Ryan Michaela Robbie, Shepherd Rebecca, Leavey Jennifer K, Gao Yuhao, Grassi Francesco, Schnell Frederick J, Qian Wei-Ping, Kersh Gilbert J, Weitzmann M Neale, Pacifici Roberto
Division of Endocrinology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16735-40. doi: 10.1073/pnas.0505168102. Epub 2005 Nov 2.
The bone wasting induced by estrogen deficiency is, in part, a consequence of increased T cell production of the osteoclastogenic cytokine TNF-alpha. This phenomenon is due to an expansion of T cells, but the responsible mechanism is unknown. We now show that ovariectomy (ovx) disregulates T lymphopoiesis and induces bone loss by stimulating, through a rise in IL-7 levels, both thymic-dependent differentiation of bone marrow-derived progenitors and thymic-independent, peripheral expansion of mature T cells. Attesting to the relevance of the thymic effects, thymectomy decreases by approximately 50% the bone loss and the stimulation of T lymphopoiesis induced by ovx. In contrast, in vivo attenuation of the elevated IL-7 completely prevents the stimulation of T lymphopoiesis and the bone loss that follow ovx. Thus, the disruption of both T cell and bone homeostasis induced by ovx is mediated by IL-7 and due to both the thymic and extrathymic mechanisms. We conclude that IL-7 is a pivotal upstream target through which estrogen regulates hematopoietic and immune functions that are critical for bone homeostasis.
雌激素缺乏所致的骨质流失，部分原因是破骨细胞生成细胞因子TNF-α的T细胞产生增加。这种现象是由于T细胞扩增，但具体机制尚不清楚。我们现在发现，卵巢切除术（ovx）会扰乱T淋巴细胞生成，并通过升高IL-7水平，刺激骨髓来源祖细胞的胸腺依赖性分化以及成熟T细胞的胸腺非依赖性外周扩增，从而导致骨质流失。胸腺切除术使ovx诱导的骨质流失和T淋巴细胞生成刺激减少约50%，证明了胸腺效应的相关性。相反，体内升高的IL-7减弱则完全阻止了ovx后T淋巴细胞生成的刺激和骨质流失。因此，ovx诱导的T细胞和骨内环境稳态破坏是由IL-7介导的，且归因于胸腺和胸腺外机制。我们得出结论，IL-7是一个关键的上游靶点，雌激素通过该靶点调节对骨内环境稳态至关重要的造血和免疫功能。
