs that may cause tendinopathy as a rare adverse effect. We exposed human tenocyte cultures to the steroid dexamethasone alone or in combination with either ciprofloxacin or levofloxacin at concentrations of 3 mg/L and 10 mg/L. At concentrations corresponding to peak levels in plasma and tissues during therapy (ca. 3–10 mg/L), ciprofloxacin caused a significant decrease in collagen type I and the β₁-integrin receptor. In contrast, no corresponding effect was induced by 3 mg/L levofloxacin. With both quinolones at 3 mg/L and 10 mg/L, the amount of matrix metalloproteinase-1 (MMP-1) and MMP-13 was increased. In addition, 3 mg/L ciprofloxacin and 10 mg/L levofloxacin activated caspase-3. Apoptotic changes were confirmed by electron microscopy. Incubation of human tenocytes with dexamethasone decreased the main matrix protein collagen type I, the transmembrane β₁-integrin receptor and the cytoskeleton protein vinculin, but only at the high concentrations tested (0.1 μM or 10 μM). Concentrations of 0.1 μM and 10 μM dexamethasone increased the amount of MMPs and activated caspase-3 as an indicator of apoptosis. Combined exposure to quinolones and dexamethasone led to more pronounced effects in tenocyte cultures at most of the analysed endpoints. The clinical observations of an increased risk of quinolone-induced tendinopathy by glucocorticoids are supported by these in vitro data.
Age-dependent effects on redox status, oxidative stress, mitochondrial activity and toxicity induced by fluoroquinolones on primary cultures of rabbit tendon cells
2006, Comparative Biochemistry and Physiology - C Toxicology and Pharmacology
The age-related difference in fluoroquinolone-induced tendon toxicity was investigated.
In vitro tendon cells from juvenile and young adult rabbits, respectively, were incubated with quinolone (nalidixic acid, NA) or fluoroquinolone (ofloxacin, OFX or pefloxacin, PEF) at 0.01 μM to 1 mM for 72 h. Redox status, glutathione (GSH), reactive oxygen species (ROS), and mitochondrial activity were assessed using intracellular fluorescent probes. Fluorescence signal was detected on living adherent tenocytes in microplates using cold-light cytofluorometry. Tendon toxicity differed significantly between the two cell groups and the difference was greatest with highest dose (1 mM). For 72 h, significant (p < 0.001) differences between immature and young adult primary tenocytes were observed for redox status decrease, GSH decrease, and ROS production increase. Mitochondrial activity remained unaltered in immature tenocytes. We confirm two groups of intrinsic tendon toxicity (OFX/NA vs. PEF) associated to oxidative stress (GSH decrease). Our in vitro experimental model confirms the clinical observations of age dependent tenotoxicity. First group (NA, OFX) showed greater intrinsic tenotoxicity for young adult than immature tenocytes, second group (PEF) was highly toxic for immature and young adult cells. The three quinolones do not altered mitochondrial activity in immature tenocytes whereas alteration was observed in young adult tenocytes.
The Research Status, Potential Hazards and Toxicological Mechanisms of Fluoroquinolone Antibiotics in the Environment
2023, Antibiotics
The research status, potential hazards and toxicological mechanisms of fluoroquinolone antibiotics in the environment
2023, Research Square
Uremic toxins and ciprofloxacin affect human tenocytes in vitro
2020, International Journal of Molecular Sciences

View all citing articles on Scopus

View full text

Effects of fluoroquinolones and glucocorticoids on cultivated tendon cells in vitro

Abstract

The clinical problems of bacterial resistance to the new quinolones

Antimicrobial Chemotherapy

Use of quinolones in treatment of prostatis and lower urinary tract infections

European Journal of Clinical Microbiology and Infectious Diseases

Treatment of suspected pneumococcal community-acquired pneumonia

The effect of injection of hydrocortisone into rabbit calcaneal tendons

Journal of Bone and Joint Surgery

ELISA zum Nachweis von Antigenen fixirter Zellen (Zell-ELISA)

Penetration of pefloxacin into bronchial secretions

Antimicrobial Agents and Chemotherapy

Histologic and histochemical changes in articular cartilages of immature beagle dogs dosed with difloxacin, a fluoroquinolone

Veterinary Pathology

Effects of cations on cartilage structure: swelling of growth plate and degradation of proteoglycans induced by chelators of divalent cations

Calcified Tissue International

Chemosensitivity testing of human lung cancer cell lines using the MTT assay

British Journal of Cancer

The structure and function of cartilage proteoglycans

Physiological Reviews

Ruptures tendineuses et fluoroquinolones: un effet indésirable de classe

Revue du Rhumatisme et des Maladies Osteo-Articulaires

A case of destructive polyarthropathy in a 17-year-old youth following pefloxacin treatment

Drug Safety

Specific toxicologic aspects of the quinolones

Reviews of Infectious Disease

Mapping by monoclonal antibody detection of glycosaminoglycans in connective tissue

Nature

Synthesis and extrusion of collagen by freshly isolated cells from chick embryo tendon

Biochimica et Biophysica Acta

Mode of action of quinolones: biochemical aspects

αlibβ3Integrin dissociation induced by EDTA results in morphological changes of the platelet surface-connected canalicular system with differential location of the two separate subunits

Journal of Cell Biology

A low-serum medium for tendon cells: effects of growth factors on tendon cell growth and collagen production

In Vitro Cellular and Developmental Biology

Quinolone arthropathy—acute toxicity to immature articular cartilage

Toxicologic Pathology

Comparison of the cartilage proteoglycan core protein synthesized by chondrocytes of different ages

Connective Tissue Research

Chondrotoxicity of quinolones in vivo and in vitro

Archives of Toxicology

Steady-state pharmacokinetics of intravenous and oral ciprofloxacin in elderly patients

Antimicrobial Agents and Chemotherapy

Achilles tendinitis and tendon rupture due to fluoroquinolone antibiotics

New England Journal of Medicine

Arthropathies et tendinopathie Achilléenne induites par la pefloxacine

Revue du Rhumatisme

Amianthoid Fibres in Ruptured Human Tendons

Pathology, Research and Practice

Kinetics for the secretion of procollagen by fresh isolated tendon cells

Journal of Biological Chemistry

Tendon rupture following local steroid injection

Post-graduate Medicine

The effects of local steroid injection on tendon: a biomechanical and microscopic correlative study

American Journal of Sports Medicine

Tendon complications during treatment with fluoroquinolones evaluated by MR imaging

Arthritis Rheumatism

α_libβ₃Integrin dissociation induced by EDTA results in morphological changes of the platelet surface-connected canalicular system with differential location of the two separate subunits