Autoimmunity and emphysema and risk of osteoporosis in smokers

 描述（由申请人提供）：低骨矿物质密度（BMD）与慢性阻塞性肺疾病（COPD）相关，与传统的骨质疏松症风险因素（包括类固醇使用、恶病质和体力活动减少）无关。虽然骨质疏松症的患病率增加有助于COPD患者的发病率和死亡率，但对该易感人群的BMD评估或骨质疏松症机制的适应症知之甚少。骨密度丢失率是骨折的独立危险因素。然而，双能X线骨密度仪（DXA）的骨密度横截面评估没有提供关于骨密度下降率的信息。免疫学改变有助于COPD和骨质疏松症的发病机制，但自身免疫在COPD相关骨质疏松症中的作用尚未研究。肺气肿和低BMD之间的独立关联已得到文献的支持，但这种关联的机制也是未知的。该项目的总体目标是研究特定的自身免疫过程如何与患有肺部疾病的男性和女性吸烟者并发肺气肿进展和加速BMD下降相关。这一目标将通过将已经建立的纵向队列延长至6年来实现，该队列具有预先存在的基线和2年BMD、放射学肺气肿、肺功能和自身免疫生物标志物水平评估。将在患有肺气肿或气流阻塞的吸烟者中研究自身免疫生物标志物抗葡萄糖调节蛋白78（GRP78）IgG与肺气肿进展（通过定量CT扫描测量）和BMD损失（通过连续DXA测量）在6年时间间隔内的相关性。将进行一系列体外破骨细胞研究，以评估GRP78（一种密切参与内质网（ER）应激反应的伴侣蛋白）自身抗体对破骨细胞形成、增殖和活性的影响。该项目的结果将 确定有加速BMD丢失风险的吸烟者的标准，其中可能需要早期和连续测量BMD，提供对肺气肿和骨质疏松症相关致病机制的深入了解，并为COPD患者的骨质疏松症预防和治疗策略提供新的靶点。

 DESCRIPTION (provided by applicant): Low bone mineral density (BMD) has been linked to chronic obstructive pulmonary disease (COPD) independent of traditional osteoporosis risk factors including steroid use, cachexia, and decreased physical activity. Although the increased prevalence of osteoporosis contributes to morbidity and mortality in COPD patients, little is known regarding indications for BMD assessment or osteoporosis mechanisms in this susceptible population. The rate of BMD loss is an independent risk factor for fracture. Yet, cross-sectional dual x-ray absorptiometry (DXA) assessment of BMD provides no information about rate of BMD decline. Immunologic alterations contribute to the pathogenesis of both COPD and osteoporosis but the role of autoimmunity in COPD-related osteoporosis has not been studied. An independent association between emphysema and low BMD has been supported by the literature, but the mechanism for this association is also unknown. This project's overall goal is to study how specific autoimmune processes relate to concurrent emphysema progression and accelerated BMD decline in male and female smokers with lung disease. This goal will be accomplished through extension to six years of an already established longitudinal cohort with pre- existing baseline and two-year assessments of BMD, radiographic emphysema, pulmonary function, and autoimmune biomarker levels. The association of an autoimmune biomarker, anti-glucose regulated protein 78 (GRP78) IgG, with emphysema progression, measured by quantitative CT scan, and BMD loss, measured by serial DXA, over the six-year time interval will be studied in smokers with emphysema or airflow obstruction. A series of in vitro osteoclast studies will be performed to assess the effect of autoantibodies to GRP78, an endoplasmic reticulum (ER) chaperone protein intimately involved in the ER stress response, on osteoclast formation, proliferation, and activity. The findings from this project will identify criteria for smokers at risk of accelerated BMD loss in whom early and serial measurements of BMD may be warranted, provide insight into pathogenic mechanisms linking emphysema and osteoporosis, and provide novel targets for osteoporosis prevention and treatment strategies in patients with COPD.