Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.
Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.
Int Immunopharmacol. 2021 Feb;91:107191. doi: 10.1016/j.intimp.2020.107191. Epub 2020 Dec 20.
This study aims to investigate the effects and mechanisms of parathyroid hormone [1-34] (PTH1-34) on TNF-α-stimulated mice chondrocytes, as well as cartilage from a meniscus injury induced osteoarthritis (MIO) mice model. The C57BL/6J mice received medial meniscectomy, and then administrated with PTH1-34. The results showed that PTH1-34 administration decreased secondary allodynia and the pain-related transcripts. The IHC, ELISA, Micro-CT imaging and histopathology analysis revealed the significantly improved subchondral plate thickness and bone porosity, the reduced pro-inflammatory cytokines in serum and joint fluid. In vitro, mice chondrocyte was treated with TNF-α or co-cultured with synovial cells. The results showed that TNF-α markedly upregulated the MMP13 expression, and the ERK1/2, NF-κB or PI3K signaling pathway inhibitors could reverse the induction effect of TNF-α on expression of MMP13 in chondrocytes. PTH1-34 alone has no effect on the expression of MMP13 and NF-κB signaling pathways, but the PTH1-34 could reverse the induction effect of TNF-α on MMP13 expression and NF-κB signaling pathway activation in chondrocytes. In addition, PTH1-34 administration inhibited the expression of TNF-α and MMP13, and chondrocyte viability, while the PKA repressor reversed the effect of PTH1-34 in chondrocytes co-cultured with synovial cells. In conclusion, PTH1-34 has an obvious analgesic and anti-inflammatory effect, inhibits the matrix synthesis and alleviates the progression of osteoarthritis. In vitro, PTH1-34 inhibited TNF-α expression and antagonized TNF-α-induced MMP13 expression via the PKA pathway and the NF-κB signaling pathways, respectively.
本研究旨在探讨甲状旁腺激素[1-34]（PTH1-34）对 TNF-α刺激的小鼠软骨细胞以及半月板损伤诱导的骨关节炎（MIO）小鼠模型软骨的作用和机制。C57BL/6J 小鼠接受内侧半月板切除术，然后给予 PTH1-34 治疗。结果显示，PTH1-34 给药可减轻继发性触诱发痛和与疼痛相关的转录物。免疫组织化学、ELISA、Micro-CT 成像和组织病理学分析显示，软骨下板厚度和骨孔隙度明显改善，血清和关节液中促炎细胞因子减少。在体外，用 TNF-α处理小鼠软骨细胞或与滑膜细胞共培养。结果表明，TNF-α可显著上调 MMP13 的表达，ERK1/2、NF-κB 或 PI3K 信号通路抑制剂可逆转 TNF-α对软骨细胞 MMP13 表达的诱导作用。PTH1-34 单独作用于 MMP13 和 NF-κB 信号通路无影响，但 PTH1-34 可逆转 TNF-α对软骨细胞 MMP13 表达和 NF-κB 信号通路激活的诱导作用。此外，PTH1-34 给药可抑制 TNF-α和 MMP13 的表达以及软骨细胞活力，而 PKA 抑制剂可逆转 PTH1-34 在与滑膜细胞共培养的软骨细胞中的作用。综上所述，PTH1-34 具有明显的镇痛和抗炎作用，抑制基质合成并缓解骨关节炎的进展。在体外，PTH1-34 通过 PKA 途径和 NF-κB 信号通路抑制 TNF-α表达，并拮抗 TNF-α诱导的 MMP13 表达。
