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Therapeutic targeting of GPCR Gbetagamma-GRK2 in osteoarthritis

GPCR Gbetagamma-GRK2 在骨关节炎中的治疗靶向

基本信息

批准号：
10558594
负责人：
Fadia Ali Kamal
金额：
$ 33.73万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-21 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10558594
关键词：
Agonist Antidepressive Agents Attenuated Binding Cartilage Cell Differentiation process Cells Chondrocytes Clinical Clinical Research Clinical Trials Collagen Coupled Data Degenerative polyarthritis Development Disease Enzymes Epiphysial cartilage FDA approved Financial Hardship Future G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits GTP-Binding Proteins Genetic Healthcare Systems Heart Diseases Homeostasis Human Hypertrophy In Vitro Kidney Diseases Knockout Mice Medial meniscus structure Mediating Modeling Mus Natural regeneration Operative Surgical Procedures PI3K/AKT PTH gene Parathyroid Hormone Receptor Paroxetine Pathologic Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Physical Function Physiological Play Process Production Proteoglycan Quality of life Receptor Signaling Regulation Reporting Role Signal Transduction System Testing Therapeutic Agents Traumatic Arthropathy Treatment Efficacy Work arthropathies cartilage degradation cartilage regeneration cell growth chondroprotection conditional knockout desensitization effective therapy gallein human tissue in vivo inhibitor mouse model new therapeutic target novel novel therapeutic intervention pre-clinical prevent protective effect receptor receptor internalization recruit regenerative small molecule small molecule inhibitor therapeutic target

项目摘要

Abstract Osteoarthritis (OA) is a debilitating disease of the joints involving progressive cartilage degeneration, with no disease modifying therapy available. Chondrocytes, the cellular component of cartilage, regulate cartilage homeostasis by modulating matrix turnover via secretion of proteoglycans and collagen as well as matrix-degrading enzymes. In OA, articular chondrocytes acquire an aberrant phenotype where they undergo differentiation and hypertrophy (CH) with increased production of matrix degrading enzymes leading to cartilage degeneration. G protein-coupled receptors (GPCRs) is a superfamily of receptors coupled to intracellular G-proteins. Agonist binding to a GPCR activates its G- protein a subunit (Ga) physiologic signaling. A parallel G-protein bg subunit (Gbg) activation and recruitment of GPCR kinases (GRK2 particularly) leads to GPCR internalization and signal termination. GRK2 expression and Gbg-GRK2 signaling are pathologically elevated in several diseases, leading to GPCR desensitization and loss of Ga signaling. Importantly, we and others have recently reported the therapeutic efficacy of Gbg-GRK2 inhibition, both by rescuing Ga physiologic activity and by inhibiting direct downstream pathological signaling that promotes cell growth and differentiation; this was achieved using both novel small molecules and FDA-approved drugs. Chondrocytes are rich in type 1 parathyroid hormone receptor (PTH1R, a GRCR), where Gas and PTH1R are key regulators of CH, both are under tight regulation by Gbg-GRK2. However, the role of Gbg-GRK2 signaling in CH and OA remains unknown. Our preliminary work to establish the role of Gbg-GRK2 in CH during OA indicates that GRK2 expression and activity are increased in articular chondrocytes of both OA patients and mice with posttraumatic OA. Interestingly, in vitro and in vivo Gbg-GRK2 inhibition attenuated CH and cartilage degeneration in mice with DMM (surgical destabilization of the medial meniscus to induce OA). These preliminary findings support our overarching hypothesis that: Gbg-GRK2 signaling plays a central role in CH during OA, and its inhibition represents a novel therapeutic strategy for OA. To validate our hypothesis we will use chondrocyte conditional knockout mice and small molecule Gbg and GRK2 inhibitors in an in vivo OA mouse model and utilize different in vitro systems (both murine and human), to (1) determine the role of GRK2 signaling in articular CH in OA, (2) determine the therapeutic efficacy of small molecule Gbg-GRk2 inhibitors in OA, and (3) determine the role of Gbg-GRK2 signaling in PTH1R chondro-protective/regenerative effect in OA. These studies enable us to discover a novel therapeutic strategy and therapeutic agents for OA (both novel and FDA-approved) in a preclinical setting, thus laying the grounds for our future clinical study to establish a novel effective OA therapy.

摘要骨关节炎（OA）是一种使关节衰弱的疾病，涉及进行性软骨退变，可用的修改治疗。软骨细胞是软骨的细胞成分，通过以下方式调节软骨稳态：通过分泌蛋白聚糖和胶原蛋白以及基质降解酶来调节基质周转。在OA中，关节软骨细胞获得异常表型，其中它们经历分化和肥大（CH），导致软骨退化的基质降解酶的产生增加。g蛋白偶联受体 GPCR是与细胞内G蛋白偶联的受体超家族。激动剂与GPCR结合激活其G- 蛋白a亚基（Ga）生理信号传导。GPCR的平行G蛋白bg亚基（Gbg）激活和募集激酶（特别是GRK2）导致GPCR内化和信号终止。GRK2表达和Gbg-GRK2 信号传导在几种疾病中病理性升高，导致GPCR脱敏和Ga信号传导丧失。重要的是，我们和其他人最近报道了Gbg-GRK2抑制的治疗效果，无论是通过挽救Ga 生理活性和抑制促进细胞生长的直接下游病理信号传导，分化;这是使用新型小分子和FDA批准的药物实现的。软骨细胞富含 1型甲状旁腺激素受体（PTH1R，一种GRCR），其中Gas和PTH1R是CH的关键调节因子，两者均在 Gbg-GRK 2的严格监管。然而，Gbg-GRK2信号传导在CH和OA中的作用仍然未知。我们初步研究表明，骨钙素受体GRK2的表达和活性与骨关节炎的发病相关。 OA患者和创伤后OA小鼠的关节软骨细胞增加。有趣的是，在体外和体内， Gbg-GRK2抑制减弱了DMM小鼠的CH和软骨变性（手术破坏内侧软骨的稳定性）。半月板以诱导OA）。这些初步发现支持了我们的总体假设，即：在CH在OA过程中的核心作用，其抑制代表了OA的新治疗策略。来验证我们假设我们将在体内使用软骨细胞条件性敲除小鼠和小分子Gbg和GRK2抑制剂， OA小鼠模型，并利用不同的体外系统（鼠和人），以（1）确定GRK2的作用（2）确定小分子Gbg-GRk2抑制剂在OA中的治疗功效，和 (3)确定Gbg-GRK2信号传导在OA中PTH1R软骨保护/再生作用中的作用。这些研究使我们能够发现一种新的治疗策略和治疗剂的OA（新的和FDA批准的），临床前环境，从而为我们未来的临床研究奠定了基础，以建立一种新的有效的OA治疗。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Standardized Histomorphometric Evaluation of Osteoarthritis in a Surgical Mouse Model.

DOI：
10.3791/60991
发表时间：
2020-05-06
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Pinamont WJ;Yoshioka NK;Young GM;Karuppagounder V;Carlson EL;Ahmad A;Elbarbary R;Kamal F
通讯作者：
Kamal F

GRK2, a novel regulator of skeletal development.

GRK2，骨骼发育的新型调节因子。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Yoshioka,NatalieK;Karuppagounder,Vengadeshprabhu;Pinamont,WilliamJ;Deiter,GinaM;Elbarbary,ReyadA;Pacifici,Maurizio;Kamal,Fadia
通讯作者：
Kamal,Fadia

Aspiration-assisted bioprinting of the osteochondral interface