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（由适用提供）：仅在美国，由于骨骼质量和密度降低，大约有4400万人患有骨质疏松症或有骨质疏松症的风险。每年，骨质疏松症负责数百万骨折，严重影响生活质量。更年期后不久，这在女性中尤其重要 由于雌激素缺乏，这种疾病称为绝经后骨质疏松症。雌激素缺乏症与破骨细胞（OC）激活增加，成骨细胞功能降低以及炎症性骨骼敏感性细胞因子（如白介素6和肿瘤坏死因子（TNFα））有关。目前可以通过阻断OC活性来治疗和/或预防骨质疏松症。然而，有证据表明，长期治疗导致骨骼形成降低，从而导致非典型骨骼分数。在此提案中，我们提出了这样一个观念，即理想的治疗情况将是损害OC功能而不会干扰OB驱动的骨形成的情况。密封环形成是正常OC功能的要求。我们最近将肌动蛋白束蛋白L-普拉斯汀（LPL）确定为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，TNFα信号通路通过介导LPL磷酸化来调节该组件。此外，我们的数据强烈表明LPL在骨骼重塑中起着重要作用，因为LPL - / - 小鼠是骨质术。这些小鼠中的OC骨质能力显着受损，而OB功能仍未改变。尽管该领域的进展，但相对于OC中密封环形成的生物学，知识的许多差距仍未解决。特别是，关于NSZ和LPL在OC中的作用知之甚少。拟议的研究将探讨LPL辐射在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介导的骨质损失的潜在治疗靶标。该提议将检验中心假设：“ LPL是OC骨吸收功能的关键调节因子。抑制LPL磷酸化将减轻与骨质疏松相关的骨质流失，我们提出以下三个具体目的。1）确定L-Plastin在NSZ形成中的作用。 TNFα在肌动蛋白束中的L-抑制素磷酸化，在破骨细胞中需要NSZ形成的过程，以及3）确定抑制内源性L-铂磷酸化的影响，在衰老和卵巢切除术在质量损失的范围中施加型骨骼的损失。体内不影响OB功能。我们预计，这些研究的结果将为翻译相关的基础，在该基础上可以实现新颖的预防和治疗选择。我们的结果最终可能会影响其他与骨丢失相关疾病的治疗，包括类风湿关节炎和牙周炎，这些疾病与骨质疏松症具有多种病理特征。