Cathepsin S controls adipocytic and osteoblastic differentiation, bone turnover, and bone microarchitecture
Cathepsin S controls adipocytic and osteoblastic differentiation, bone turnover, and bone microarchitecture
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DOI：
10.1016/j.bone.2014.04.022
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发表时间：
2014-07-01
期刊：
影响因子：
4.1
通讯作者：
Pietschmann, P.
中科院分区：
文献类型：
--
作者：
Rauner, M.;Foeger-Samwald, U.;Pietschmann, P.
组织蛋白酶S是控制脂肪细胞分化的半胱氨酸蛋白酶，并且与肥胖的血管和代谢并发症有关。考虑到成骨细胞和脂肪细胞及其共同的前体细胞的反向关系，我们假设组织蛋白酶S也可能影响成骨细胞的分化和骨重建。因此，测定了年轻（3个月大）和老年（12或18个月大）的组织蛋白酶S敲除（KO）和野生型（WT）小鼠的脂肪和骨表型。此外，组织蛋白酶S缺乏损害脂肪细胞形成（-38%，p <0.001），这伴随着脂肪细胞相关基因的较低表达以及血清瘦素、IL-6和CCL2的降低（p <0.001）。显微CT分析显示，在两个年龄段的组织蛋白酶S KO小鼠中，骨小梁体积分数和密度不变，而组织矿物质密度显著降低。老年KO小鼠还具有较低的皮质骨质量（~23%，p <0.05）。在微结构水平，组织蛋白酶S KO小鼠具有更薄的小梁（-8.3%），但连接更好的小梁网络（+24%）。骨形成标志物1型前胶原氨基末端前肽和骨钙素的血清水平在组织蛋白酶S KO小鼠中均比矿化表面高2 - 3倍。一致地，成骨分化增加2倍沿着成骨细胞特异性基因表达的增加。有趣的是，组织蛋白酶S基因敲除小鼠的血清I型胶原C末端肽水平也较高（+43%），组织学破骨细胞参数和体外破骨细胞分化也较高，因此，组织蛋白酶S缺陷改变了脂肪细胞和成骨细胞分化之间的平衡，增加了骨转换，并改变了骨微结构。因此，在临床上使用组织蛋白酶S抑制剂时，应监测骨和脂肪代谢。(C)2014 Elsevier Inc. All rights reserved.
Cathepsin S is a cysteine protease that controls adipocyte differentiation and has been implicated in vascular and metabolic complications of obesity. Considering the inverse relation of osteoblasts and adipocytes and their mutual precursor cell, we hypothesized that cathepsin S may also affect osteoblast differentiation and bone remodeling. Thus, the fat and bone phenotypes of young (3 months old) and aged (12 or 18 months old) cathepsin S knock-out (KO) and wild-type (WT) mice were determined.Cathepsin S KO mice had a normal body weight at both ages investigated, even though the amount of subscapular and gonadal fat pads was reduced by 20%. Further, cathepsin S deficiency impaired adipocyte formation (-38%, p < 0.001), which was accompanied by a lower expression of adipocyte-related genes and a reduction in serum leptin, IL-6 and CCL2 (p < 0.001). Micro-CT analysis revealed an unchanged trabecular bone volume fraction and density, while tissue mineral density was significantly lower in cathepsin S KO mice at both ages. Aged KO mice further had a lower cortical bone mass (-23%, p < 0.05). At the microarchitectural level, cathepsin S KO mice had thinner trabeculae (-8.3%), but a better connected trabecular network (+24%). Serum levels of the bone formation marker type 1 procollagen amino-terminal-propeptide and osteocalcin were both 2-3-fold higher in cathepsin S KO mice as was the mineralized surface. Consistently, osteogenic differentiation was increased 2-fold along with an increased expression of osteoblast-specific genes. Interestingly, serum levels of C-terminal-telopeptide of type I collagen were also higher (+43%) in cathepsin S KO mice as were histological osteoclast parameters and ex vivo osteoclast differentiation.Thus, cathepsin S deficiency alters the balance between adipocyte and osteoblast differentiation, increases bone turnover, and changes bone microarchitecture. Therefore, bone and fat metabolisms should be monitored when using cathepsin S inhibitors clinically. (C) 2014 Elsevier Inc. All rights reserved.