Identification of Senescent Cells in the Bone Microenvironment.
Identification of Senescent Cells in the Bone Microenvironment.
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DOI：
10.1002/jbmr.2892
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发表时间：
2016-11
期刊：
影响因子：
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通讯作者：
Khosla S
中科院分区：
文献类型：
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作者：
Farr JN;Fraser DG;Wang H;Jaehn K;Ogrodnik MB;Weivoda MM;Drake MT;Tchkonia T;LeBrasseur NK;Kirkland JL;Bonewald LF;Pignolo RJ;Monroe DG;Khosla S
细胞衰老是细胞保持代谢活性但停止分裂并经历不同表型改变的基本机制，包括p16 Ink 4a的上调、深刻的分泌组变化、端粒缩短和近着丝粒卫星DNA的解凝聚。由于衰老细胞随着衰老在多种组织中积累，这些细胞及其分泌的功能障碍因子，称为衰老相关分泌表型（SASP），越来越多地被认为是预防年龄相关退行性病变（包括骨质疏松症）的有希望的治疗靶点。然而，骨微环境中的细胞类型在体内随着衰老而衰老，这一点仍然知之甚少，这主要是因为以前的研究集中在培养细胞的衰老上。因此，在年轻（年龄6个月）和老年（年龄24个月）小鼠中，我们在体内测量了高度富集的细胞群中的衰老和SASP标志物，所有这些细胞群都是在没有体外培养的情况下从骨/骨髓中快速分离的。在女性和男性中，p16 Ink 4a的表达通过实时定量聚合酶链反应（rt-qPCR）显着较高的B细胞，T细胞，骨髓细胞，成骨细胞祖细胞，成骨细胞和骨细胞的老化。此外，对衰老相关卫星扩张（SADS）的体内定量，即大规模的着丝粒周围卫星DNA解开，显示老年骨皮质中的衰老骨细胞明显多于年轻骨皮质（11%对2%，p < 0.001）。此外，来自老年小鼠的原代骨细胞具有比来自年轻小鼠的骨细胞多六倍（p < 0.001）的端粒功能障碍诱导的病灶（TIF）。与衰老骨细胞的年龄相关性积累相对应的是，老年小鼠与年轻小鼠相比，骨细胞中多种SASP标志物的表达显著更高，其中几种也显示出骨髓细胞中与年龄相关的显著上调。这些数据表明，随着衰老，骨微环境中各种谱系的细胞亚群变得衰老，尽管衰老的骨髓细胞和衰老的骨细胞主要发育SASP。鉴于骨细胞在骨重建中的关键作用，我们的研究结果表明，衰老的骨细胞及其SASP可能有助于年龄相关的骨丢失。
Cellular senescence is a fundamental mechanism by which cells remain metabolically active yet cease dividing and undergo distinct phenotypic alterations, including upregulation of p16Ink4a, profound secretome changes, telomere shortening, and decondensation of pericentromeric satellite DNA. Because senescent cells accumulate in multiple tissues with aging, these cells and the dysfunctional factors they secrete, termed the senescence-associated secretory phenotype (SASP), are increasingly recognized as promising therapeutic targets to prevent age-related degenerative pathologies, including osteoporosis. However, the cell type(s) within the bone microenvironment that undergoes senescence with aging in vivo has remained poorly understood, largely because previous studies have focused on senescence in cultured cells. Thus in young (age 6 months) and old (age 24 months) mice, we measured senescence and SASP markers in vivo in highly enriched cell populations, all rapidly isolated from bone/marrow without in vitro culture. In both females and males, p16Ink4a expression by real-time quantitative polymerase chain reaction (rt-qPCR) was significantly higher with aging in B cells, T cells, myeloid cells, osteoblast progenitors, osteoblasts, and osteocytes. Further, in vivo quantification of senescence-associated distension of satellites (SADS), ie, large-scale unraveling of pericentromeric satellite DNA, revealed significantly more senescent osteocytes in old compared with young bone cortices (11% versus 2%, p < 0.001). In addition, primary osteocytes from old mice had sixfold more (p < 0.001) telomere dysfunction-induced foci (TIFs) than osteocytes from young mice. Corresponding with the age-associated accumulation of senescent osteocytes was significantly higher expression of multiple SASP markers in osteocytes from old versus young mice, several of which also showed dramatic age-associated upregulation in myeloid cells. These data show that with aging, a subset of cells of various lineages within the bone microenvironment become senescent, although senescent myeloid cells and senescent osteocytes predominantly develop the SASP. Given the critical roles of osteocytes in orchestrating bone remodeling, our findings suggest that senescent osteocytes and their SASP may contribute to age-related bone loss.