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Identification of novel regulators governing osteoclast-osteoblast coupling

鉴定控制破骨细胞-成骨细胞偶联的新型调节剂

基本信息

批准号：
9385624
负责人：
Jae-Hyuck Shim
金额：
$ 26.46万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385624
关键词：
Adult Affect Affinity Chromatography Biochemical Bioinformatics Biology Biomechanics Bone Diseases Bone Matrix Bone Resorption Bone remodeling Cells Charge Complex Conditioned Culture Media Core Facility Coupled Coupling Data Deposition Deubiquitinating Enzyme Development Disease Effectiveness Elderly Equilibrium Forteo Generations Grant High Pressure Liquid Chromatography Human In Vitro Laboratories Mass Spectrum Analysis Mediating Molecular Multivesicular Body Mus Osteitis Deformans Osteoblasts Osteoclasts Osteogenesis Osteoporosis Pathogenesis Pathway interactions Phenotype Process Property Proteins Proteomics Recombinant Proteins Regulation Secondary to Signal Transduction Sorting - Cell Movement TNFSF11 gene Therapeutic Ubiquitin Ubiquitination base bisphosphonate bone bone loss bone mass bone turnover early onset human disease in vivo inhibitor/antagonist knock-down microCT migration mouse model novel osteoblast differentiation osteoclastogenesis osteogenic overexpression public health relevance screening skeletal spatiotemporal stem cells transcriptome

项目摘要

DESCRIPTION (provided by applicant): Spatiotemporal coupling of the activity of osteoblasts (OB) and osteoclasts (OC) is required for balance in bone remodeling. However, this coupling activity can limit the effectiveness of current therapies to treat osteoporosis, as therapies that increase bone formation (e.g. teraparatide) also increase bone resorption, and treatments that block bone resorption (e.g. bisphosphonates) arrest new bone formation. Dysregulation of this coupling process also contributes to pathological changes in bone mass, such as osteoporosis and Paget's disease of bone (PDB). PDB is a prevalent disorder affecting approximately 5% of elderly adults and is characterized by focal regions of highly exaggerated bone remodeling. Hence, understanding the molecular basis of OC/OB coupling is central to developing new treatments for bone loss and other disorders of bone remodeling. Here, we propose to expand our prior discovery that the late endosomal sorting protein CHMP5 is a novel dampener of NF-B signaling and OC/OB coupling in OCs with the following aims. In Aim 1, we will determine the contribution of OC-specific deletion of CHMP5 to PDB-like phenotypes by examining whether transfer of CHMP5-deficient hematopoetic stem cells (HSCs) results in PDB-like phenotypes in irradiated WT mice and whether transfer of WT HSCs reverses PDB-like phenotypes in irradiated CHMP5-deficient mice. Additionally, to confirm relevance of CHMP5 to human disease, we will examine whether CHMP5 deficiency can result in Pagetic phenotypes in human OCs. In Aim 2, we will build upon our preliminary data that CHMP5 is a key regulator of NF-B signaling and ubiquitin-mediated proteasomal degradation in OCs by performing biochemical studies to determine how dysregulation of the CHMP5 complex contributes to Pagetic phenotypes in OCs. First, we will examine whether inhibition of enhanced NF-B activity can reverse PDB-like phenotypes of CHMP5-deficient mice. Additionally, we will identify the proteins regulated by the CHMP5 complex in OCs using a combination of ubiquitination proteomics and affinity purification-based mass spectrometry. Finally, functions of the identified proteins in NF-B signaling and osteoclastogenesis will be validated in OCs. In Aim 3, given our preliminary data that the conditioned medium obtained from CHMP5-deficient OCs enhances OB activity, we will identify the OC-derived coupling factor(s) that promote OB activity using HPLC-based mass spectrometry. These putative osteogenic factors will be further validated by examining effects of overexpression and/or knockdown on promoting OB migration and/or differentiation. Upon completion of these aims, we will better understand how CHMP5 deletion in OCs contributes to the pathogenesis of PDB. As this disorder displays dramatic increases in OB activity that occur secondary to enhanced OC activity, harnessing this mechanism to promote bone formation would be an attractive approach for the treatment of disorders of low bone mass.