TY - JOUR
T1 - Uremic Toxins and Ciprofloxacin Affect Human Tenocytes In Vitro
AU - Popowski, Erman
AU - Kohl, Benjamin
AU - Schneider, Tobias
AU - Jankowski, Joachim
AU - Schulze-Tanzil, Gundula
N1 - Funding Information:
Funding: J.J. was supported by grants from Deutsche Forschungsgemeinschaft (DFG) (SFB TRR 219; C-04, S-03). G.S.-T. was supported by DFG grant SCHU1979/14-1.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/6/2
Y1 - 2020/6/2
N2 - Tendinopathy is a rare but serious complication of quinolone therapy. Risk factors associated with quinolone-induced tendon disorders include chronic kidney disease accompanied by the accumulation of uremic toxins. Hence, the present study explored the effects of the representative uremic toxins phenylacetic acid (PAA) and quinolinic acid (QA), both alone and in combination with ciprofloxacin (CPX), on human tenocytes in vitro. Tenocytes incubated with uremic toxins +/-CPX were investigated for metabolic activity, vitality, expression of the dominant extracellular tendon matrix (ECM) protein type I collagen, cell-matrix receptor β1-integrin, proinflammatory interleukin (IL)-1β, and the ECM-degrading enzyme matrix metalloproteinase (MMP)-1. CPX, when administered at high concentrations (100 mM), suppressed tenocyte metabolism after 8 h exposure and at therapeutic concentrations after 72 h exposure. PAA reduced tenocyte metabolism only after 72 h exposure to very high doses and when combined with CPX. QA, when administered alone, led to scarcely any cytotoxic effect. Combinations of CPX with PAA or QA did not cause greater cytotoxicity than incubation with CPX alone. Gene expression of the pro-inflammatory cytokine IL-1β was reduced by CPX but up-regulated by PAA and QA. Protein levels of type I collagen decreased in response to high CPX doses, whereas PAA and QA did not affect its synthesis significantly. MMP-1 mRNA levels were increased by CPX. This effect became more pronounced in the form of a synergism following exposure to a combination of CPX and PAA. CPX was more tenotoxic than the uremic toxins PAA and QA, which showed only distinct suppressive effects.
AB - Tendinopathy is a rare but serious complication of quinolone therapy. Risk factors associated with quinolone-induced tendon disorders include chronic kidney disease accompanied by the accumulation of uremic toxins. Hence, the present study explored the effects of the representative uremic toxins phenylacetic acid (PAA) and quinolinic acid (QA), both alone and in combination with ciprofloxacin (CPX), on human tenocytes in vitro. Tenocytes incubated with uremic toxins +/-CPX were investigated for metabolic activity, vitality, expression of the dominant extracellular tendon matrix (ECM) protein type I collagen, cell-matrix receptor β1-integrin, proinflammatory interleukin (IL)-1β, and the ECM-degrading enzyme matrix metalloproteinase (MMP)-1. CPX, when administered at high concentrations (100 mM), suppressed tenocyte metabolism after 8 h exposure and at therapeutic concentrations after 72 h exposure. PAA reduced tenocyte metabolism only after 72 h exposure to very high doses and when combined with CPX. QA, when administered alone, led to scarcely any cytotoxic effect. Combinations of CPX with PAA or QA did not cause greater cytotoxicity than incubation with CPX alone. Gene expression of the pro-inflammatory cytokine IL-1β was reduced by CPX but up-regulated by PAA and QA. Protein levels of type I collagen decreased in response to high CPX doses, whereas PAA and QA did not affect its synthesis significantly. MMP-1 mRNA levels were increased by CPX. This effect became more pronounced in the form of a synergism following exposure to a combination of CPX and PAA. CPX was more tenotoxic than the uremic toxins PAA and QA, which showed only distinct suppressive effects.
KW - ciprofloxacin
KW - tenocytes
KW - uremic toxins
KW - phenylacetic acid
KW - quinolinic acid
KW - integrin
KW - interleukin-1beta
KW - matrix metalloproteinase-1
KW - QUADRICEPS TENDON-RUPTURE
KW - PHENYLACETIC ACID
KW - ACHILLES-TENDON
KW - BILATERAL QUADRICEPS
KW - INDUCED TENDINOPATHY
KW - QUINOLINIC ACID
KW - FLUOROQUINOLONE ANTIBIOTICS
KW - TRYPTOPHAN-METABOLISM
KW - CELL-PROLIFERATION
KW - HEMODIALYSIS
U2 - 10.3390/ijms21124241
DO - 10.3390/ijms21124241
M3 - Article
C2 - 32545914
SN - 1661-6596
VL - 21
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 12
M1 - 4241
ER -