Targeting the PTH1R Signaling Pathway for Osteoarthritis Therapy by a Novel Disruptor Peptide

通过新型干扰肽靶向 PTH1R 信号通路治疗骨关节炎

• 批准号: 10472490
• 负责人: Bin Wang
• 金额: $ 33.98万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472490
• 关键词: Affinity; Amino Acids; Anabolic Agents; Award; Binding; Binding Proteins; Binding Sites; Biochemical; Cartilage; Catabolism; Cells; Chondrocytes; Clinical Trials; Complex; Cyclic AMP; Data; Degenerative polyarthritis; Dependovirus; Development; Disease Progression; Doxycycline; Event; GTP-Binding Protein alpha Subunits, Gs; Genetic Materials; Goals; Human; Hypertrophy; Injections; Joints; Knee joint; Lesion; Mediating; Mesenchymal; Modeling; Mus; NF-kappa B; Natural regeneration; Outcome; Oxidative Stress; PTH gene; Parathyroid Hormone Receptor; Pathogenesis; Pathogenicity; Pathway interactions; Peptides; Play; Prevention; Protein Inhibition; Publishing; Reactive Oxygen Species; Receptor Signaling; Regulation; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Tropism; WNT Signaling Pathway; Work; arm; articular cartilage; base; beta catenin; cartilage degradation; cartilage repair; cost effective; design; enzyme activity; enzyme pathway; improved; in vivo; medication compliance; molecular modeling; mouse model; novel; parathyroid hormone (1-34); parathyroid hormone-related protein; particle; pre-clinical; prevent; protective effect; receptor; response; transgene delivery

Project Summary/Abstract The long-term goal of this project is to design cost-effective anabolic agents with less toxicity, and convenient use for the treatment of osteoarthritis (OA). Current treatments of OA have limited effects on the prevention and progression of cartilage degeneration. Complex signaling events in cartilage underlie OA pathogenesis and these can be targeted. Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) bind to the type I PTH/PTHrP receptor (PTH1R) to elicit both Gs/cAMP and Gq/PLC signaling pathways. Published as well as our preliminary data demonstrate a PTH1R Gs/cAMP signaling arm that is therapeutic and a Gq/PLC signaling arm that is pathogenic. Beta-catenin mediates canonical Wnt signaling, facilitates chondrocyte hypertrophic differentiation and plays an important role in OA development. However, the interplay between PTH1R and beta-catenin that contributes to OA pathogenesis remains poorly understood. Recent data from others and our group have demonstrated that beta-catenin interacts with the PTH1R and switches PTH1R signaling from Gs/cAMP to Gq/PLC activation. Moreover, beta-catenin expression is increased in human OA, the outcome of which promotes the PTH1R signaling switch and causes articular cartilage loss and OA development. It has been established that systemic or intra-articular administration of PTH or PTHrP is able to prevent cartilage degeneration and regenerate the damaged cartilage. However, daily injection of PTH or PTHrP is inconvenient and reduces medication adherence. PTHrP is normally secreted by chondrocytes in low levels and is increased in OA. The carboxyl-terminal region of six amino acids is the beta- catenin binding site in PTH1R. Our preliminary studies have determined that this six-amino-acid peptide (disruptor peptide) blocks beta-catenin binding to PTH1R. Based on these findings, we hypothesize that the disruptor peptide biases endogenous PTHrP-induced PTH1R signaling to favor the therapeutic signaling arm and improve the ability of PTHrP to inhibit cartilage degeneration and treat/prevent OA. Three specific aims are proposed to test this hypothesis. Aim 1 will develop a superior disruptor peptide (SDP) to efficiently block the interaction of beta-catenin with PTH1R and inhibit the beta-catenin-mediated PTH1R signaling switch. In Aim 2, we will establish whether the adeno-associated virus expressing SDP prevents cartilage lesions and increase cartilage repair in a mouse OA model. Aim 3 will characterize mechanisms by which the SDP regulates PTHrP effects on chondrocyte hypertrophic differentiation and chondrocyte catabolism. Successful completion of these studies therefore constitutes important preclinical findings that would facilitate advancement of this work toward clinical trials of OA, and ultimate application in humans.

项目摘要/摘要 该项目的长期目标是设计具有较小毒性和方便的成本效益合成代谢代理 用于治疗骨关节炎（OA）。 OA的当前治疗对预防的影响有限 软骨变性的进展。 OA发病机理的软骨基础中的复杂信号事件 这些可以针对目标。甲状旁腺激素（PTH）和甲状旁腺激素相关蛋白（PTHRP）结合 到I型PTH/PTHRP受体（PTH1R），以引起GS/CAMP和GQ/PLC信号通路。出版 以及我们的初步数据还展示了PTH1R GS/CAMP信号传导组， 致病性的GQ/PLC信号传导臂。 β-catenin介导规范的Wnt信号传导，促进 软骨细胞肥厚性分化，在OA发育中起重要作用。但是， 有助于OA发病机理的PTH1R和Beta-catenin之间的相互作用仍然很少理解。 来自他人和我们的小组的最新数据表明，β-catenin与PTH1R相互作用 开关PTH1R信号从GS/CAMP到GQ/PLC激活。而且，β-catenin的表达是 人OA的增加，其结果促进了PTH1R信号开关并引起关节 软骨损失和OA发展。已经确定了系统的或关节内给药 PTH或PTHRP能够防止软骨变性并再生受损的软骨。但是，每天 注射PTH或PTHRP是不方便的，可降低药物依从性。 PTHRP通常由 软骨细胞低水平，在OA中增加。六个氨基酸的羧基末端区域是β- pth1r中的catenin结合位点。我们的初步研究确定这种六氨基酸肽 （破坏肽）阻断与PTH1R结合的β-catenin结合。根据这些发现，我们假设 破坏肽偏见内源性PTHRP诱导的PTH1R信号传导，有利于治疗信号臂 并提高PTHRP抑制软骨变性并治疗/预防OA的能力。三个具体目标是 提议检验这一假设。 AIM 1将开发出优质的破坏者肽（SDP），以有效地阻止 β-catenin与PTH1R的相互作用并抑制β-catenin介导的PTH1R信号开关。目标 2，我们将确定表达SDP的腺相关病毒是否可以防止软骨病变和 增加小鼠OA模型中的软骨修复。 AIM 3将表征SDP的机制 调节PTHRP对软骨细胞肥厚性分化和软骨细胞分解代谢的影响。成功的 因此，这些研究的完成构成了重要的临床前发现，这将有助于 这项工作朝着OA的临床试验以及在人类中的最终应用方面的进步。