Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density
Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density
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DOI：
10.1152/ajpendo.00516.2009
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发表时间：
2010-08-01
影响因子：
5.1
通讯作者：
Loh, Y. Peng
中科院分区：
文献类型：
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作者：
Cawley, Niamh X.;Yanik, Tulin;Loh, Y. Peng
科利·恩克斯，亚尼克·T，沃诺维茨·A，张伟，马里尼·JC，罗伊普。肥胖的羧肽酶E基因敲除小鼠在多肽激素处理过程中表现出多种缺陷，导致骨密度降低。AM J生理学内分泌代谢酶299：E189-E197,2010。2010年5月11日首次发表；doi:10.1152/ajpendo.00516.2009.-Carboxypeptidase E(CPE)是一种激素前体/前神经肽处理酶，携带CPE突变的小鼠表现出肥胖和糖尿病的表型。对CPE基因敲除(KO)小鼠的研究表明，前激素处理不良，导致胰岛素、促性腺激素释放激素以及可卡因和苯丙胺调节转录本(CART)等多肽激素/神经肽缺乏。在这里，我们显示了肥胖动物模型CPE KO小鼠的骨密度(BMD)低，并伴有血浆CTX-1(羧基末端胶原交联物)和骨钙素的升高，骨钙素是骨转换增加的指标。KO组动物股骨中核因子-kappa B受体激活剂配体(RANKL)的表达水平较骨保护素高2倍，提示KO组小鼠的破骨活性增强。在下丘脑，一种与进食行为和骨骼新陈代谢有关的多肽-成熟CART是检测不到的。下丘脑中的黑素皮质素和神经肽Y(NPY)系统也与骨重建有关，因为MC4R KO和NPY KO小鼠增加了骨密度。然而，MC4R的主要配体α-MSH的减少高达94%，以及在CPE KO的下丘脑中缺乏可检测到的NPY，并不能概括单基因KO的表型。这项研究强调了参与能量代谢和骨形成的多肽之间复杂的生理相互作用，并进一步表明，携带CPE和CART突变导致这些分子的非活性形式的患者可能处于患骨质疏松症的更高风险。
Cawley NX, Yanik T, Woronowicz A, Chang W, Marini JC, Loh YP. Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density. Am J Physiol Endocrinol Metab 299: E189-E197, 2010. First published May 11, 2010; doi:10.1152/ajpendo.00516.2009.-Carboxypeptidase E (CPE) is a prohormone/proneuropeptide processing enzyme, and mice bearing CPE mutations exhibit an obese and diabetic phenotype. Studies on CPE knockout (KO) mice revealed poor prohormone processing, resulting in deficiencies in peptide hormones/neuropeptides such as insulin, gonadotropin-releasing hormone, and cocaine-and amphetamine-regulated transcript (CART). Here, we show that CPE KO mice, an obese animal model, have low bone mineral density (BMD) accompanied by elevated plasma CTX-1 (carboxy-terminal collagen crosslinks), and osteocalcin, indicators of increased bone turnover. Receptor activator for NF-kappa B ligand (RANKL) expression was elevated similar to 2-fold relative to osteoprotegerin in the femur of KO animals, suggesting increased osteoclastic activity in the KO mice. In the hypothalamus, mature CART, a peptide involved in eating behavior and implicated in bone metabolism, was undetectable. The melanocortin and neuropeptide Y (NPY) systems in the hypothalamus have also been implicated in bone remodeling, since MC4R KO and NPY KO mice have increased BMD. However, reduction of alpha-MSH, the primary ligand of MC4R by up to 94% and the lack of detectable NPY in the hypothalamus of CPE KO do not recapitulate the single-gene KO phenotypes. This study highlights the complex physiological interplay between peptides involved in energy metabolism and bone formation and furthermore suggests the possibility that patients, bearing CPE and CART mutations leading to inactive forms of these molecules, may be at a higher risk of developing osteoporosis.