Impairment of glyoxalase-1, an advanced glycation end-product detoxifying enzyme, induced by inflammation in age-related osteoarthritis.

ABSTRACT:

Background

Accumulation of advanced glycation end-products (AGEs) is involved in age-related osteoarthritis (OA). Glyoxalase (Glo)-1 is the main enzyme involved in the removal of AGE precursors, especially carboxymethyl-lysine (CML). We aimed to investigate the expression of several AGEs and Glo-1 in human OA cartilage and to study chondrocytic Glo-1 regulation by inflammation, mediated by interleukin (IL)-1?.

Methods

Ex vivo, we quantified AGEs (pentosidine, CML, methylglyoxal-hydroimidazolone-1) in knee cartilage from 30 OA patients. Explants were also incubated with and without IL-1?, and we assessed Glo-1 protein expression and enzymatic activity. In vitro, primary cultured murine chondrocytes were stimulated with increasing concentrations of IL-1? to assess Glo-1 enzymatic activity and expression. To investigate the role of oxidative stress in the IL-1? effect, cells were also treated with inhibitors of mitochondrial oxidative stress or nitric oxide synthase.

Results

Ex vivo, only the human cartilage CML content was correlated with patient age (r?=?0.78, p?=?0.0031). No statistically significant correlation was found between Glo-1 protein expression and enzymatic activity in human cartilage and patient age. We observed that cartilage explant stimulation with IL-1? decreased Glo-1 protein expression and enzymatic activity. In vitro, we observed a dose-dependent decrease in Glo-1 mRNA, protein quantity, and enzymatic activity in response to IL-1? in murine chondrocytes. Inhibitors of oxidative stress blunted this downregulation.

Conclusion

Glo-1 is impaired by inflammation mediated by IL-1? in chondrocytes through oxidative stress pathways and may explain age-dependent accumulation of the AGE CML in OA cartilage.

SUBMITTER: Trellu S 

PROVIDER: S-EPMC6330409 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature