Osteoclastic Protein-Tyrosine Phosphatase and Resorption

破骨蛋白酪氨酸磷酸酶和吸收

• 批准号: 8391128
• 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
• 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/8391128
• 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; 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; public health relevance; receptor; repaired; research study; rho; rho GTP-Binding Proteins; sex; skeletal; substantia spongiosa; therapeutic target

DESCRIPTION (provided by applicant): 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) 1 signaling through an upregulation of the c-Src-dependent phosphorylation of ER1 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) 1 signaling through the c-Src-dependent phosphorylation of ER1 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 ER1 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 ER1 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.

描述（由申请人提供）：

项目成果

Opposing effects of Sca-1(+) cell-based systemic FGF2 gene transfer strategy on lumbar versus caudal vertebrae in the mouse.

基于SCA-1（+）基于细胞的全身FGF2基因转移策略对腰椎与小鼠尾椎的相反影响。

• DOI: 10.1038/gt.2016.21
• 发表时间: 2016-06
• 期刊: Gene therapy
• 影响因子: 5.1
• 作者: Lau KH;Chen ST;Wang X;Mohan S;Wergedal JE;Kesavan C;Srivastava AK;Gridley DS;Hall SL
• 通讯作者: Hall SL

EphA4 receptor is a novel negative regulator of osteoclast activity.

EphA4受体是破骨细胞活性的新型负调节因子。

• DOI: 10.1002/jbmr.2084
• 发表时间: 2014
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Stiffel,Virginia;Amoui,Mehran;Sheng,MatildaH-C;Mohan,Subburaman;Lau,K-HWilliam
• 通讯作者: Lau,K-HWilliam