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(申请人提供)：仅在美国，估计就有大约4400万人患有骨质疏松症或由于骨量和密度下降而有发生骨质疏松症的风险。每年，骨质疏松症导致数百万严重影响生活质量的骨折。这在绝经后不久的女性中尤为明显。 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)功能降低以及炎症性骨吸收细胞因子如白介素6和肿瘤坏死因子α增加有关。目前有几种靶向治疗方法可以通过阻断OC活性来治疗和/或预防骨质疏松症。然而，有证据表明，长期治疗导致OBS的骨形成减少，导致不典型的骨骼骨折。在这个方案中，我们提出了一个理想的治疗方案，即在不干扰OB驱动的骨形成的情况下，损害OC的功能。密封圈的形成是正常OC功能的要求。我们最近发现肌动蛋白捆绑蛋白L-血浆蛋白(LPL)是在密封环形成的早期阶段组装前体或新生密封区(NSZ)的关键因素。我们的初步发现表明，肿瘤坏死因子α信号通路通过介导脂蛋白脂酶的磷酸化来调节这种组装。此外，我们的数据有力地表明LPL在骨重建中起主要作用，因为LPL-/-小鼠是成骨的。这些小鼠的OC骨吸收能力显著受损，而OB功能保持不变。尽管该领域取得了进展，但与接触网密封环形成的生物学相关的许多知识空白仍未解决。特别是，人们对NSZ和LPL在OCS中的作用知之甚少。建议的研究将探索LPL磷酸化在OC功能和骨丢失中的重要作用。我们的总体目标是确定LPL作为OC介导性骨丢失的潜在治疗靶点。这项建议将检验“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相关的骨丢失”这一中心假设。我们提出了以下三个特定的目标：1)确定L-纤溶酶在破骨细胞中非整合素αvβ3信号转导中的作用；2)阐明L-纤溶酶在肌动蛋白结合中的重要作用，这是破骨细胞形成非整合素所必需的过程；3)确定抑制内源性L-纤溶酶磷酸化在增龄和卵巢切除所致的体内骨丢失中的作用。这些研究的结果将阐明LPL抑制肽在不影响OB功能的情况下，在小鼠体内模型中损害OC功能和减少骨丢失的能力。骨质疏松症与雌激素缺乏和衰老有关。它仍然是一个严重的公共卫生问题，目前的治疗方案有重要的局限性。因此，迫切需要新的和改进的治疗方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提供一个翻译相关的基础，在此基础上可以实现骨质疏松症的新的预防和治疗方案。我们的结果可能最终影响其他骨丢失相关疾病的治疗，包括类风湿性关节炎和牙周炎，这些疾病与骨质疏松症有几个共同的病理特征。