Diverse effects of somatopause and aging on the skeleton

躯体更年期和衰老对骨骼的多种影响

• 批准号: 10399513
• 负责人: MITCHELL B SCHAFFLER
• 金额: $ 45.07万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399513
• 关键词: Adult; Affect; Age-Related Bone Loss; Aging; Apoptosis; Biology; Biomechanics; Bone Matrix; Bone Resorption; Bone Tissue; Carbonates; Cell Death; Cell Survival; Cells; Cessation of life; Collaborations; Development; Energy Metabolism; Environment; Fracture; Health; Health Care Costs; Homeostasis; Hormonal; Hormonal Change; Impairment; Insulin-Like Growth Factor I; Life; Life Expectancy; Link; Mechanics; Menopause; Metabolic; Metabolic stress; Metabolism; Minerals; Mitochondria; Molecular; Morbidity - disease rate; Morphology; Mus; Osteoblasts; Osteoclasts; Osteocytes; Osteoporosis; Outcome; Outcome Study; Oxidation-Reduction; Physiology; Process; Production; Property; Reactive Oxygen Species; Regulation; Resistance; Risk; Signal Transduction; Skeleton; Somatotropin; Stress; System; Testing; Tissues; age related; aged; bone; bone cell; bone health; bone loss; bone quality; crystallinity; detection of nutrient; flexibility; improved; in vivo; inorganic phosphate; insulin mediators; intercellular communication; mechanical load; mechanical properties; mineralization; mitochondrial dysfunction; normal aging; novel; preservation; response; sex

ABSTRACT: To date age-related changes in bone are thought to result from two distinct and potentially synergistic causes: i) systemic hormonal changes, particularly somatopause, the age-related declines in growth hormone [GH] and its mediator insulin-like growth factor-1 [IGF-1] and ii) “intrinsic” cumulative or temporal changes in bone cell activity and tissue properties. These processes are concomitant and overlapping, and their distinct effects on age-related bone loss were not established. We have developed an integrative molecular-to whole bone approach to study novel mechanisms controlling bone integrity during aging. We build on a long-standing collaboration between Dr. Schaffler, an expert in osteocytes and bone biomechanics, and Dr. Yakar, an expert in GH/IGF-1 physiology, and a new collaboration with Dr. Pavlov, an expert in mitochondria. We focus on osteocytes, which comprise > 95% of bone cells and are extremely long-lived. Osteocytes integrate the bone's hormonal and mechanical environment, produce the key signals that turn on osteoblasts and osteoclasts, and also directly influence bone material properties. In this proposal we will study the effects of the somatotropic axis on the viability and function of the aging osteocytes via the following aims: 1) Determine the cellular mechanisms by which GH/IGF-1 affect bone tissue quality; 2) Determine how GH/IGF-1 axis controls osteocyte viability and metabolic flexibility during aging. Our studies link three hallmarks of aging “altered intercellular communication”, which is central to tissue integrity, “mitochondrial dysfunction”, which is central to cell survival, and “deregulated nutrient sensing”, which is central to cellular metabolism. We expect unraveling the distinct and overlapping effects of normal aging and somatopause specifically on bone health. Completion of our studies will determine the morphological and the molecular mechanisms by which the GH/IGF-1 axis affects osteocytes of the aging skeleton.

文摘:

项目成果

ZYG11A Is Expressed in Epithelial Ovarian Cancer and Correlates With Low Grade Disease.

• DOI: 10.3389/fendo.2021.688104
• 发表时间: 2021
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Achlaug L;Somri-Gannam L;Meisel-Sharon S;Sarfstein R;Dixit M;Yakar S;Hallak M;Laron Z;Werner H;Bruchim I
• 通讯作者: Bruchim I

Lifelong Excess in GH Elicits Sexually Dimorphic Effects on Skeletal Morphology and Bone Mechanical Properties.

• DOI: 10.1002/jbmr.4699
• 发表时间: 2022-11
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Dixit, Manisha;Louis, Leeann D.;Basta-Pljakic, Jelena;Yildirim, Gozde;Poudel, Sher-Bahadur;Kumararaja, Fancy;List, Edward O.;Duran, Silvana Ortiz;Kopchick, John J.;Ruff, Ryan R.;Schaffler, Mitchell B.;Yakar, Shoshana
• 通讯作者: Yakar, Shoshana

Excess growth hormone triggers inflammation-associated arthropathy, subchondral bone loss, and arthralgia.

• DOI: 10.1016/j.ajpath.2023.02.010
• 发表时间: 2023-03
• 期刊: The American journal of pathology
• 作者: S. Poudel;R. Ruff;G. Yildirim;M. Dixit;B. Michot;J. Gibbs;Silvana Durán Ortiz;J. Kopchick;T. Kirsch;S. Yakar

Identification of ZYG11A as a candidate IGF1-dependent proto-oncogene in endometrial cancer.

• DOI: 10.18632/oncotarget.27055
• 发表时间: 2019-07-09
• 期刊: Oncotarget
• 作者: Achlaug, Laris;Sarfstein, Rive;Werner, Haim
• 通讯作者: Werner, Haim

The Olfactory Receptor Gene Product, OR5H2, Modulates Endometrial Cancer Cells Proliferation via Interaction with the IGF1 Signaling Pathway.

• DOI: 10.3390/cells10061483
• 发表时间: 2021-06-12
• 期刊: Cells
• 影响因子: 6
• 作者: Shibel R;Sarfstein R;Nagaraj K;Lapkina-Gendler L;Laron Z;Dixit M;Yakar S;Werner H
• 通讯作者: Werner H