Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells.
Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells.
复制标题
脂蛋白通过启动间充质干细胞促进骨髓肥胖。
DOI：
10.7554/elife.69209
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发表时间：
2021-06-22
期刊：
影响因子：
7.7
通讯作者：
Qiang L
中科院分区：
文献类型：
--
作者：
Aaron N;Kraakman MJ;Zhou Q;Liu Q;Costa S;Yang J;Liu L;Yu L;Wang L;He Y;Fan L;Hirakawa H;Ding L;Lo J;Wang W;Zhao B;Guo E;Sun L;Rosen CJ;Qiang L
骨髓脂肪组织（MAT）已被证明是至关重要的调节代谢和维持骨骼稳态在骨髓（BM）生态位。作为BM重塑的反映，MAT对营养波动、激素变化和代谢紊乱（如肥胖和糖尿病）高度敏感。MAT的扩张也与小鼠和人类的骨质流失密切相关。然而，骨髓可塑性的调控仍然知之甚少，骨髓脂肪变化与骨重塑之间的联系机制也是如此。我们研究了在C57BL/6小鼠和骨保护PPARγ组成性去乙酰化2KR小鼠中Adipsin及其下游效应物C3的缺失，以评估BM的可塑性。小鼠分别接受噻唑烷二酮治疗、卡路里限制或衰老，以诱导骨质流失和MAT扩张。采用μCT扫描分析骨密度和骨髓脂肪，并采用RNA分析评估脂肪细胞和成骨细胞标志物。在体外研究中，将原代骨髓基质细胞分离出来，进行成骨或成脂分化或化学处理，然后进行形态学和分子分析。临床数据是从先前在健康人类志愿者中进行的禁食和高热量饮食临床试验的样本中获得的。我们发现，在小鼠和人类的MAT扩增过程中，以PPARγ乙酰化依赖的方式，Adipsin是上调幅度最大的脂肪因子。在限制热量摄入、噻唑烷二酮治疗和衰老过程中，遗传消融小鼠Adipsin特异性抑制MAT扩张，但对外周脂肪储存没有作用，并改善骨量。这些作用是通过其下游效应物补体成分C3介导的，通过抑制Wnt/β-catenin信号传导，将共同祖细胞诱导成脂肪而不是成骨细胞。脂素促进新的脂肪细胞形成并影响BM生态位的骨骼重塑。我们的研究揭示了一种新的机制，即基底细胞通过一种独特的脂肪因子的旁分泌和内分泌作用来维持其自身的可塑性。本工作由美国国立卫生研究院T32DK007328 （NA）、F31DK124926 （NA）、R01DK121140 （JCL）、R01AR068970 （BZ）、R01AR071463 （BZ）、R01DK112943 （LQ）、R24DK092759 （CJR）和P01HL087123 （LQ）支持。
Marrow adipose tissue (MAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the bone marrow (BM) niche. As a reflection of BM remodeling, MAT is highly responsive to nutrient fluctuations, hormonal changes, and metabolic disturbances such as obesity and diabetes mellitus. Expansion of MAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling. We studied deletion of Adipsin, and its downstream effector, C3, in C57BL/6 mice as well as the bone-protected PPARγ constitutive deacetylation 2KR mice to assess BM plasticity. The mice were challenged with thiazolidinedione treatment, calorie restriction, or aging to induce bone loss and MAT expansion. Analysis of bone mineral density and marrow adiposity was performed using a μCT scanner and by RNA analysis to assess adipocyte and osteoblast markers. For in vitro studies, primary bone marrow stromal cells were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high-calorie diet in healthy human volunteers. We show that Adipsin is the most upregulated adipokine during MAT expansion in mice and humans in a PPARγ acetylation-dependent manner. Genetic ablation of Adipsin in mice specifically inhibited MAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/β-catenin signaling. Adipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine. This work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), R24DK092759 (CJR), and P01HL087123 (LQ).