RANKL and lymphocyte-mediated bone loss

RANKL 和淋巴细胞介导的骨丢失

• 批准号: 9275307
• 负责人: CHARLES A O'BRIEN
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275307
• 关键词: Address; Alleles; B cell differentiation; B-Lymphocytes; Bone Growth; Bone Marrow; Bone Marrow Cells; Bone Resorption; Bone remodeling; Cell Count; Cells; Cytokine Receptors; Development; Environment; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Female; Funding; Genes; Genetic study; Gonadal Steroid Hormones; Histologic; Homeostasis; Immune; In Vitro; Label; Lead; Ligands; Lymphocyte; Measures; Mediating; Menopause; Modeling; Molecular; Mus; Osteoblasts; Osteoclasts; Osteocytes; Ovariectomy; Pathologic; Play; Postmenopause; Premenopause; Production; Rattus; Reporter; Role; Skeletal Development; Skeleton; Source; Stromal Cells; T-Cell Activation; T-Lymphocyte; Tumor necrosis factor receptor 11b; Wild Type Mouse; Woman; Work; base; bone; bone loss; bone mass; cell type; cortical bone; cytokine; differentiated B cell; in vivo; male; osteoclastogenesis; prevent; progenitor; public health relevance; receptor; receptor activator of NF-kappa B; receptor expression; skeletal; substantia spongiosa

DESCRIPTION (provided by applicant): 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.

描述(由申请人提供)： 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而导致骨丢失。雌激素控制破骨细胞数量的机制只有部分了解，但之前的研究表明淋巴细胞发挥着重要作用。例如，小鼠或大鼠卵巢切除后，骨髓中的B淋巴细胞数量不断增加。这种B细胞数量的增加被认为是通过不同的机制促进破骨细胞的形成，如B细胞产生破骨细胞因子受体激活的核因子-kappa-B配体(RANKL)和B细胞前体细胞分化为破骨细胞。然而，直到最近，还没有功能证据表明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B淋巴细胞产生的细胞因子受体激活因子核因子-kappa-B配体(RANKL)在雌激素缺乏引起的小鼠松质骨丢失中是必不可少的。重要的是，由于雌激素缺乏导致B细胞数量增加，RANKL也是必需的。卵巢切除不能增加野生型小鼠B细胞RANKL的水平。综上所述，这些结果表明，在这个模型中，B细胞数量的增加是卵巢切除导致骨丢失所必需的。同样重要的是要注意，从B细胞中删除RANKL并不能防止雌激素缺乏引起的皮质骨丢失。因此，除B细胞外，其他类型的细胞产生的RANKL必须参与该骨室破骨细胞的形成。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，然后B细胞可以作为破骨祖细胞。此外，我们认为雌激素的丢失通过改变成骨细胞系细胞产生RANKL而导致皮质骨丢失。为了解决这些假说，将进行谱系追踪研究，以确定B细胞在其发育的任何阶段是否可以在体内分化为骨吸收破骨细胞。此外，雌激素是否通过直接作用于这些细胞来抑制B细胞的数量，将取决于有条件地从这种细胞类型中删除雌激素受体α。最后，从成骨细胞系的骨细胞或基质细胞中删除RANKL基因的小鼠将被切除卵巢，以确定这些细胞类型产生的RANKL是否与雌激素缺乏导致的皮质骨丢失有关。