L-plastin: a novel target for intervention in the treatment of osteoporosis

L-plastin：干预治疗骨质疏松症的新靶点

• 批准号: 8816501
• 负责人: MEENAKSHI A CHELLAIAH
• 金额: $ 33.77万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816501
• 关键词: Actins; Adhesions; Adverse effects; Affect; Age; Age-Years; Aging; Aging-Related Process; Applications Grants; Attenuated; Biology; Bone Density; Bone Resorption; Bone Surface; Bone remodeling; Bundling; Data; Disease; Estrogen Replacement Therapy; Estrogens; Foundations; Fracture; Goals; Health; Hip Fractures; Homeostasis; Hormones; Human; Inflammatory; Integrins; Interleukin-6; Intervention; Investigation; Knowledge; L-Plastin; Lead; Mediating; Menopause; Modeling; Molecular Weight; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Osteopenia; Osteoporosis; Outcome; Outcome Study; Ovariectomy; Pathologic; Pathway interactions; Patients; Peptides; Periodontitis; Phase; Phosphorylation; Play; Postmenopausal Osteoporosis; Postmenopause; Prevention; Process; Proteins; Public Health; Quality of life; Relative (related person); Research; Rheumatoid Arthritis; Risk; Role; Signal Pathway; Signal Transduction; TNF gene; Testing; Therapeutic; Tumor Necrosis Factor-alpha; United States; Woman; base; bone; bone loss; bone mass; bone quality; cancer risk; cytokine; improved; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; men; mouse model; new therapeutic target; novel; novel therapeutics; prevent; research study; seal; skeletal; skeletal tissue; therapeutic target

DESCRIPTION (provided by applicant): In the United States alone, about 44 million people are estimated to have osteoporosis or at risk of developing osteoporosis due to decreased bone mass and density. Annually, osteoporosis is responsible for millions of bone fractures that severely affect the quality of life. This is particularly significant in women soon after menopause due to estrogen deficiency, a condition referred to as postmenopausal osteoporosis. Estrogen deficiency is associated with increased osteoclast (OC) activation, decreased osteoblast (OB) function and increased inflammatory bone-resorbing cytokines such as interleukin-6 and tumor necrosis factor (TNFα). Several targeted therapies are currently available to treat and/or prevent osteoporosis by blocking OC activity. However, evidence has shown that long-term treatments have caused a reduction in bone formation by OBs, resulting in atypical skeletal fractures. In this proposal, we put forward the notion that an ideal therapeutic scenario would be one that impairs OC function without interfering with OB-driven bone formation. Sealing ring formation is a requirement for normal OC function. We recently identified the actin bundling protein L-Plastin (LPL) as a critical factor in the assembly of precursor or nascent sealing zones (NSZs) at the early phase of sealing ring formation. Our preliminary findings show that the TNFα signaling pathway regulates this assembly by mediating LPL phosphorylation. In addition, our data strongly suggest that LPL plays a major role in bone remodeling since LPL-/- mice are osteopetrotic. OC bone-resorbing capacity in these mice is significantly impaired, while OB function remains unaltered. Despite progress in the field, many gaps in knowledge are still unsolved relative to the biology of sealing ring formation in OCs. In particular, little is known about NSZs and the role of LPL in OCs. The proposed studies will explore the essential function of LPL phosphorylation in OC function and bone loss. Our overall goal is to identify LPL as a potential therapeutic target for OC-mediated bone loss. This proposal will test the central hypotheses that "LPL is a key regulator of OC bone resorptive function. Inhibiting LPL phosphorylation will attenuate osteoporosis-associated bone loss". We propose the following three specific aims: 1) To determine the role of L-plastin in NSZ formation, independently of integrin αvβ3 signaling in osteoclasts; 2) To elucidate the essential function of L-plastin phosphorylation by TNFα in actin bundling, a process required for NSZ formation in osteoclasts, and 3) To determine the impact of inhibiting endogenous L-plastin phosphorylation in aging- and ovariectomy- induced bone loss in vivo. The outcome of the proposed studies will elucidate the ability of LPL inhibitory peptides to impair OC function and reduce bone loss in mouse models in vivo without affecting OB function. Osteoporosis is related to estrogen deficiency and aging. It remains a significant public health problem and current treatment options have important limitations. Therefore, novel and improved therapies are critically needed to more efficiently target osteoporosis. We anticipate that the outcomes of these studies will provide a translationally relevant foundation on which novel prevention and treatment options for osteoporosis can be achieved. Our results may ultimately impact treatment of other bone loss-associated diseases, including rheumatoid arthritis and periodontitis, which share several pathologic features with osteoporosis.

