Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
J Immunol. 2010 Jun 15;184(12):7238-46. doi: 10.4049/jimmunol.0903841. Epub 2010 May 17.
We previously demonstrated the suppressive effects of regulatory T cells (Treg cells) on osteoclast differentiation in vitro. In this article, we show that blood markers of bone resorption inversely correlate with the amount of circulating Treg cells in healthy controls and rheumatoid arthritis patients, further suggesting that Treg cells may control bone destruction in vivo. Indeed, bone marrow from Foxp3-transgenic (Foxp3tg) mice fully protected human TNF transgenic (hTNFtg) mice from TNF-alpha-induced bone destruction, whereas Foxp3-deficient bone marrow enhanced local and systemic bone loss. The same protective effect was also obtained by treating hTNFtg mice with the CD28 superagonist mAb (CD28 SA), which increased Treg cell numbers. In both models, bone protection by Treg cells was associated with reduced osteoclast numbers, resulting in less bone-resorbing activity. Reduced osteoclast numbers were not caused by an intrinsic defect in osteoclast differentiation because osteoclast precursors from hTNFtg/Foxp3tg chimeras responded normally to M-CSF and receptor activator of NF-kappaB ligand. Although a decrease in the clinical signs of arthritis was observed in Foxp3tg bone marrow-transferred and CD28 SA-treated hTNFtg mice, the bone-protective effect of Treg cells was independent of the suppression of inflammation, as demonstrated by the increased systemic bone density observed in wild-type mice treated with CD28 SA. This work demonstrated that increasing Treg cell numbers improved clinical signs of arthritis and suppressed local and systemic bone destruction. Thus, enhancing the activity of Treg cells would be beneficial for the treatment of inflammation-induced bone loss observed in rheumatoid arthritis.
我们之前证明了调节性 T 细胞（Treg 细胞）在体外对破骨细胞分化的抑制作用。在本文中，我们表明健康对照者和类风湿关节炎患者的骨吸收血液标志物与循环 Treg 细胞的数量呈负相关，这进一步表明 Treg 细胞可能在体内控制骨破坏。事实上，Foxp3 转基因（Foxp3tg）小鼠的骨髓完全保护了人类 TNF 转基因（hTNFtg）小鼠免受 TNF-α诱导的骨破坏，而 Foxp3 缺陷型骨髓则增强了局部和全身骨质流失。用 CD28 超激动剂 mAb（CD28 SA）治疗 hTNFtg 小鼠也获得了相同的保护作用，该 mAb 增加了 Treg 细胞数量。在这两种模型中，Treg 细胞的骨保护作用与破骨细胞数量减少有关，导致骨吸收活性降低。破骨细胞数量的减少不是由于破骨细胞分化的内在缺陷引起的，因为 hTNFtg/Foxp3tg 嵌合体的破骨细胞前体对 M-CSF 和 NF-κB 配体受体激活剂的反应正常。尽管在 Foxp3tg 骨髓移植和 CD28 SA 治疗的 hTNFtg 小鼠中观察到关节炎临床症状的减少，但 Treg 细胞的骨保护作用与炎症的抑制无关，这从用 CD28 SA 治疗的野生型小鼠中观察到的全身性骨密度增加得到证明。这项工作表明，增加 Treg 细胞数量可改善关节炎的临床症状，并抑制局部和全身骨质破坏。因此，增强 Treg 细胞的活性将有益于治疗类风湿关节炎中观察到的炎症诱导的骨质流失。
