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Osteoclastic Protein-Tyrosine Phosphatase and Resorption

破骨蛋白酪氨酸磷酸酶和吸收

基本信息

批准号：
8195632
负责人：
Kin-Hing William Lau
金额：
--
依托单位：
VA LOMA LINDA HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-10-01 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8195632
关键词：
Actins Address Adhesions Adult Affinity Aging Attenuated B-Lymphocytes Binding Biology Bone Diseases Bone Marrow Transplantation Bone Resorption Bone Resorption Inhibition CD29 Antigen Cell Differentiation process Cell fusion Cells Chimeric Proteins Clinical Complex Cytoskeleton Data Dendritic Cells Development Dimerization Disease Enzymes EphA Receptors EphA4 Receptor Ephrin B Receptor Ephrins Equilibrium Estrogen Receptor 1 Estrogen Receptor alpha Estrogen Replacements Estrogens Etiology Evaluation Exhibits FOS gene Family Female Foundations Fracture Functional disorder Future Gene Expression Genes Glutathione S-Transferase Growth Guanosine Triphosphate Health Hematopoietic Hematopoietic stem cells Hip Fractures Human ITAM ITIM In Vitro Incidence Integral Membrane Protein Integrin Inhibition Integrin beta3 Integrins Knock-out Knockout Mice Knowledge Laboratories Ligand Binding Ligands MAPK9 gene Marrow Mediating Mediator of activation protein Medical Metabolic Mission Modality Molecular Molecular Mechanisms of Action Monomeric GTP-Binding Proteins Morbidity - disease rate Mus Mutate NR0B2 gene Osteoblasts Osteoclasts Osteogenesis Osteoporosis Ovariectomy Pathway interactions Patient Care Patients Pattern Formation Pharmacogenomics Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotyrosine Physiology Play Postmenopausal Osteoporosis Process Protein Dephosphorylation Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Quality of life RU-486 Recombinants Regulation Research Project Grants Retroviral Vector Role SRC gene Signal Transduction Signaling Protein Small Interfering RNA Stem cells Symptoms TNFSF11 gene Tail Talin Testing Transgenic Mice Transgenic Organisms Tyrosine Phosphorylation Up-Regulation Vertebral column Veterans Wasting Syndrome Wild Type Mouse Work base bone bone loss bone mass cell motility cell type clinically relevant cost effective therapy ephexin improved in vitro activity in vivo inhibitor/antagonist insight interest macrophage male member migration monocyte mutant novel overexpression patient population paxillin prepuberty prevent protein-tyrosine kinase c-src receptor repaired research study rho rho GTP-Binding Proteins sex skeletal substantia spongiosa therapeutic target

项目摘要

The ultimate objective of this research project is to identify the molecular mechanism (and/or key mediators) by which osteoclastic resorption is regulated. In this regard, recent studies showed that targeted over-expression of a structurally unique osteoclastic protein-tyrosine phosphatase (PTP-oc) in osteoclastic cells led to a large increase in bone resorption and a marked decrease in bone mass in male but not female transgenic mice, compared to corresponding wild-type littermates. Very recent preliminary studies discovered two novel molecular mechanisms of PTP-oc to regulate the overall osteoclast activity: 1) the EphA4 signaling may function as a negative regulatory mechanism of osteoclastic resorption and PTP-oc stimulates osteoclast differentiation and activity through relieving the inhibitory actions of the EphA4 signaling via dephosphorylation of EphA4; and 2) the PTP-oc signaling increases estrogen receptor (ER) ¿ signaling through an upregulation of the c-Src-dependent phosphorylation of ER¿ in osteoclasts, which in turn suppresses bone resorption in adult female but not male PTP-oc transgenic mice. This proposal has three Specific Objectives to investigate these two novel mechanisms of PTP-oc. The first Objective is to demonstrate that the EphA4 signaling is negative regulator of osteoclasts through differential regulation of the various Rho GTPases and through suppression of the Erk1/2-c-Fos-NFAT1c cascade. This will be accomplished through evaluation of the bone phenotype of EphA4-deficient mice in vivo and to determine the effects of deficient EphA4 expression in osteoclast precursors of EphA4 null mice or transgenic over-expression of EphA4 in wild-type precursors on the formation, fusion, adhesion, migration, actin cytoskeleton re-organization, and resorption activity of osteoclasts in vitro. Effects of deficient EphA4 signaling in EphA4 null osteoclasts on the activation states of the various Rho GTPases and the Erk1/2-c-Fos-NFATc1 signaling cascade are also determined. The second Objective is to determine whether PTP-oc enhances by osteoclastic resorption, in part, through suppressing the inhibitory actions of the EphA4 on osteoclasts through direct dephosphorylation of EphA4. This is achieved by confirming that EphA4 is a cellular substrate of PTP-oc, and by demonstrating that over-expression of WT-PTP-oc, but not PD-PTP-oc, would inhibit the suppressive effects of the EphA4 signaling on osteoclast differentiation and activity. It is also tested by showing that the hemotopoietic stem cell-based marrow transplantation with WT- EphA4, but not the mutant lacking the key phosphotyrosine residues, would reverse the osteoporotic phenotype of EphA4 null mice. The third Objective is to determine whether the PTP-oc signaling increases estrogen receptor (ER) ¿ signaling through the c-Src-dependent phosphorylation of ER¿ in osteoclasts, which in turn suppresses bone resorption in adult female but not male PTP-oc transgenic mice. This is achieved by a) comparing the bone phenotype and the ER¿ signaling in osteoclasts of pre-pubertal male and female PTP-oc transgenic mice, 2) evaluating the effects of ovariectomy and estrogen replacement on the osteoclastic phenotype of adult female PTP-oc transgenic mice, and 3) evaluating the effects of PTP-oc over-expression in osteoclasts of ER¿ null female mice. Our work should provide important insights into the molecular mechanism of the osteoclast activation and/or the role of a unique osteoclastic enzyme (PTP-oc) in the regulation of two novel signaling mechanisms of osteoclastic resorption. Potential clinical relevance is that aberration in PTP-oc function could be involved in some patients with excess bone resorption and, as such, PTP-oc could be a target for pharmacogenomic treatments of osteoporosis and related bone-wasting diseases.

本研究项目的最终目的是确定分子机制（和/或关键介质）