描述（由申请人提供）：仅在美国，估计就有约 4400 万人患有骨质疏松症或由于骨量和密度下降而面临患骨质疏松症的风险。每年，骨质疏松症都会导致数以百万计的骨折，严重影响生活质量。这对于绝经后不久的女性尤其重要 由于雌激素缺乏，这种情况被称为绝经后骨质疏松症。雌激素缺乏与破骨细胞 (OC) 激活增加、成骨细胞 (OB) 功能下降以及炎症性骨吸收细胞因子（如白细胞介素 6 和肿瘤坏死因子 (TNFα)）增加有关。目前有几种靶向疗法可通过阻断 OC 活性来治疗和/或预防骨质疏松症。然而，有证据表明，长期治疗会导致 OB 导致骨形成减少，从而导致非典型骨骼骨折。在这项提案中，我们提出了这样的概念：理想的治疗方案是损害 OC 功能而不干扰 OB 驱动的骨形成。密封环的形成是正常 OC 功能的必要条件。我们最近发现肌动蛋白捆绑蛋白 L-塑蛋白 (LPL) 是密封环形成早期前体或新生密封区 (NSZ) 组装的关键因素。我们的初步研究结果表明，TNFα 信号通路通过介导 LPL 磷酸化来调节该组装。此外，我们的数据强烈表明，LPL 在骨重塑中发挥着重要作用，因为 LPL-/- 小鼠是骨质疏松的。这些小鼠的 OC 骨吸收能力显着受损，而 OB 功能保持不变。尽管该领域取得了进展，但与 OC 中密封环形成的生物学相关的许多知识差距仍未解决。特别是，人们对 NSZ 和 LPL 在 OC 中的作用知之甚少。拟议的研究将探讨 LPL 磷酸化在 OC 功能和骨质流失中的基本功能。我们的总体目标是将 LPL 确定为 OC 介导的骨质流失的潜在治疗靶点。该提案将检验中心假设：“LPL 是 OC 骨吸收功能的关键调节因子。抑制 LPL 磷酸化将减轻骨质疏松症相关的骨丢失”。我们提出以下三个具体目标：1）确定L-plastin在NSZ形成中的作用，独立于破骨细胞中的整合素αvβ3信号传导； 2) 阐明肌动蛋白成束中 TNFα 引起的 L-塑性蛋白磷酸化的基本功能，肌动蛋白成束是破骨细胞中 NSZ 形成所需的过程，以及 3) 确定抑制内源性 L-塑性蛋白磷酸化对衰老和卵巢切除引起的体内骨质流失的影响。拟议研究的结果将阐明 LPL 抑制肽在不影响 OB 功能的情况下损害体内小鼠模型中的 OC 功能并减少骨丢失的能力。骨质疏松症与雌激素缺乏和衰老有关。它仍然是一个重大的公共卫生问题，目前的治疗方案有很大的局限性。因此，迫切需要新的和改进的疗法来更有效地针对骨质疏松症。我们预计这些研究的结果将为实现骨质疏松症的新预防和治疗方案提供转化相关的基础。我们的结果可能最终影响其他骨质流失相关疾病的治疗，包括类风湿性关节炎和牙周炎，它们与骨质疏松症有一些共同的病理特征。