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Molecular regulation of osteoclast maturation

破骨细胞成熟的分子调控

基本信息

批准号：
9220645
负责人：
YONGWON CHOI
金额：
$ 35.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9220645
关键词：
Actins Address Adhesions Adverse effects Affect Biological Process Biology Bone Marrow Cells Bone Resorption Cells Chemicals Clinical Trials Complex Coupled Data Development Differentiation Antigens Disease Eligibility Determination Exhibits FOS gene Family member Gene Expression Generations Genes Genetic Homeostasis Hybrids In Vitro Individual Inflammation Inflammatory Ions Ligands Link Molecular Mus Mutant Strains Mice Osteoblasts Osteoclasts Osteogenesis Osteoporosis prevention Ovariectomy P2X-receptor Pathogenicity Pathologic Pathway interactions Pattern Phase Physiological Play Proteins Purinoceptor Regulation Reporting Resolution Role Signal Transduction Specificity Staining method Stains TNFSF11 gene Testing Therapeutic Therapeutic Agents Tissues Vesicle X-Ray Computed Tomography bisphosphonate bone bone loss bone strength cathepsin K cell motility design differential expression experimental study improved in vivo inhibitor/antagonist member novel programs public health relevance receptor therapeutic target trafficking treatment strategy vacuolar H+-ATPase virtual

项目摘要

DESCRIPTION (provided by applicant): Bone homeostasis is maintained by bone-forming osteoblasts (OBs) and bone-resorbing osteoclasts (OCs). Excessive OC activity can cause pathogenic bone loss, so it is important to understand the molecular signaling and genetic programs controlling the roughly three phases of OC biology: commitment, maturation, and resorption. Current bone loss treatments, bisphosphonates and anti-RANKL, may target early OC commitment and/or late viability. While anti-resorptive, long-term use of these treatments may cause compromised bone strength. This side effect may be due to inhibition of coupled bone formation, which requires positive interplay between OCs and OBs. Therefore, a better treatment strategy may be to target late-stage OCs rather than early OC differentiation. Recent clinical trials targeting OC resorption support this idea, inhibiting resorption without diminutionof either OC numbers or coupled bone formation. Studies in mice lacking late-stage OC factors DC-STAMP or Atp6v0d2 further support this idea. Therefore, better understanding the regulatory factors and mechanisms of OC maturation may be extremely useful for providing better therapeutic targets. For this reason, we designed a screening protocol to identify genes associated with OC maturation. The gene that best fit our criteria was identified as P2X5, a member of the P2X subfamily of purinergic receptors about which little is known. We are now employing P2X5-/- mice and preliminarily show P2X5-/- OC maturation in vitro is defective. This new data may identify P2X5 as a potential target of P2X subfamily inhibitors reported to affect OC function, and P2X5 may represent the necessary genetic link to further pursue potential OC maturation- related therapeutic strategies. We therefore propose the following specific aims: 1. Investigate the effect of P2X5 deficiency on osteoclast development and function. To begin to define the requirement for P2X5 in OC biology per se, we will first assess early P2X5-/- OC commitment ex vivo, and then interrogate P2X5-/- OC maturation through gene expression and cell biologic approaches ex vivo. To examine the effects of P2X5 deficiency on bone homeostasis, OC function and maturation in vivo, we will subject P2X5-/- bones and bone sections obtained under normal, OVX, PTH-treated, or inflammatory conditions to high-resolution micro- computed tomography and histomorphometry, as well as TRAP staining. 2. Determine mechanisms of P2X5 function in the context of osteoclast biology. To begin to determine by what mechanism(s) P2X5 functions in OCs, we will assess differentiation/maturation of P2X5-/- OCs retrovirally-rescued with various P2X subfamily members as well as TM1 and TM2 domain hybrids. Further, we will examine the occurrence and potential importance of OC-specific P2X5 hetero-oligomerization with other P2X members. Finally, to both determine target specificity and to begin to assess therapeutic potential, we will examine the effects of P2X5 deficiency on OC sensitivity to the P2X ligand ATP and to known P2X chemical inhibitors. Together, these studies should greatly improve our understanding of OC maturation and its relationship to P2X5 function.