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.

雌激素水平下降（例如在更年期发生）会增加骨质流失，从而导致骨质流失。 骨吸收破骨细胞的数量。雌激素的控制机制 破骨细胞的数量仅被部分了解，但之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始终导致 骨髓中B淋巴细胞的数量。 B 细胞数量的增加 建议通过不同机制促进破骨细胞形成，例如 B 细胞产生 NF-κ-B 配体破骨细胞因子受体激活剂 (RANKL) 和 B 细胞前体分化为破骨细胞。然而，直到最近，还有 没有功能性证据表明 B 细胞在卵巢切除术引起的骨质流失中发挥重要作用。 在导致该应用的研究中，我们发现细胞因子受体的产生 B 淋巴细胞的 NF-κ-B 配体 (RANKL) 激活剂对于松质骨至关重要 小鼠雌激素缺乏引起的损失。重要的是，RANKL 也是必需的 雌激素缺乏引起的 B 细胞数量增加。另外，卵巢切除术并没有 增加野生型小鼠 B 细胞中 RANKL 的水平。总之，这些结果表明 是该模型中卵巢切除引起的骨质流失所需的 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 并不能阻止皮质的损失。 雌激素缺乏引起的骨质疏松。因此，RANKL 由 B 以外的细胞类型产生 细胞必须参与该骨骼室中破骨细胞的形成。基于这些 结果，我们假设雌激素的损失导致松质骨损失，部分原因是通过增加 B 细胞的数量，然后可以充当破骨细胞祖细胞。此外，我们建议 雌激素的丧失通过改变 RANKL 的产生而导致皮质骨丢失 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为骨 在体内重吸收破骨细胞。此外，雌激素是否通过作用抑制B细胞数量？ 直接在这些细胞上的作用将通过有条件地删除雌激素受体α来确定 这种细胞类型。最后，从骨细胞或骨细胞中删除 RANKL 基因的小鼠 来自成骨细胞谱系的基质细胞将被切除卵巢以确定是否有 RANKL 这些细胞类型产生的细胞会导致雌激素引起的皮质骨丢失 不足。