Androgens, estrogens, and bone loss in males
男性雄激素、雌激素和骨质流失
基本信息
- 批准号:10254219
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-01-01 至 2021-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAndrogen ReceptorAndrogensApoptosisApoptoticApplications GrantsAttenuatedB-LymphocytesBone MarrowBone Marrow CellsBone remodelingCD19 geneCXCL12 geneCXCR4 geneCalvariaCell Culture TechniquesCellsCoculture TechniquesDendrimersDevelopmentDown-RegulationEstradiolEstrogen Receptor alphaEstrogensFamilyFemaleFundingGenerationsHematopoieticHomingHormonesHydrogen PeroxideIn VitroLifeLongevityMaintenanceMalignant neoplasm of prostateMediatingMesenchymalMesenchymal Stem CellsMessenger RNAMitochondriaMolecularMusNuclearNull LymphocytesOrchiectomyOsteoblastsOsteoclastsOsteocytesOsteoporosisPharmaceutical PreparationsPlasmaProductionProteinsReceptor SignalingResearchRoleSignal TransductionSurfaceTNFSF11 geneTestingTestosteroneVeteransWomanWorkattenuationbasebonebone lossbone masscell typechemokinecortical bonedentin matrix protein 1gonad functioninsightmacrophagemalemalignant breast neoplasmmenmouse modelnovelnovel therapeuticsosteoclastogenesisosteoporosis with pathological fracturepreventprogenitorprotective effectreceptorreproductive organsexsubstantia spongiosa
项目摘要
Both androgens and estrogens contribute to the maintenance of bone mass during adult life in men, but the cell
targets and molecular mechanisms of these effects remain poorly understood. During the preceding funding
period, we found that the effects of androgens on cancellous bone result from AR signaling in cells of the
mesenchymal lineage leading to a decrease in osteoclasts; and orchidectomy (ORX) increases soluble RANKL
levels as well as the number of B-lymphocytes in the murine bone marrow. RANKL derived from osteocytes is
critical for cancellous bone remodeling and B-lymphocyte-derived RANKL contributes to the loss of cancellous
bone mass in ovariectomized (OVX) mice. In cortical bone, however, the effects of androgens do not require AR
signaling in any cell type of the mesenchymal lineage, nor do they require ERα signaling downstream of
committed osteoblast progenitors targeted by Osx1-Cre, or AR or ERα signaling in the osteoclast lineage.
Estrogens, nonetheless, attenuate endocortical resorption in females by ERα signaling in uncommitted
mesenchymal progenitors targeted by Prx1-Cre. In addition, the mRNA and secreted protein levels of SDF1 – a
chemotactic cytokine of the CXC family that is abundantly expressed in Prx1-Cre targeted cells and promotes
osteoclast generation – are higher in GFP-tagged ERα null cells as well as bone marrow cell cultures from female
ERαf/f;Prx1-Cre mice as compared to identical cultures from littermate controls; and so is osteoclastogenesis in
co-cultures of ERα null BM stromal or calvaria cells with macrophages. Furthermore, both OVX and ORX
increase SDF1 in the bone marrow plasma, administration of E2 to ORX mice prevents this increase, and E2,
but not DHT, prevents cortical bone loss in ORX mice. Finally, we found that the OVX- or ORX-induced cortical
bone loss is prevented by restraining H2O2 generation in osteoclast mitochondria; and the loss of cortical bone
mass in OVX mice is prevented by a 17β-E2 dendrimer conjugate (EDC), incapable of stimulating nuclear-
initiated actions of ERα. Based on these advances, we will test the interrelated hypotheses that: in males, the
protective effects of androgens on cancellous bone result from AR signaling in osteocytes, B-lymphocytes, or
both. These actions result in the attenuation of RANKL and thereby attenuation of the number of cancellous
osteoclasts. The protective effects of androgens against endocortical resorption result, at least in part, from ERα-
mediated actions (upon aromatization of androgens to estrogens) on Prx1-Cre targeted uncommitted
mesenchymal progenitors. These actions repress SDF1 production, thereby attenuating osteoclast formation
and homing at the endosteal surfaces. The suppressive effect of estrogens on SDF1 production ultimately leads
to the restraining of H2O2 accumulation in osteoclasts and results from non-nuclear-initiated signaling of the
ERα. To advance these hypotheses we will try to elucidate the mechanism of the protective effects of androgens
on cancellous bone by determining the role of osteocyte- and B-lymphocyte-derived RANKL as well as the role
of the B lymphocyte AR in these effects. To do this we will study: i) mice in which RANKL is deleted from mature
osteoblasts/osteocytes (RANKLf/f;Dmp1-Cre), ii) mice in which both AR and RANKL are deleted from
osteoblasts/osteocytes (RANKLf/f;ARf/y;Dmp1-Cre), iii) mice in which RANKL is deleted from B-lymphocytes
(RANKLf/f;CD19-Cre), and iv) mice in which AR is deleted from B-lymphocytes (ARf/y;CD19-Cre). In addition, we
will elucidate the mechanism of the protective effects of androgens on cortical bone by investigating: a) whether
down-regulation of SDF1 in uncommited mesenchymal progenitors is responsible for some of these effects
using: i) mice in which SDF1 is deleted in Prx1-Cre targeted cells, and ii) mice in which the SDF1 receptor,
CXCR4, is deleted in LysM-Cre targeted cells; and b) whether the effect of androgens results from ERα-mediated
actions upon androgen aromatization to estrogens using ERαf/f;Prx1-Cre mice. Using co-cultures of stromal and
hematopoietic cells, we will also examine whether SDF1 promotes osteoclastogenesis via H2O2; and whether
the effect of estrogens on SDF1 results from non-nuclear-initiated signaling of the ERα.
雄激素和雌激素都有助于维持成年男性的骨量,但细胞
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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STAVROS C. MANOLAGAS其他文献
STAVROS C. MANOLAGAS的其他文献
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{{ truncateString('STAVROS C. MANOLAGAS', 18)}}的其他基金
Estrogens, androgens, aging, and bone loss in males
男性雌激素、雄激素、衰老和骨质流失
- 批准号:
8244288 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Estrogens, androgens, aging, and bone loss in males
男性雌激素、雄激素、衰老和骨质流失
- 批准号:
8413601 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Estrogens, androgens, aging, and bone loss in males
男性雌激素、雄激素、衰老和骨质流失
- 批准号:
8598056 - 财政年份:2012
- 资助金额:
-- - 项目类别:
MOLECULAR MECHANISMS OF THE SKELETAL EFFECTS OF ESTROGEN IN OLD AGE
雌激素对老年骨骼影响的分子机制
- 批准号:
7094994 - 财政年份:2006
- 资助金额:
-- - 项目类别:
HORMONAL CONTROL OF CYTOKINES IN BONE AND MARROW CELLS
骨细胞和骨髓细胞中细胞因子的激素控制
- 批准号:
6316954 - 财政年份:2000
- 资助金额:
-- - 项目类别:
HORMONAL CONTROL OF CYTOKINES IN BONE AND MARROW CELLS
骨细胞和骨髓细胞中细胞因子的激素控制
- 批准号:
6098701 - 财政年份:1999
- 资助金额:
-- - 项目类别:
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