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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：
STAVROS C. MANOLAGAS
金额：
--
依托单位：
CENTRAL ARKANSAS VETERANS HLTHCARE SYS
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：
https://reporter.nih.gov/project-details/10254219
关键词：
Adult Androgen Receptor Androgens Apoptosis Apoptotic Applications Grants Attenuated B-Lymphocytes Bone Marrow Bone Marrow Cells Bone remodeling CD19 gene CXCL12 gene CXCR4 gene Calvaria Cell Culture Techniques Cells Coculture Techniques Dendrimers Development Down-Regulation Estradiol Estrogen Receptor alpha Estrogens Family Female Funding Generations Hematopoietic Homing Hormones Hydrogen Peroxide In Vitro Life Longevity Maintenance Malignant neoplasm of prostate Mediating Mesenchymal Mesenchymal Stem Cells Messenger RNA Mitochondria Molecular Mus Nuclear Null Lymphocytes Orchiectomy Osteoblasts Osteoclasts Osteocytes Osteoporosis Pharmaceutical Preparations Plasma Production Proteins Receptor Signaling Research Role Signal Transduction Surface TNFSF11 gene Testing Testosterone Veterans Woman Work attenuation base bone bone loss bone mass cell type chemokine cortical bone dentin matrix protein 1 gonad function insight macrophage male malignant breast neoplasm men mouse model novel novel therapeutics osteoclastogenesis osteoporosis with pathological fracture prevent progenitor protective effect receptor reproductive organ sex substantia 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