3-巯基丙酮酸硫转移酶（3-MST）-硫化氢（HS）通路对实验性骨关节炎的保护作用。
The protective role of the 3-mercaptopyruvate sulfurtransferase (3-MST)-hydrogen sulfide (HS) pathway against experimental osteoarthritis.
机构信息
Service of Rheumatology, Department of Musculoskeletal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
First Department of Critical Care and Pulmonary Services, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
出版信息
Arthritis Res Ther. 2020 Mar 17;22(1):49. doi: 10.1186/s13075-020-02147-6.
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 (HS) has been implicated in mineralization but has never been studied in OA. Here, we investigated the role of the HS-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 HS protects against joint calcification and experimental OA. Enhancing HS production in chondrocytes may represent a potential disease modifier to treat OA.
背景
骨关节炎（OA）的特征是关节组织中形成和沉积含钙晶体，但潜在机制尚不清楚。气体递质硫化氢（HS）已被牵涉到矿化过程中，但从未在 OA 中进行过研究。在这里，我们研究了产生 HS 的酶 3-巯基丙酮酸硫转移酶（3-MST）在软骨钙化和 OA 发展中的作用。
方法
分析了不同 OA 程度的软骨和羟磷灰石（HA）晶体刺激的软骨中的 3-MST 表达。通过比较 sham 手术和 MNX 膝关节软骨，研究了 3-MST 在半月板切除术（MNX）小鼠 OA 模型中的体内表达调节。通过定量 WT 和 3-MST 半月板切除膝关节的关节钙化和软骨降解，研究了 3-MST 的作用。在 WT 和 3-MST 细胞中测量了软骨细胞的体外矿化。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 刺激下减少。相应地，与 sham 手术的健康膝关节相比，MNX 切除 OA 膝关节的软骨中 3-MST 减少。此外，与 WT 小鼠相比，3-MST 小鼠的关节钙化和 OA 严重程度加剧。在体外，软骨细胞中 3-MST 的遗传或药物抑制导致矿化增强和 IL-6 分泌增加。最后，氧化应激降低了 3-MST 的表达并增加了软骨细胞的矿化，可能是通过诱导促矿化基因。
结论
3-MST 产生的 HS 可防止关节钙化和实验性 OA。增强软骨细胞中的 HS 产生可能是治疗 OA 的潜在疾病修饰剂。
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