RANKL and lymphocyte-mediated bone loss

RANKL 和淋巴细胞介导的骨丢失

• 批准号: 8633709
• 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/8633709
• 关键词: Address; Alleles; Alpha Cell; 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; Gonadal Steroid Hormones; Histologic; Homeostasis; Immune; In Vitro; Label; Lead; Ligands; Lymphocyte; Measures; Mediating; Menopause; Modeling; Molecular; Mus; Osteoblasts; Osteoclasts; Osteocytes; Ovariectomy; Play; Postmenopause; Premenopause; Production; Rattus; Relative (related person); Reporter; Role; Skeletal Development; Skeleton; Source; Staging; Stromal Cells; T-Cell Activation; T-Lymphocyte; TRANCE protein; Tumor necrosis factor receptor 11b; Wild Type Mouse; Woman; Work; base; bone; bone loss; bone mass; cell type; cytokine; in vivo; male; osteoclastogenesis; prevent; progenitor; public health relevance; receptor; receptor activator of NF-kappa B; skeletal

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.

雌激素水平的下降，如发生在绝经期，通过增加骨质疏松症， 骨吸收破骨细胞的数量。雌激素控制的机制 破骨细胞的数量只有部分了解，但以前的研究表明，淋巴细胞， 发挥重要作用。例如，小鼠或大鼠的卵巢切除术一致地导致增加的 骨髓中B淋巴细胞的数量。这种B细胞数量的增加， 提示通过不同机制促进破骨细胞形成，如B NF-κ-B配体的破骨细胞生成细胞因子受体激活剂的细胞产生 （RANKL）和B细胞前体向破骨细胞的分化。然而，直到最近， 没有功能性证据表明B细胞在卵巢切除术诱导的骨丢失中起重要作用。 在导致这种应用的研究中，我们发现细胞因子受体的产生 由B淋巴细胞激活的NF-κ-B配体（RANKL）对松质骨是必需的 雌激素缺乏引起的小鼠体内雌激素的减少。重要的是，RANKL也是 由雌激素缺乏引起的B细胞数量增加。此外，卵巢切除术并没有 增加野生型小鼠B细胞中RANKL的水平。这些结果表明， 是该模型中卵巢切除术诱导的骨丢失所需的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并不能防止皮质骨丢失。 由于雌激素缺乏引起的骨质疏松。因此，由除B细胞类型以外的细胞类型产生的RANKL 细胞必须参与该骨骼隔室中破骨细胞的形成。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，然后可以作为破骨细胞祖细胞。此外，我们建议， 雌激素的丢失通过改变骨组织细胞RANKL的产生而引起皮质骨丢失。 成骨细胞谱系。为了解决这些假设，将进行谱系追踪研究， 确定B细胞在其发育的任何阶段是否可以分化成骨 体内再吸收破骨细胞。此外，雌激素是否通过作用于B细胞抑制B细胞数量， 直接在这些细胞上的雌激素受体α的条件性缺失将通过从 这种细胞类型。最后，RANKL基因已从骨细胞或骨髓细胞中删除的小鼠， 从成骨细胞谱系的基质细胞中提取的RANKL将被卵巢切除，以确定RANKL是否 由这些细胞类型产生的雌激素会导致皮质骨丢失 缺陷