Independent Roles of Estrogen Deficiency and Cellular Senescence in the Pathogenesis of Osteoporosis: Evidence in Young Adult Mice and Older Humans
Independent Roles of Estrogen Deficiency and Cellular Senescence in the Pathogenesis of Osteoporosis: Evidence in Young Adult Mice and Older Humans
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DOI：
10.1002/jbmr.3729
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发表时间：
2019-08-01
影响因子：
6.2
通讯作者：
Khosla, Sundeep
中科院分区：
文献类型：
--
作者：
Farr, Joshua N.;Rowsey, Jennifer L.;Khosla, Sundeep
雌激素缺乏是骨质疏松症发病机制的重要机制。然而，越来越多的证据表明，细胞衰老是导致多种年龄相关疾病的基本机制，也会导致骨质疏松症。最近，我们系统地鉴定了随着衰老，小鼠骨/骨髓和人骨中衰老细胞的积累，其特征是 p16(Ink4a) 和 p21(Cip1) 水平增加以及衰老相关分泌表型 (SASP) 的发展。然后，我们证明，消除衰老细胞可以通过多种方法预防与年龄相关的骨质流失，例如，用 AP20187 治疗表达“自杀”转基因 INK-ATTAC 的老年小鼠以诱导 p16(Ink4a) 衰老细胞凋亡，或定期用“senolytics”（即消除衰老细胞的药物）治疗老年野生型小鼠。在这里，我们使用多种方法研究雌激素在调节细胞衰老中的可能作用。首先，在年轻成年（4个月大）野生型小鼠中，卵巢切除术（OVX，n = 15）或睾丸切除术（ORCH，n = 15）与假手术（SHAM，n = 15/性别）后2个月性类固醇缺乏并没有改变衰老生物标志物或诱导骨骼中的SASP。接下来，在老年绝经后妇女中，与不治疗（n = 10；78 +/- 5 年）相比，3 周的雌激素治疗（n = 10；74 +/- 5 年）并没有改变衰老生物标志物或人骨活检中的 SASP。最后，将年轻成年（4 个月大）雌性 INK-ATTAC 小鼠（n = 17/组）随机分配至 SHAM+Vehicle、OVX+Vehicle 或 OVX+AP20187 组，为期 2 个月。正如预期的那样，与 SHAM+载体相比，OVX+载体引起显着的小梁/皮质骨损失。然而，用 AP20187 治疗（消除 INK-ATTAC 小鼠的衰老细胞）并不能挽救 OVX 诱导的骨质流失或改变衰老生物标志物。总的来说，我们的数据确定了雌激素缺乏和细胞衰老在骨质疏松症发病机制中的独立作用，这对于测试新型抗衰老药物的骨骼功效具有重要意义，因为这些药物需要在临床前衰老模型中进行评估，而不是目前 FDA 预防 OVX 引起的骨质流失的模型。 (c) 2019 年美国骨与矿物质研究学会。
Estrogen deficiency is a seminal mechanism in the pathogenesis of osteoporosis. Mounting evidence, however, establishes that cellular senescence, a fundamental mechanism that drives multiple age-related diseases, also causes osteoporosis. Recently, we systematically identified an accumulation of senescent cells, characterized by increased p16(Ink4a) and p21(Cip1) levels and development of a senescence-associated secretory phenotype (SASP), in mouse bone/marrow and human bone with aging. We then demonstrated that elimination of senescent cells prevented age-related bone loss using multiple approaches, eg, treating old mice expressing a "suicide" transgene, INK-ATTAC, with AP20187 to induce apoptosis of p16(Ink4a)-senescent cells or periodically treating old wild-type mice with "senolytics," ie, drugs that eliminate senescent cells. Here, we investigate a possible role for estrogen in the regulation of cellular senescence using multiple approaches. First, sex steroid deficiency 2 months after ovariectomy (OVX, n = 15) or orchidectomy (ORCH, n = 15) versus sham surgery (SHAM, n = 15/sex) in young adult (4-month-old) wild-type mice did not alter senescence biomarkers or induce a SASP in bone. Next, in elderly postmenopausal women, 3 weeks of estrogen therapy (n = 10; 74 +/- 5 years) compared with no treatment (n = 10; 78 +/- 5 years) did not alter senescence biomarkers or the SASP in human bone biopsies. Finally, young adult (4-month-old) female INK-ATTAC mice were randomized (n = 17/group) to SHAM+Vehicle, OVX+Vehicle, or OVX+AP20187 for 2 months. As anticipated, OVX+Vehicle caused significant trabecular/cortical bone loss compared with SHAM+Vehicle. However, treatment with AP20187, which eliminates senescent cells in INK-ATTAC mice, did not rescue the OVX-induced bone loss or alter senescence biomarkers. Collectively, our data establish independent roles of estrogen deficiency and cellular senescence in the pathogenesis of osteoporosis, which has important implications for testing novel senolytics for skeletal efficacy, as these drugs will need to be evaluated in preclinical models of aging as opposed to the current FDA model of prevention of OVX-induced bone loss. (c) 2019 American Society for Bone and Mineral Research.