RANKL and lymphocyte-mediated bone loss

雌激素水平的下降，例如发生在更年期，通过增加 骨吸收破骨细胞的数量。雌激素控制的机制 破骨细胞的数量只被部分了解，但先前的研究表明淋巴细胞 发挥重要作用。例如，摘除小鼠或大鼠的卵巢始终会导致 骨髓中B淋巴细胞的数量。B细胞数量的这种增加是 建议通过不同的机制促进破骨细胞的形成，如B 破骨细胞因子受体激活剂核因子-kappaB配体的细胞生产 (RANKL)和B细胞前体向破骨细胞分化。然而，直到最近，还有 没有功能证据表明B细胞在卵巢切除引起的骨丢失中起重要作用。 在导致这一应用的研究中，我们发现细胞因子受体的产生 B淋巴细胞激活核因子-kappaB配体(RANKL)对松质骨的作用 小鼠因雌激素缺乏造成的损失。重要的是，RANKL也是 由雌激素缺乏引起的B细胞数量的增加。此外，卵巢切除也没有 提高野生型小鼠B细胞RANKL水平。总而言之，这些结果表明 在这个模型中，卵巢切除导致的骨丢失所需的B细胞数量的增加。 同样重要的是要注意，从B细胞中删除RANKL并不能阻止皮质的丢失 由雌激素缺乏引起的骨骼。因此，RANKL由B以外的细胞类型产生 在这个骨骼间隔中，细胞必须参与破骨细胞的形成。基于这些 结果，我们假设雌激素的丢失导致松质骨丢失，部分是通过增加 B细胞的数量，它可以作为破骨细胞的祖细胞。此外，我们建议 雌激素的丢失通过改变细胞产生RANKL而导致皮质骨丢失 成骨细胞谱系。为了解决这些假设，将进行血统追踪研究，以 确定B细胞在其发育的任何阶段是否可以分化为骨 体内吸收破骨细胞。此外，雌激素是否通过作用抑制B细胞数量 直接作用于这些细胞将通过有条件地删除雌激素受体 此单元格类型。最后，RANKL基因从骨细胞或骨细胞中删除的小鼠 将来自基质细胞的成骨细胞谱系摘除卵巢以确定RANKL是否 这些细胞类型产生的物质导致雌激素引起的皮质骨丢失 缺乏症。

A decline in estrogen levels, such as occurs at the menopause, causes bone loss by increasing the number of bone resorbing osteoclasts. The mechanisms by which estrogen controls osteoclast number are only partially understood, but previous studies suggest that lymphocytes play an important role. For example, ovariectomy of mice or rats consistently leads to increased numbers of B lymphocytes in the bone marrow. This increase in B cell number has been suggested to contribute to increased osteoclast formation by different mechanisms, such as B cell production of the osteoclastogenic cytokine receptor activator of NF-kappa-B ligand (RANKL) and differentiation of B cell precursors into osteoclasts. However, until recently, there was no functional evidence that B cells play an essential role in ovariectomy-induced bone loss. In studies leading to this application, we have found that production of the cytokine receptor activator of NF-kappa-B ligand (RANKL) by B lymphocytes is essential for the cancellous bone loss caused by estrogen deficiency in mice. Importantly, RANKL is also required for the increase in B cell number that is caused by estrogen deficiency. Also, ovariectomy did not increase the levels of RANKL in B cells in wild type mice. Together, these results suggest that it is the increase in B cell number that is required for ovariectomy-induced bone loss in this model. It is also important to note that deletion of RANKL from B cells did not prevent loss of cortical bone caused by estrogen deficiency. Therefore, RANKL produced by cell types other than B cells must be involved in the osteoclast formation in this skeletal compartment. Based on these results, we hypothesize that loss of estrogen causes cancellous bone loss, in part, by increasing the number of B cells, which can then act as osteoclast progenitors. Further, we propose that loss of estrogen causes cortical bone loss by altering production of RANKL by cells of the osteoblast lineage. To address these hypotheses, lineage-tracing studies will be performed to determine whether B cells, at any stage of their development, can differentiate into bone resorbing osteoclasts in vivo. In addition, whether estrogen suppresses B cell number by acting directly on these cells will be determined by conditional deletion of estrogen receptor alpha from this cell type. Lastly, mice in which the RANKL gene has been deleted from either osteocytes or from stromal cells of the osteoblast lineage will be ovariectomized to determine whether RANKL produced by these cell types contributes to the cortical bone loss caused by estrogen deficiency.