Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1beta in human tendon-derived cells. A potential mechanism of fluoroquinolone-induced tendinopathy.
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-1beta (IL-1beta), 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-1beta 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-1beta-stimulated MMP-3 output, reflecting a similar effect on MMP-3 mRNA expression. Ciprofloxacin also potentiated IL-1beta-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.


CONCLUSIONS
Ciprofloxacin can selectively enhance MMP expression in tendon-derived cells. Such effects might compromise tendon microstructure and integrity.
Corps
Anthony N
AN
Addenbrooke's Hospital, Cambridge, UK. Rheumatology Research Unit, Box 194, Unit E6, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. anc@mole.bio.cam.ac.uk
Harrall
Rebecca L
RL
Curry
Valerie A
VA
Fenwick
Steven A
SA
Hazleman
Brian L
BL
Riley
Graham P
GP
D000890:Anti-Infective Agents / Q000009:adverse effects; D002478:Cells, Cultured; D002939:Ciprofloxacin / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D009140:Musculoskeletal Diseases / Q000139:chemically induced; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013710:Tendons / Q000166:cytology*
D000890:Anti-Infective Agents; D007375:Interleukin-1; D012333:RNA, Messenger; D002939:Ciprofloxacin; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1