Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin‐1β in human tendon‐derived cells

Abstract

Objective. To determine whether the fluoroquinolone antibiotic ciprofloxacin, which can cause tendon pain and rupture in a proportion of treated patients, affects the expression of matrix metalloproteinases (MMPs) in human tendon-derived cells in culture.Methods. Cell cultures were derived from 6 separate tendon explants, and were incubated in 6-well culture plates for 2 periods of 48 hours each, with ciprofloxacin (or DMSO in controls) and interleukin-1␤ (IL-1␤), alone and in combination. Samples of supernatant medium from the second 48-hour incubation were assayed for MMPs 1, 2, and 3 by Western blotting. RNA was extracted from the cells and assayed for MMP messenger RNA (mRNA) by semiquantitative reverse transcription-polymerase chain reaction, with normalization for GAPDH mRNA.Results. Unstimulated tendon cells expressed low or undetectable levels of MMP-1 and MMP-3, and substantial levels of MMP-2. IL-1␤ induced a substantial output of both MMP-1 and MMP-3 into cell supernatants, reflecting increases (typically 100-fold) in MMP mRNA, but had only minor effects on MMP-2 expression. Ciprofloxacin had no detectable effect on MMP output in unstimulated cells. Preincubation with ciprofloxacin potentiated IL-1␤-stimulated MMP-3 output, reflecting a similar effect on MMP-3 mRNA expression. Ciprofloxacin also potentiated IL-1␤-stimulated MMP-1 mRNA expression, but did not potentiate the output of MMP-1, and had no significant effects on MMP-2 mRNA expression or output.Conclusion. Ciprofloxacin can selectively enhance MMP expression in tendon-derived cells. Such effects might compromise tendon microstructure and integrity.

In Vitro Discrimination of Fluoroquinolones Toxicity on Tendon Cells: Involvement of Oxidative Stress

“…As suggested by Corps et al (2002), matrix metalloproteinases expression can be selectively activated by fluoroquinolones in tendon cells. Another study (Williams et al, 2000) showed that fluoroquinolones increased proteolytic activity.…”

Extracellular Matrix Molecules: Potential Targets in Pharmacotherapy

“…Furthermore, skeletal consequences (particularly increased risk of bone fractures in the appendicular skeleton in women with type 2 diabetes, caused by thiazolidinediones, an antidiabetic drug class) has been noticed (Grey, 2008). Statin and fluoroquinoloneinduced tendinopathies have mainly been attributed to the ability of these two drug classes to modulate the activity of specific MMPs in tendon cells (Corps et al, 2002(Corps et al, , 2005Pullatt et al, 2007). The side effects of thiazolidinediones on bones are thought to be mainly due to the proadipocytic and antiosteoblastogenic effects of these drugs on pluripotent mesenchymal stem cells (Lecka-Czernik et al, 2002;Shockley et al, 2009).…”

Tendinopathy and statin use: The role of matrix metalloproteinases or eicosanoids? Comment on the letter by Beri and Khattri and the article by Marie et al

“…Although Marie et al (2) had previously reported that statin-associated tendon toxicity might be due to 1) reduced cholesterol content of tendon cell membranes, making them unstable, or 2) reduced levels of regulatory proteins involved in the maintenance of tendon cells, Beri and Khattri (1) described that hydroxymethylglutaryl-coenzyme A blockers acting as matrix metalloproteinase (MMP) inhibitors are quite attractive, because it was reported that simvastatin inhibited MMP-9 secretion from human saphenous vein smooth muscle cells by inhibiting the RhoA/ROCK pathway (3). The possible role of MMPs in the statin-associated tendinopathy was first postulated by Pullatt et al (4), who speculated that the inhibition of MMP-9 and augmentation of tissue inhibitor of metalloproteinases 1 (TIMP-1) in macrophages by statins could impair tendon remodeling and contribute to tendinopathy.…”

“…We read with interest the letter by Beri and Khattri (1) and the article by Marie et al (2), published in recent issues of Arthritis Care & Research. Although Marie et al (2) had previously reported that statin-associated tendon toxicity might be due to 1) reduced cholesterol content of tendon cell membranes, making them unstable, or 2) reduced levels of regulatory proteins involved in the maintenance of tendon cells, Beri and Khattri (1) described that hydroxymethylglutaryl-coenzyme A blockers acting as matrix metalloproteinase (MMP) inhibitors are quite attractive, because it was reported that simvastatin inhibited MMP-9 secretion from human saphenous vein smooth muscle cells by inhibiting the RhoA/ROCK pathway (3).…”