Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research, Chattar Manzil, Lucknow, India.
PLoS One. 2012;7(9):e44552. doi: 10.1371/journal.pone.0044552. Epub 2012 Sep 10.
Th17 cells produce IL-17, and the latter promotes bone loss in collagen-induced arthritis in mice. Blocking IL-17 action in mouse model of rheumatoid arthritis reduces disease symptoms. These observations suggest that Th17 cells may be involved in the pathogenesis of bone loss. However, the role of Th17 cell in estrogen (E2) deficiency-induced bone loss is still not very clear. We investigated the effect of E2 on Th17 differentiation in vivo and IL-17 mediated regulation of osteoclast and osteoblast differentiation. Additionally, effect of IL-17 functional block under E2 deficiency-induced bone loss was studied. In murine bone marrow cells, E2 suppressed IL-17 mediated osteoclast differentiation. IL-17 inhibited formation of mineralized nodules in osteoblasts and this effect was suppressed by E2. E2 treatment to mouse calvarial osteoblasts inhibited the IL-17-induced production of osteoclastogenic cytokines and NF-kB translocation. In ovariectomized mice, there was increase in the number of Th17 cells, transcription factors promoting Th17 cell differentiation and circulating IL-17 levels. These effects were reversed by E2 supplementation. Treatment of neutralizing IL-17 monoclonal antibody to Ovx mice mitigated the E2 deficiency-induced trabecular bone loss and reversed the decreased osteoprotegerin-to-receptor activator of nuclear factor kappa B ligand (RANKL) transcript levels in long bones, increased osteoclast differentiation from the bone marrow precursor cells and decreased osteoblast differentiation from the bone marrow stromal cells. Our findings indicate that E2 deficiency leads to increased differentiation of Th17 cells with attendant up regulation of STAT3, ROR-γt and ROR-α and downregulation of Foxp3 which antagonizes Th17 cell differentiation. Increased IL-17 production in turn induces bone loss by increasing pro-osteoclastogenic cytokines including TNF-α, IL-6 and RANKL from osteoblasts and functional block of IL-17 prevents bone loss. IL-17 thus plays a critical causal role in Ovx-induced bone loss and may be considered a potential therapeutic target in pathogenesis of post menopausal osteoporosis.
Th17 细胞产生白细胞介素-17（IL-17），后者促进胶原诱导关节炎小鼠的骨丢失。在类风湿关节炎的小鼠模型中阻断 IL-17 的作用可减轻疾病症状。这些观察结果表明 Th17 细胞可能参与骨丢失的发病机制。然而，Th17 细胞在雌激素（E2）缺乏诱导的骨丢失中的作用尚不清楚。我们研究了 E2 对体内 Th17 分化的影响以及 IL-17 对破骨细胞和成骨细胞分化的调节作用。此外，还研究了在 E2 缺乏诱导的骨丢失下，IL-17 功能阻断的效果。在鼠骨髓细胞中，E2 抑制了 IL-17 介导的破骨细胞分化。IL-17 抑制成骨细胞中矿化结节的形成，而这种作用可被 E2 抑制。E2 处理鼠颅骨成骨细胞可抑制 IL-17 诱导的破骨细胞生成细胞因子和 NF-kB 易位。在去卵巢小鼠中，Th17 细胞数量增加，促进 Th17 细胞分化的转录因子和循环中 IL-17 水平增加。这些作用可被 E2 补充所逆转。用中和 IL-17 的单克隆抗体治疗 Ovx 小鼠可减轻 E2 缺乏诱导的小梁骨丢失，并逆转长骨中骨保护素与核因子 kappa B 配体受体激活剂（RANKL）转录物水平的降低、增加骨髓前体细胞的破骨细胞分化和减少骨髓基质细胞的成骨细胞分化。我们的研究结果表明，E2 缺乏导致 Th17 细胞分化增加，随之而来的是 STAT3、ROR-γt 和 ROR-α 的上调以及 Th17 细胞分化拮抗物 Foxp3 的下调。IL-17 产生增加继而通过增加 TNF-α、IL-6 和 RANKL 等促破骨细胞生成细胞因子从成骨细胞诱导骨丢失，而 IL-17 的功能阻断可预防骨丢失。因此，IL-17 在 Ovx 诱导的骨丢失中起着关键的因果作用，可被视为绝经后骨质疏松症发病机制的潜在治疗靶点。
