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

• 批准号: 8150378
• 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
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150378
• 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; public health relevance; sialomucin; sialomucins; skeletal; sodium-hydrogen exchanger regulatory factor; spine bone structure; substantia spongiosa; tissue culture

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. PUBLIC HEALTH RELEVANCE: Bone loss associated with aging and postmenopausal osteoporosis is due to excess osteoclast-mediated bone resorption. Excess bone loss leads to risks of debilitating fractures. An estimated 44 million Americans are at risk of osteoporosis. Within the U.S., 10 million people are estimated to already have this disease and an additional 34 million are suspected of having low bone mass and at risk of developing the disease. There are 1.5 million osteoporotic fractures in the U.S. each year and the cost of caring for these fractures is estimated at $12 billion to $18 billion. Indirect costs in lost productivity of patients and care givers add billions to this cost. Thus, therapies that target bone resorbing osteoclasts while preserving bone formation have the potential to have a significant impact on patients.

描述（由申请人提供）：我们的长期目标是描述破骨细胞有助于骨代谢的分子机制，并希望该知识指导更有效的疗法以促进骨骼健康。理想情况下，减少破骨细胞介导的骨质流失的新疗法靶标将阻塞破骨细胞，同时保留骨形成。这可能是具有挑战性的，因为有证据表明，骨细胞（无论它们是否能够吸收骨骼）是由成骨细胞形成正常的骨骼。我们检查了CD34家族成员PODXL在造血/破骨细胞谱系细胞中删除的小鼠的椎骨。骨密度和成骨细胞数量均升高。出乎意料的是，破骨细胞的数量和大小也明显更高。因此，早期破骨细胞谱系细胞中PODXL的丧失会减少骨吸收，同时保留成骨细胞募集和骨形成。我们的体外研究支持破骨细胞谱系细胞中的PODXL表达减少破骨细胞的分化。但是，破骨细胞肌动蛋白环形成和骨吸收需要相对较低的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，即必须降低PODXL膜络合物的早期祖细胞膜表达水平，包括CXCR4和NHERF1，以允许前体融合，并且该复合物的较低水平是激活骨质细胞的，从而使它们能够吸收骨质骨骼。以下特定目的旨在检验该假设1。确定破骨细胞谱系PODXL表达在骨骼采集和骨骼维持中的作用。 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老鼠。 2。询问PODXL，CXCR4和NHERF-1复合物会影响破骨细胞细胞的分子机制。 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. 公共卫生相关性：与衰老和绝经后骨质疏松症相关的骨质流失是由于破骨细胞介导的骨吸收过量引起的。骨质流失过多会导致骨折的风险。估计有4400万美国人有骨质疏松症的风险。在美国，估计有1000万人已经患有这种疾病，另外3400万人怀疑骨骼质量低，并且有患这种疾病的风险。美国每年有150万个骨质疏松性骨折，照顾这些裂缝的费用估计为120亿美元至180亿美元。患者和护理人员丧失生产力的间接成本增加了数十亿美元的成本。因此，靶向骨分辨破骨细胞同时保存骨形成的疗法有可能对患者产生重大影响。