Abstract
BackgroundOsteoarthritis (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 (H2S) has been implicated in mineralization but has never been studied in OA. Here, we investigated the role of the H2S-producing enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) in cartilage calcification and OA development.Methods3-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.Results3-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.Conclusion3-MST-generated H2S protects against joint calcification and experimental OA. Enhancing H2S production in chondrocytes may represent a potential disease modifier to treat OA.
Highlights
Osteoarthritis (OA) is characterized by the formation and deposition of calcium-containing crystals in joint tissues, but the underlying mechanisms are poorly understood
Calcium-containing crystals within joint structures are another prominent features of OA, and they participate in its initiation and progression
Another evidence was that in knee cartilage from both MNX mice (Fig. 2a) and OA patients (Fig. 1b) we found an inverse correlation between 3-mercaptopyruvate sulfurtransferase (3-MST) expression, and the extent of calcification as well as OA severity
Summary
Osteoarthritis (OA) is characterized by the formation and deposition of calcium-containing crystals in joint tissues, but the underlying mechanisms are poorly understood. Osteoarthritis (OA) is the most common joint disease affecting millions of people [1] It is characterized by cartilage degradation, subchondral bone sclerosis and synovitis [2]. Calcium-containing crystals within joint structures are another prominent features of OA, and they participate in its initiation and progression. These crystals were found in 50% up to 100% of synovial fluid [3] and cartilage [4] from OA patients undergoing joint replacement. We observed BCP calcific deposits in joints following meniscectomy. We hypothesize that inhibiting crystal formation and deposition in the joint could be of therapeutic value for OA treatment
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