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LOXL2 in Temporomandibular Joint Osteoarthritis

LOXL2 在颞下颌关节骨关节炎中的作用

基本信息

批准号：
9100747
负责人：
Manish Bais
金额：
$ 12.28万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
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：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9100747
关键词：
Adult Affect Aftercare Age Age-Months Anabolic Agents Apoptosis Attenuated BMP2 gene Binding Biological Markers Calcified Career Mobility Cartilage Catabolism Cells Chondrocytes Clinical Collagen Collagen Type II Complex Copper Data Degenerative Disorder Degenerative polyarthritis Deposition Development Disease Experimental Animal Model Extracellular Matrix Extracellular Matrix Proteins Family member Female Fibrocartilages Fracture Healing Future Genetic Goals Human Immunohistochemistry In Vitro Inflammatory Injection of therapeutic agent Insulin-Like Growth Factor I Interleukin-1 beta Jaw Joints Knee Knee Osteoarthritis LOXL2 gene Lead Mandible Mediating Mediator of activation protein Modeling Molecular Analysis Mus Natural regeneration Nucleotides Operative Surgical Procedures Orofacial Pain Pathogenesis Pathology Pathway interactions Patients Prevalence Prevention Production Protein-Lysine 6-Oxidase Proteins Publishing Regenerative response Research Personnel Role Signal Pathway Specimen Staging Supplementation Symptoms Synovial Membrane System TNF gene Temporomandibular Joint Temporomandibular Joint Disorders Temporomandibular joint osteoarthritis Tissues Transforming Growth Factors Transgenic Mice United States amine oxidase articular cartilage base bone bone morphogenetic protein 2 cartilage development chondrodysplasia clinical application condylar cartilage crosslink cytokine insight joint mobilization loss of function male molecular marker mouse model overexpression preclinical study prevent protein function public health relevance repaired response sound substantia spongiosa therapeutic development therapeutic protein

项目摘要

DESCRIPTION (provided by applicant): Temporomandibular joint (TMJ) osteoarthritis (OA) is a degenerative disease that affects both cartilage and subchondral bone. The prevalence among adults in the United States of is 33% and the female-to-male ratio from 3:1 to 9:1. Our studies showed that lysyl oxidase like-2 (LOXL2) is expressed during regenerative response to fracture healing and is required for chondrocyte development. Preliminary studies showed that LOXL2 expression is increased in clinical TMJ- and knee-OA as a compensatory late-stage anabolic response because its expression upregulated by mediator of OA, it inhibits effects and apoptosis induced by catabolic mediators. Overexpression of LOXL2 increases COL2A1 and SOX9 without activating key catabolic mediators of OA such as MMP13 and ADAMTS5 expression. We hypothesize that LOXL2 is a mediator of anabolic signaling pathways, and could promote anabolic response to prevent or repair Cho/+ TMJ-OA mouse and TMJ-OA patient-derived cells. Specific Aims of the study are: 1) to determine the effect and mechanism of LOXL2 in attenuating human and mouse TMJ-OA and 2) to determine LOXL2 function in prevention/ regeneration of TMJ-OA fibrocartilage in female Cho/+ OA mouse models and patient-derived TMJ- OA cells. The completion of Aim 1 will determine if LOXL2 has a role in the pathogenesis and if early administration of rLOXL2 prevents TMJ-OA in genetic mouse models and patient-derived TMJ-OA cells. Alternatively, we will use surgical TMJ OA mouse models. Thus, the study will evaluate our hypothesis that LOXL2 mediated mechanism in TMJ-OA and LOXL2 induced collagen crosslinking and anabolic response promotes repair in mouse and TMJ-OA. In the future, a LOXL2 inducible transgenic mouse model will be generated to study the effect of inducible LOXL2 expression on TMJ-OA. The long-term goal is to develop LOXL2 as a potential therapeutic protein for clinical application in TMJ OA.

描述(申请人提供)：颞下颌关节(TMJ)骨关节炎(OA)是一种同时影响软骨和软骨下骨的退行性疾病。在美国成人中的发病率为33%，男女比例从3：1到9：1。我们的研究表明，赖氨酰氧化酶样-2(LOXL2)在骨折愈合的再生反应中表达，是软骨细胞发育所必需的。初步研究表明，LOXL2在临床TMJ和膝关节骨性关节炎中的表达增加，是一种代偿性的晚期合成代谢反应，其原因是其表达受骨性关节炎介质的上调，抑制分解代谢介质诱导的效应和细胞凋亡。LOXL2的过表达增加了COL2A1和SOX9的表达，而没有激活关键的OA分解代谢介质，如MMP13和ADAMTS5的表达。我们推测LOXL2是合成代谢信号通路的中介体，可以促进合成代谢反应，以预防或修复CHO/+TMJ-OA小鼠和TMJ-OA患者来源的细胞。本研究的具体目的是：1)确定LOXL2对人和小鼠TMJ-OA的减毒作用及其机制；2)确定LOXL2在CHO/+OA雌性小鼠模型和患者来源的TMJ-OA细胞中预防/再生TMJ-OA的作用。Aim 1的完成将确定LOXL2是否在发病机制中发挥作用，以及早期应用rLOXL2是否可以阻止遗传小鼠模型和患者来源的TMJ-OA细胞中的TMJ-OA。或者，我们将使用外科手术的TMJ OA小鼠模型。因此，本研究将评估我们的假设，即LOXL2介导的TMJ-OA和LOXL2诱导的胶原交联和合成反应促进小鼠和TMJ-OA修复的机制。未来将建立LOXL2诱导的转基因小鼠模型，研究LOXL2的诱导表达对TMJ-OA的影响。长期目标是开发LOXL2作为一种潜在的治疗蛋白用于TMJ OA的临床应用。