LOXL2 in Temporomandibular Joint Osteoarthritis

LOXL2 在颞下颌关节骨关节炎中的作用

• 批准号: 8951806
• 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
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8951806
• 关键词: Adult; Affect; Aftercare; Age; Age-Months; Anabolic Agents; Apoptosis; Attenuated; BMP2 gene; Binding; Biological Markers; Calcified; 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; Jaw; Joints; Knee; Knee Osteoarthritis; 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; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint osteoarthritis; Tissues; Transforming Growth Factors; Transgenic Mice; Tumor Necrosis Factor-alpha; United States; amine oxidase; articular cartilage; base; bone; bone morphogenetic protein 2; bone morphogenetic protein 7; career; 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

 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（由申请人提供）：颞下颌关节（TMJ）骨关节炎（OA）是一种影响软骨和软骨下骨的退行性疾病。美国成年人的患病率为 33%，男女比例为 3:1 至 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过程中表达，并且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 OA 中表达增加，作为代偿性晚期合成代谢反应，因为 OA 介质上调其表达，抑制分解代谢介质诱导的效应和细胞凋亡。 LOXL2 的过表达会增加 COL2A1 和 SOX9，而不激活 OA 的关键分解代谢介质（例如 MMP13 和 ADAMTS5 表达）。我们假设 LOXL2 是合成代谢信号通路的介质，并且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。该研究的具体目的是：1) 确定 LOXL2 在减弱人类和小鼠 TMJ-OA 方面的作用和机制，2) 确定 LOXL2 在雌性 Cho/+ OA 小鼠模型和患者来源的 TMJ-OA 细胞中预防/再生 TMJ-OA 纤维软骨的功能。目标 1 的完成将确定 LOXL2 是否在发病机制中发挥作用，以及早期施用 rLOXL2 是否可以预防遗传小鼠模型和患者来源的 TMJ-OA 细胞中的 TMJ-OA。或者，我们将使用手术 TMJ OA 小鼠模型。因此，该研究将评估我们的假设，即 LOXL2 在 TMJ-OA 中介导的机制，以及 LOXL2 诱导的胶原交联和合成代谢反应促进小鼠和 TMJ-OA 的修复。未来将建立LOXL2诱导型转基因小鼠模型来研究诱导型LOXL2表达对TMJ-OA的影响。长期目标是将LOXL2开发为潜在的治疗蛋白，用于TMJ OA的临床应用。