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: 8927529
• 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/8927529
• 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; 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; targeted treatment; 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 (TNF)-α. 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 TNF-α 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 αvß3 signaling in osteoclasts; 2) To elucidate the essential function of L-plastin phosphorylation by TNF-α 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，估计约有4400万人患有骨质疏松症或由于骨量和密度降低而有患骨质疏松症的风险。每年，骨质疏松症导致数百万严重影响生活质量的骨折。这在绝经后不久的妇女中尤为显著 由于雌激素缺乏，一种被称为绝经后骨质疏松症的病症。雌激素缺乏与破骨细胞（OC）活化增加、成骨细胞（OB）功能降低和炎性骨吸收细胞因子（如白细胞介素-6和TNF-α）增加相关。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骨形成减少，导致非典型骨折。在这个提议中，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功能。密封圈成形是正常OC功能的要求。我们最近发现肌动蛋白集束蛋白L-Plastin（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。我们的初步发现表明TNF-α信号通路通过介导LPL磷酸化来调节这种组装。此外，我们的数据强烈表明，LPL在骨重建中起着重要作用，因为LPL-/-小鼠是骨硬化症。这些小鼠的OC骨吸收能力显著受损，而OB功能保持不变。尽管在该领域取得了进展，但相对于OC中密封环形成的生物学，许多知识空白仍未解决。特别是，人们对NSZ和LPL在业主立案法团中的作用知之甚少。本研究将探讨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介导的骨丢失的潜在治疗靶点。该提案将测试中心假设，即“LPL是OC骨吸收功能的关键调节因子。抑制LPL磷酸化将减弱骨质疏松相关的骨丢失”。我们提出了以下三个具体目标：1）确定L-纤维蛋白酶在NSZ形成中的作用，独立于破骨细胞中的整合素α v β 3信号传导; 2）阐明TNF-α磷酸化L-纤维蛋白酶在肌动蛋白成束中的基本功能，肌动蛋白成束是破骨细胞形成NSZ所必需的过程，和3）确定抑制内源性L-纤溶酶原蛋白磷酸化在衰老和卵巢切除术诱导的体内骨丢失中的影响。所提出的研究的结果将阐明LPL抑制肽在体内小鼠模型中损害OC功能和减少骨丢失而不影响OB功能的能力。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，目前的治疗方案有重要的局限性。因此，迫切需要新的和改进的疗法来更有效地靶向骨质疏松症。我们预期这些研究的结果将为骨质疏松症的新的预防和治疗方案的实现提供一个与预防相关的基础。我们的研究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。