Inducible hydrogen sulfide synthesis in chondrocytes and mesenchymal progenitor cells: is H2S a novel cytoprotective mediator in the inflamed joint?
Bottom Line: Oxidative stress-induced cell death was significantly inhibited by GYY4137 treatment but increased by pharmacological inhibition of H(2)S synthesis or by CBS/CSE-siRNA treatment.These data suggest CSE is an inducible source of H(2)S in cultured HACs and MPCs.H(2)S may represent a novel endogenous mechanism of cytoprotection in the inflamed joint, suggesting a potential opportunity for therapeutic intervention.
Affiliation: Peninsula Medical School, University of Exeter, St. Luke's Campus, Exeter, Devon, UK.Show MeSH
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Mentions: There is increasing evidence for perturbed mitochondrial function in inflammatory and degenerative joint disease [29,43,58] and that mitochondrial dysfunction may potentiate inflammation . Because SIN-1 , 4-HNE  and H2O2  have previously been shown to collapse mitochondrial DCm in human chondrocytes, we next investigated whether pharmacological H2S could protect mitochondria in situ from oxidative injury by examining mitochondrial DCm, mitochondrial ATP and cytoplasmic cytochrome c. In MPCs, inhibition of CSE (with PAG) or CBS (with AOAA) significantly increased the loss of mitochondrial DCm induced by SIN-1 (Fig. 8A), H2O2 and 4-HNE (Fig. 8B), whereas GYY4137 added at a final concentration of 200 μmol/l or 500 μmol/l significantly inhibited mitochondrial toxicity. In agreement with these observations, treatment of chondrocytes with CSE-siRNA or CBS-siRNA but not non-coding controls (see figure legend) similarly increased oxidative stress-induced collapse of mitochondrial DCm. In these additional experiments, GYY4137 (500 μmol/l) also inhibited SIN-1-, H2O2- and 4-HNE-induced mitochondrial toxicity in CSE-siRNA and CBS-siRNA-treated chondrocytes (Fig. 8C).
Affiliation: Peninsula Medical School, University of Exeter, St. Luke's Campus, Exeter, Devon, UK.