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Background  Osteoarthritis (OA) is characterized by the formation and deposition of calcium-containing crystals in joint tissues, but the underlying mechanisms are poorly understood. The gasotransmitter hydrogen sulfide (H 2 S) has been implicated in mineralization but has never been studied in OA. Here, we investigated the role of the H 2 S-producing enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) in cartilage calcification and OA development.    Methods  3-MST expression was analyzed in cartilage from patients with different OA degrees, and in cartilage stimulated with hydroxyapatite (HA) crystals. The modulation of 3-MST expression in vivo was studied in the meniscectomy (MNX) model of murine OA, by comparing sham-operated to MNX knee cartilage. The role of 3-MST was investigated by quantifying joint calcification and cartilage degradation in WT and 3-MST −/−  meniscectomized knees. Chondrocyte mineralization in vitro was measured in WT and 3-MST −/−  cells. Finally, the effect of oxidative stress on 3-MST expression and chondrocyte mineralization was investigated.    Results  3-MST expression in human cartilage negatively correlated with calcification and OA severity, and diminished upon HA stimulation. In accordance, cartilage from menisectomized OA knees revealed decreased 3-MST if compared to sham-operated healthy knees. Moreover, 3-MST −/−  mice showed exacerbated joint calcification and OA severity if compared to WT mice. In vitro ,  genetic or pharmacologic inhibition of 3-MST in chondrocytes resulted in enhanced mineralization and IL-6 secretion. Finally, oxidative stress decreased 3-MST expression and increased chondrocyte mineralization, maybe via induction of pro-mineralizing genes.    Conclusion  3-MST-generated H 2 S protects against joint calcification and experimental OA. Enhancing H 2 S production in chondrocytes may represent a potential disease modifier to treat OA.

The protective role of the 3-mercaptopyruvate sulfurtransferase (3-MST)-hydrogen sulfide (H2S) pathway against experimental osteoarthritis