LOXL2 in Temporomandibular Joint Osteoarthritis

 描述（由申请人提供）：颞下颌关节（TMJ）骨关节炎（OA）是一种退行性疾病，影响软骨和软骨下骨。美国成年人的患病率为33%，女性与男性的比例为3：1至9：1。我们的研究表明赖氨酰氧化酶样-2（LOXL 2）在骨折愈合的再生反应中表达，并且是软骨细胞发育所需的。初步研究显示，LOXL 2表达在临床TMJ-和膝关节-OA中增加作为补偿性晚期合成代谢反应，因为其表达被OA介质上调，其抑制分解代谢介质诱导的作用和凋亡。LOXL 2的过表达增加了COL 2A 1和SOX 9，而不激活OA的关键分解代谢介质，如MMP 13和ADAMTS 5表达。我们假设LOXL 2是合成代谢信号通路的介导者，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。本研究的具体目的是：1）确定L0 XL 2在减弱人和小鼠TMJ-OA中的作用和机制，和2）确定L0 XL 2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LOXL 2是否在发病机制中起作用，以及rLOXL 2的早期给药是否在遗传小鼠模型和患者来源的TMJ-OA细胞中预防TMJ-OA。或者，我们将使用手术TMJ OA小鼠模型。因此，本研究将评估我们的假设，即LOXL 2介导的机制在TMJ-OA和LOXL 2诱导的胶原交联和合成代谢反应促进修复小鼠和TMJ-OA。将来，将建立LOXL 2诱导型转基因小鼠模型，以研究诱导型LOXL 2表达对TMJ-OA的影响。长期目标是开发LOXL 2作为TMJ OA临床应用的潜在治疗蛋白。

 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.