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Targeting the ubiquitin-proteasome pathway to reverse catabolic action of PTH in bone

靶向泛素-蛋白酶体途径逆转 PTH 在骨中的分解代谢作用

基本信息

批准号：
10450164
负责人：
Bin Wang
金额：
$ 32万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450164
关键词：
Adverse effects Anabolic Agents Anabolism Arginine Bone Marrow Cells Bone Resorption Bone remodeling CRISPR/Cas technology Calcium Calvaria Catabolism Cells Clinical Data Coculture Techniques Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Down-Regulation Exposure to GTP-Binding Protein alpha Subunits, Gs Goals Grant Histologic Homeostasis Implant In Vitro Infusion procedures Injections Knock-out Left Ligands Lysine Mediating Metabolic Bone Diseases Modeling Molecular Mus National Institute of Arthritis and Musculoskeletal and Skin Diseases Nuclear Oral Osteoblasts Osteoclasts Osteogenesis Osteoporosis PTH gene Parathyroid Hormone Receptor Pathogenicity Pathway interactions Phospholipase Phospholipase C Play Production Proteasome Inhibitor Publishing Receptor Activation Receptor Signaling Regulation Research Role Safety Scanning Signal Pathway Signal Transduction Techniques Testing Therapeutic Toxic effect Treatment Efficacy Ubiquitin Ubiquitin-Proteasomal Pathway Ubiquitination arm base beta catenin bone bone loss bone marrow mesenchymal stem cell bone metabolism cost effective desensitization design extracellular improved in vivo microCT mineralization mouse model multicatalytic endopeptidase complex osteoblast differentiation pre-clinical prevent receptor receptor downregulation receptor expression response side effect

项目摘要

Project Summary/Abstract Intermittent parathyroid hormone (PTH) by daily injection increases bone formation, whereas continuous PTH causes bone resorption and limits its therapeutic value. Understanding the molecular mechanisms that promote both the beneficial anabolic PTH actions and the problematic adverse effects is critical to improving the therapeutic efficacy of PTH-based treatments. The ubiquitin-proteasome pathway plays an important role in regulating and controlling bone metabolism. The type 1 PTH receptor (PTHR) desensitizes in response to brief exposure to PTH and sustained treatment with PTH downregulates the PTHR in osteoblasts. It is unknown whether continuous PTH-caused bone loss is mediated through the ubiquitin-proteasome pathway. In studies supported by an NIAMS R03 grant, we determined that continuous PTH treatment induces PTHR ubiquitination and degradation, thereby inhibiting osteoblast differentiation and promoting osteoclast resorptive activity. In addition, PTH activates multiple signaling pathways but not all of them are anabolic. Recent data from others and our group have demonstrated that beta-catenin interacts with the PTHR carboxyl-terminal region and switches PTHR signaling from Gs/cAMP to Gq/PLC activation. Furthermore, our preliminary data show that ixazomib, a newly approved oral proteasome inhibitor with less toxicity, is able to block continuous PTH-induced PTHR proteasomal degradation and reverse PTHR signaling switch by dissociating beta-catenin from the PTHR. Based on these findings, we hypothesize that ixazomib is capable of converting the catabolic effect of continuous PTH to an anabolic effect by blocking PTHR degradation and dissociating beta-catenin. The goals of our proposed studies are to: 1) establish the proof-of-principle that inhibition of PTHR downregulation and PTHR interaction with beta-catenin renders continuous PTHR activation more effective in promoting bone formation; and 2) generate important pre-clinical data assessing the efficacy, safety, and side effects of ixazomib in our murine model of continuous PTH-mediated bone loss. Three specific aims are developed to test this hypothesis and achieve these goals, employing independent and complementary strategies. Aim 1 will detail how ixazomib rescues continuous PTH-induced PTHR catabolic signaling. In Aim 2, we will establish whether ixazomib converts continuous PTH catabolic effect to bone anabolism in vivo. Aim 3 will characterize mechanisms by which ixazomib reverses the osteocatabolic effect of continuous PTH in vitro. Successful completion of the proposed research will greatly advance our understanding of the mechanisms that promote/limit PTH effects on bone formation, and provide strong basic and preclinical data that will clarify the path to a more effective osteoporosis treatment.

项目总结/文摘