Bone Marrow Adiposity in Models of Radiation- and Aging-Related Bone Loss Is Dependent on Cellular Senescence.
Bone Marrow Adiposity in Models of Radiation- and Aging-Related Bone Loss Is Dependent on Cellular Senescence.
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DOI：
10.1002/jbmr.4537
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发表时间：
2022-05
影响因子：
6.2
通讯作者：
Pignolo, Robert J.
中科院分区：
文献类型：
--
作者：
Chandra, Abhishek;Lagnado, Anthony B.;Farr, Joshua N.;Schleusner, Megan;Monroe, David G.;Saul, Dominik;Passos, Joao F.;Khosla, Sundeep;Pignolo, Robert J.
氧化应激诱导的活性氧、DNA损伤、细胞凋亡和细胞衰老与骨髓脂肪组织(BMAT)的骨祖细胞减少是相互关联的；然而，细胞衰老和BMAT之间的直接(因果)联系仍然难以捉摸。衰老细胞的积累发生在自然老化和局部照射的骨组织中，但尽管衰老细胞清除后年龄和辐射相关的骨丢失有所改善，但BMAT增加之前的分子事件在很大程度上是未知的。在这里，我们通过RNA测序数据表明，BMAT相关基因是C57BL/6小鼠辐射后骨骼中表达最高的基因亚集。使用焦点辐射作为了解骨骼年龄相关变化的模型，我们对细胞衰老和BMAT进行了纵向评估。应用实时定量逆转录聚合酶链式反应(qRT-PCR)、p21转录本的RNA原位杂交和端粒功能障碍的组织学评估作为衰老的标志，我们观察到从照射后第1天起，骨细胞的衰老细胞负荷增加，而没有BMAT的存在。BMAT在照射后第7天显著升高，证实了qRT-PCR数据，其中大多数BMAT相关基因在第7天开始升高，并且这种趋势一直持续到照射后第42天。同样，BMAT相关基因在老年小鼠的骨骼中也观察到了升高。Dasatinib(D)和Quercetin(Q)(即D+Q)的抗衰老鸡尾酒清除衰老细胞，减少老化和辐射骨骼中的BMAT。与衰老标志物p21相连的microRNAs(miRNAs或miRs)在辐射和老化的骨骼中表达下调，而与BMAT增加相关的miR-27A在辐射和老化的骨骼中都升高。照射后42天，D+Q使受照骨中miR-27A表达下调。总体而言，我们的研究提供了证据表明，在氧化应激的骨骼环境中，如辐射和衰老，BMAT的发生是按照共同的途径诱导的，并依赖于衰老细胞的存在。
Oxidative stress-induced reactive oxygen species, DNA damage, apoptosis, and cellular senescence have been associated with reduced osteoprogenitors in a reciprocal fashion to bone marrow adipocyte tissue (BMAT); however, a direct (causal) link between cellular senescence and BMAT is still elusive. Accumulation of senescent cells occur in naturally aged and in focally radiated bone tissue, but despite amelioration of age- and radiation-associated bone loss after senescent cell clearance, molecular events that precede BMAT accrual are largely unknown. Here we show by RNA-Sequencing data that BMAT-related genes were the most upregulated gene subset in radiated bones of C57BL/6 mice. Using focal radiation as a model to understand age-associated changes in bone, we performed a longitudinal assessment of cellular senescence and BMAT. Using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA in situ hybridization of p21 transcripts and histological assessment of telomere dysfunction as a marker of senescence, we observed an increase in senescent cell burden of bone cells from day 1 postradiation, without the presence of BMAT. BMAT was significantly elevated in radiated bones at day 7, confirming the qRT-PCR data in which most BMAT-related genes were elevated by day 7, and the trend continued until day 42 postradiation. Similarly, elevation in BMAT-related genes was observed in bones of aged mice. The senolytic cocktail of Dasatinib (D) plus Quercetin (Q) (ie, D + Q), which clears senescent cells, reduced BMAT in aged and radiated bones. MicroRNAs (miRNAs or miRs) linked with senescence marker p21 were downregulated in radiated and aged bones, whereas miR-27a, a miR that is associated with increased BMAT, was elevated both in radiated and aged bones. D + Q downregulated miR-27a in radiated bones at 42 days postradiation. Overall, our study provides evidence that BMAT occurrence in oxidatively stressed bone environments, such as radiation and aging, is induced following a common pathway and is dependent on the presence of senescent cells.
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影响因子：
4.4
作者：
Bou M;Montfort J;Le Cam A;Rallière C;Lebret V;Gabillard JC;Weil C;Gutiérrez J;Rescan PY;Capilla E;Navarro I
通讯作者：
Navarro I
影响因子：
4.3
作者：
Brennan TA;Egan KP;Lindborg CM;Chen Q;Sweetwyne MT;Hankenson KD;Xie SX;Johnson FB;Pignolo RJ
通讯作者：
Pignolo RJ
影响因子：
82.9
作者：
Farr JN;Xu M;Weivoda MM;Monroe DG;Fraser DG;Onken JL;Negley BA;Sfeir JG;Ogrodnik MB;Hachfeld CM;LeBrasseur NK;Drake MT;Pignolo RJ;Pirtskhalava T;Tchkonia T;Oursler MJ;Kirkland JL;Khosla S
通讯作者：
Khosla S
骨髓脂肪形成增加不会导致雌性小鼠年龄依赖性的阑尾骨质流失。
影响因子：
7.8
作者：
Almeida M;Kim HN;Han L;Zhou D;Thostenson J;Porter RM;Ambrogini E;Manolagas SC;Jilka RL
通讯作者：
Jilka RL
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J