Experimental Gerontology ( IF 3.9 ) Pub Date : 2021-08-10 , DOI: 10.1016/j.exger.2021.111516 Stephen A Martin 1 , Ruben T Riordan 2 , Rong Wang 3 , Zhen Yu 3 , Allan M Aguirre-Burk 4 , Carmen P Wong 4 , Dawn A Olson 4 , Adam J Branscum 5 , Russell T Turner 4 , Urszula T Iwaniec 4 , Viviana I Perez 2
Advanced age is the strongest risk factor for osteoporosis. The immunomodulator drug rapamycin extends lifespan in numerous experimental model organisms and is being investigated as a potential therapeutic to slow human aging, but little is known about the effects of rapamycin on bone. We evaluated the impact of rapamycin treatment on bone mass, architecture, and indices of bone turnover in healthy adult (16–20 weeks old at treatment initiation) female wild-type (ICR) and Nrf2−/− mice, a mouse model of oxidative damage and aging-related disease vulnerability. Rapamycin (4 mg/kg bodyweight) was administered by intraperitoneal injection every other day for 12 weeks. Mice treated with rapamycin exhibited lower femur bone mineral content, bone mineral density, and bone volume compared to vehicle-treated mice. In midshaft femur diaphysis (cortical bone), rapamycin-treated mice had lower cortical volume and thickness, and in the distal femur metaphysis (cancellous bone), rapamycin-treated mice had higher trabecular spacing and lower connectivity density. Mice treated with rapamycin exhibited lower bone volume, bone volume fraction, and trabecular thickness in the 5th lumbar vertebra. Rapamycin-treated mice had lower levels of bone formation in the distal femur metaphysis compared to vehicle-treated mice which occurred co-incidentally with increased serum CTX-1, a marker of global bone resorption. Rapamycin had no impact on tibia inflammatory cytokine gene expression, and we found no independent effects of Nrf2 knockout on bone, nor did we find any interactions between genotype and treatment. These data show that rapamycin may have a negative impact on the skeleton of adult mice that should not be overlooked in the clinical context of its usage as a therapy to retard aging and reduce the incidence of age-related pathologies.
中文翻译:
雷帕霉素不依赖于 Nrf2 影响年轻成年小鼠的骨生长
高龄是骨质疏松症的最大危险因素。免疫调节剂药物雷帕霉素可延长许多实验模型生物的寿命,并且正在研究作为减缓人类衰老的潜在疗法,但对雷帕霉素对骨骼的影响知之甚少。我们评估了雷帕霉素治疗对健康成人(治疗开始时 16-20 周龄)雌性野生型 (ICR) 和 Nrf2 -/- 的骨量、结构和骨转换指数的影响小鼠,一种氧化损伤和衰老相关疾病易感性的小鼠模型。雷帕霉素 (4 mg/kg 体重) 每隔一天通过腹腔注射给药,持续 12 周。与载体治疗的小鼠相比,用雷帕霉素治疗的小鼠表现出较低的股骨骨矿物质含量、骨矿物质密度和骨体积。在股骨中段骨干(皮质骨)中,雷帕霉素处理的小鼠皮质体积和厚度较低,而在股骨远端干骺端(松质骨)中,雷帕霉素处理的小鼠具有更高的小梁间距和更低的连接密度。用雷帕霉素治疗的小鼠的第 5 腰椎骨体积、骨体积分数和小梁厚度均较低。与载体治疗的小鼠相比,雷帕霉素治疗的小鼠股骨远端干骺端的骨形成水平较低,这与血清 CTX-1(整体骨吸收的标志物)增加同时发生。雷帕霉素对胫骨炎性细胞因子基因表达没有影响,我们没有发现 Nrf2 敲除对骨骼的独立影响,也没有发现基因型和治疗之间的任何相互作用。这些数据表明,雷帕霉素可能对成年小鼠的骨骼产生负面影响,在将其用作延缓衰老和减少与年龄相关的病理发生率的治疗的临床背景下,不应忽视这一点。我们也没有发现基因型和治疗之间有任何相互作用。这些数据表明,雷帕霉素可能对成年小鼠的骨骼产生负面影响,在将其用作延缓衰老和减少与年龄相关的病理发生率的治疗的临床背景下,不应忽视这一点。我们也没有发现基因型和治疗之间有任何相互作用。这些数据表明,雷帕霉素可能对成年小鼠的骨骼产生负面影响,在将其用作延缓衰老和减少与年龄相关的病理发生率的治疗的临床背景下,不应忽视这一点。