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The Role Of Osteoclast PODXL, A Mediator Of Cell Adhesion, In Bone Metabolism

破骨细胞 PODXL（细胞粘附介质）在骨代谢中的作用

基本信息

批准号：
8692752
负责人：
MERRY JO OURSLER
金额：
$ 30.35万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8692752
关键词：
Actins Adhesives Affect Age Aging American Binding Bone Density Bone Resorption CD34 gene CXCR4 gene Caregivers Caring Cell Adhesion Cell Lineage Cells Charge Co-Immunoprecipitations Complex Data Disease Down-Regulation Facilities and Administrative Costs Family member Female Fracture Gene Expression Glass Goals Health Hematopoietic In Vitro Integrins Knowledge Lead Macrophage Colony-Stimulating Factor Maintenance Marrow Mediating Mediator of activation protein Membrane Molecular Mucins Mus Osteoblasts Osteoclasts Osteogenesis Osteoporosis Ovariectomy Pathway interactions Patient Care Patients Phenotype Plastics Postmenopausal Osteoporosis Productivity Repression Risk Role Series Skeletal Development Testing bone bone health bone loss bone mass bone metabolism c-myc Genes cathepsin K cost design effective therapy expectation extracellular in vivo male mutant new therapeutic target novel osteoporosis with pathological fracture progenitor protein expression sialomucin sialomucins skeletal sodium-hydrogen exchanger regulatory factor spine bone structure substantia spongiosa tissue culture

项目摘要

DESCRIPTION (provided by applicant): Our long term goal is to delineate the molecular mechanisms by which osteoclasts contribute to bone metabolism with the expectation that this knowledge will guide more effective therapies to promote skeletal health. Ideally, new therapy targets to reduce osteoclast-mediated bone loss will block osteoclasts while also preserving bone formation. This may be challenging since evidence is mounting that osteoclasts, whether or not they are capable of resorbing bone, are needed for normal bone formation by osteoblasts. We have examined the vertebrae of mice in which the CD34 family member PODXL is deleted in hematopoietic/osteoclast lineage cells (hem lineage-PODXLdel mice). Bone density and osteoblast numbers were both elevated. Unexpectedly, the number and size of osteoclasts were also significantly higher. Thus, loss of PODXL in early osteoclast lineage cells reduces bone resorption while preserving osteoblast recruitment and bone formation. Our in vitro studies support that PODXL expression in osteoclast lineage cells reduces osteoclast differentiation. However, a relatively low level of PODXL expression is required for osteoclast actin ring formation and bone resorption. Our studies and the known functions of PODXL lead to our central hypothesis that early progenitor membrane expression levels of a PODXL membrane complex including CXCR4 and NHERF1 must be reduced to allow for precursor fusion and lower levels of this complex are required for activation of osteoclasts, enabling them to resorb bone. The following Specific Aims are designed to test this hypothesis 1. Determine the role of osteoclast lineage PODXL expression changes in skeletal acquisition and bone maintenance. We will comprehensively phenotype the hem lineage-PODXLdel mice, establish the effects of ovariectomy on bone metabolism in hem lineage-PODXLdel mice, define the impact of loss of PODXL in early osteoclast lineage cells during anabolic PTH treatment, and compare mice with PODXL deleted in late osteoclast lineage cells to the hem lineage-PODXLdel mice. 2. Interrogate the molecular mechanisms by which the PODXL, CXCR4, and NHERF-1 complex influences osteoclast lineage cells. We will identify structural domains of PODXL and NHERF1 involved in complex formation, membrane expression, differentiation, and internalization during differentiation, resolve the mechanism of down regulation of PODXL, CXCR4, and NHERF1 gene expression by M-CSF, and ascertain the influences of PODXL and binding partners on integrin interactions, actin ring formation, and osteoclast function.

描述(申请人提供)：我们的长期目标是描绘破骨细胞促进骨代谢的分子机制，期望这一知识将指导更有效的治疗以促进骨骼健康。理想情况下，减少破骨细胞介导的骨丢失的新的治疗靶点将阻止破骨细胞，同时也保护骨形成。这可能是具有挑战性的，因为越来越多的证据表明，破骨细胞，无论它们是否有能力吸收骨，都是成骨细胞正常骨形成所必需的。我们研究了CD34家族成员PODXL在造血/破骨细胞系细胞(HEM Lineage-PODXLdel小鼠)中缺失的小鼠的脊椎。骨密度和成骨细胞数均升高。出乎意料的是，破骨细胞的数量和大小也明显更高。因此，早期破骨细胞系细胞中PODXL的丢失减少了骨吸收，同时保留了成骨细胞的招募和骨形成。我们的体外研究支持PODXL在破骨细胞系细胞中的表达减少了破骨细胞的分化。然而，破骨细胞肌动蛋白环的形成和骨吸收需要相对较低水平的PODXL表达。我们的研究和PODXL的已知功能导致了我们的中心假设，即包括CXCR4和NHERF1在内的PODXL膜复合体的早期祖细胞膜表达水平必须降低，以允许前体融合，并且激活破骨细胞需要较低水平的该复合体，使其能够吸收骨。研究目的如下：1.确定破骨细胞系PODXL表达变化在骨获得和骨维持中的作用。我们将全面表型HEM系PODXLdel小鼠，建立卵巢切除对HEM系PODXLdel小鼠骨代谢的影响，确定在合成甲状旁腺素治疗过程中早期破骨细胞系细胞PODXL丢失的影响，并将晚期破骨细胞系细胞缺失的PODXL小鼠与HEM系PODXLdel小鼠进行比较。2.探讨PODXL、CXCR4和NHERF-1复合体影响破骨细胞系细胞的分子机制。我们将确定PODXL和NHERF1的结构域，参与复合体的形成、膜表达、分化和分化过程中的内化，解决M-CSF下调PODXL、CXCR4和NHERF1基因表达的机制，并确定PODXL和结合伙伴对整合素相互作用、肌动蛋白环形成和破骨细胞功能的影响。