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 (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. 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 H2S protects against joint calcification and experimental OA. Enhancing H2S production in chondrocytes may represent a potential disease modifier to treat OA.

中文翻译：

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3-巯基丙酮酸硫转移酶（3-MST）-硫化氢（H2S）途径对实验性骨关节炎的保护作用。

背景技术骨关节炎（OA）的特征在于关节组织中含钙晶体的形成和沉积，但是其潜在机制尚不清楚。气体递质硫化氢（H2S）与矿化有关，但从未在OA中进行过研究。在这里，我们调查了产生H2S的酶3-巯基丙酮酸硫转移酶（3-MST）在软骨钙化和OA发育中的作用。方法分析不同OA度患者的软骨和羟基磷灰石（HA）晶体刺激的软骨中3-MST的表达。通过比较假手术和MNX膝关节软骨，在小鼠OA的半月板切除（MNX）模型中研究了体内3-MST表达的调节。通过定量WT和3-MST-/-半月板切除的膝盖中的关节钙化和软骨降解来研究3-MST的作用。在WT和3-MST-/-细胞中测量了体外软骨细胞的矿化。最后，研究了氧化应激对3-MST表达和软骨细胞矿化的影响。结果人类软骨中的3-MST表达与钙化和OA严重程度呈负相关，并在HA刺激下减弱。因此，与假手术的健康膝盖相比，经半月板切除的OA膝关节的软骨显示3-MST降低。此外，与WT小鼠相比，3-MST-/-小鼠表现出加剧的关节钙化和OA严重程度。体外，遗传或药理抑制软骨细胞中3-MST导致矿化和IL-6分泌增加。最后，氧化应激可能通过诱导矿化前基因而降低了3-MST表达并增加了软骨细胞矿化作用。结论3-MST生成的H2S可以防止关节钙化和实验性OA。增强软骨细胞中H2S的产生可能是治疗OA的潜在疾病改良剂。