Common Inflammation Pathways between Aging and Hypertension That Weaken Bone

衰老和高血压之间削弱骨骼的常见炎症途径

• 批准号: 10618349
• 负责人: David G Harrison
• 金额: $ 51.41万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618349
• 关键词: Adult; Affect; Age; Age-Related Bone Loss; Aging; American Heart Association; Animals; Antibodies; Biological Assay; Biology; Blood Pressure; Blood Pressure Monitors; Bone Marrow; Bone Resorption; Bone remodeling; Cell Culture Techniques; Cell Differentiation process; Cells; Cessation of life; Clinical Pharmacology; Coculture Techniques; Collaborations; Communication; Data; Dendritic Cells; Denervation; Deterioration; Diagnosis; Disease; Disease model; Early Diagnosis; Early treatment; Economic Burden; Endothelial Cells; Endothelium; Enterobacteria phage P1 Cre recombinase; Estrogens; Exposure to; Fracture; Genes; Goals; Health; Hematopoietic; Hip Fractures; Human; Hypertension; IL17 gene; Immune; Individual; Inflammation; Inflammatory; Interleukins; Longevity; Macrophage; Macrophage Colony-Stimulating Factor; Measurement; Mechanical Stimulation; Mechanics; Mediating; Mediator; Menopause; Methodology; Modeling; Molecular; Mus; Mutant Strains Mice; Myeloid Cell Activation; Myeloid Cells; Myelopoiesis; Osteoblasts; Osteoclasts; Osteoporosis; Osteoporosis prevention; Pathway interactions; Patients; Persons; Phenotype; Play; Positioning Attribute; Pre-Clinical Model; Prevention strategy; Production; Qualifying; Quality of life; Recombinant Proteins; Research; Resistance; Role; Signal Transduction; Societies; Source; Stimulus; Stretching; Structure; Sympathetic Nervous System; Systemic hypertension; T cell transcription factor 1; T-Cell Activation; Techniques; Technology; Testing; Vascular Endothelium; Vascular remodeling; Withdrawal; Work; age related; aged; antagonist; arteriole; blood pressure elevation; blood pressure reduction; bone; bone loss; bone mass; bone quality; bone strength; cytokine; designer receptors exclusively activated by designer drugs; experimental study; fracture risk; fragility fracture; hypertensive; immune activation; improved; inducible Cre; long bone; mature animal; mechanical force; monocyte; mouse model; multidisciplinary; neutralizing antibody; new therapeutic target; novel; novel therapeutic intervention; postnatal; premature; prevent; receptor; release factor; response; skills; success; tool; translatable strategy; translational goal; treatment strategy; vasoconstriction; venule

Project Summary / Abstract Osteoporosis is under diagnosed and under treated. It is essential that we develop novel tools for early detection and treatment strategies to reduce the number of fragility fractures that accompany aging. Systemic hypertension is another disease of aging that commonly co-exists with osteoporosis and likely predisposes individuals to the disease. In this multidisciplinary project, we will investigate a common molecular basis between hypertension and osteoporosis that weakens bone during aging. Our preliminary data indicate that experimental hypertension involving mice is associated with a striking loss in bone strength, which is mediated in part by the production of colony stimulating factor 1 (CSF1) in the bone marrow. The first goal of the project will be to test the hypothesis that enhanced endothelial cell deformation and elevated blood pressure promote the age-related decline in bone strength. We will employ cell culture experiments in which endothelial cells are dynamically stretched below human monocytes with and without exogenous recombinant proteins to determine if factors released by the activated endothelium promote osteoclast differentiation. In addition, we will lower blood pressure of aged mice and determine if this improves bone strength by reducing inflammatory cytokines that favor bone resorption. The second goal will be to test the hypothesis that enhanced sympathetic tone in aging and hypertension promotes immune activation and bone loss. We are experts at modulating sympathetic tone using a technique called Designer Receptor Exclusively Activated by Designer Drugs and by local denervation techniques. Thus, we will increase sympathetic tone to determine if this mimics the age-related decline in bone strength and decrease sympathetic tone to determine if this prevents hypertension and aging-induced loss in bone strength. The third goal will be to delete the endothelial CSF1 gene in adult mice to firmly establish the endothelium as a mediator of osteoporosis. Finally, our prior work has established a critical role of the cytokine interleukin (IL) 17A in hypertension, and others have shown that it plays a critical role in bone loss due estrogen withdrawal (menopause). We will therefore generate mutant mice that will allow deletion of IL17 receptor A in adult mice and determine if this prevents hypertension-related bone loss. As a translational goal, we will treat aged or hypertensive mice with a control antibody and vehicle, a neutralizing anti-CSF1 antibody, or an IL-17RA antagonist and determine if these strategies improve bone strength. In all aims we will 1) monitor blood pressure and bone mass, 2) assess immune cell profiles in the bone marrow, and 3) comprehensively characterize bone strength including toughness and other bone quality measurements. By understanding how hypertension affects bone marrow in the context of aging and by working as a collaborative research team comprised of different skill sets, new therapeutic strategies can be identified to prevent the age-related increase in fracture risk.

项目摘要/摘要