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

Abstract

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 Sproducing 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.

Intraarticular Administration Effect of Hydrogen Sulfide on an In Vivo Rat Model of Osteoarthritis

“…We observed that intraarticular GYY-4137 administration protected cartilage against deterioration induced by the OA model. Previous studies support these findings [ 26 , 28 , 34 ]. For instance, the intra-articular injection of sodium hydrosulfide (NaSH), a fast-releasing H 2 S donor, slowed the development of degenerative changes in the articular cartilage in a model of gonarthrosis [ 26 ].…”

“…A growing number of findings suggest that impaired H 2 S biosynthesis in the joint might be a contributing factor to OA [ 24 , 34 ]. We recently observed that OA cartilage shows reduced levels of the mitochondrial enzyme 3-Mercaptopyruvate sulfurtransferase (3-MPST) that could be responsible for the diminished H 2 S levels in this tissue [ 24 ].…”

“…We recently observed that OA cartilage shows reduced levels of the mitochondrial enzyme 3-Mercaptopyruvate sulfurtransferase (3-MPST) that could be responsible for the diminished H 2 S levels in this tissue [ 24 ]. Additionally, Nasi et al (2020) described that the oxidative stress decreases the 3-MPST expression in the chondrocyte and in turn may reinforce the impairment of H 2 S biosynthesis in the OA joint [ 34 ]. Thus, in the current study the increment in oxidative stress after the surgical destabilization of the joint could be underlying a reduction in the H 2 S levels.…”

“…For instance, the intra-articular injection of sodium hydrosulfide (NaSH), a fast-releasing H 2 S donor, slowed the development of degenerative changes in the articular cartilage in a model of gonarthrosis [ 26 ]. Likewise, cartilage damage as well as proteoglycan loss were exacerbated in 3-MST KO joints compared to WT joints in an experimental OA in mice [ 34 ]. By ex vivo and in vitro experimental approaches, a great number of studies also indicate the activation of H 2 S signaling as a protective pathway against cartilage break down.…”

H2S, Polysulfides, and Enzymes: Physiological and Pathological Aspects

“…Peleli et al [55] recently reported that MST-KO mice were protected against ischemic reperfusion of the heart. Nasi et al [56] reported that mice showed accelerated joint calcification and osteoarthritis due to an increase in chondrocyte mineralization. Interestingly, these two findings indicate that MST demonstrates both good and bad effects on living organisms.…”