Comparison of inbred mouse strains shows diverse phenotypic outcomes of intervertebral disc aging
Comparison of inbred mouse strains shows diverse phenotypic outcomes of intervertebral disc aging
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DOI：
10.1111/acel.13148
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发表时间：
2020-04-22
期刊：
影响因子：
7.8
通讯作者：
Risbud, Makarand V.
中科院分区：
文献类型：
--
作者：
Novais, Emanuel J.;Tran, Victoria A.;Risbud, Makarand V.
椎间盘退变表现出广泛的临床退变椎间盘表型;然而，尚未确定遗传背景对退变结局的影响。我们的特点是不同的软骨再生潜力在6个月和23个月：C57 BL/6，LG/J和SM/J的3个小鼠品系的脊髓表型。所有菌株表现出不同的老化表型。重要的是，随着年龄的增长，LG/J小鼠尾椎间盘中营养不良性椎间盘钙化的患病率增加。LG/J和SM/J尾椎间盘的定量组织学分析证明与BL 6相比加速变性，分别伴有NP的细胞解体和细胞丢失以及纤维化。沿着更高级别的椎间盘退变，SM/J在6个月时，与其他品系相比，NP基因表达差异也最大。此外，虽然我们发现BL 6和LG/J老化之间有共同的DEG，但大多数菌株之间存在差异。值得注意的是，在LG/J和BL 6衰老中改变的共同DEG与炎症过程、应激反应、细胞分化、细胞代谢和细胞分裂相关。结果表明，在LG/J椎间盘钙化导致的营养不良的钙化过程可能加剧细胞死亡，基质重塑，钙/磷稳态和细胞转化的变化。最后，我们报告了7种不同的人类椎间盘退变表型的基础上转录组学的配置文件，提出了类似的途径和DEG中发现的老化小鼠品系。总之，我们的研究结果表明，椎间盘衰老和退行性变取决于遗传背景，并涉及各种分子途径的变化，这可能有助于解释椎间盘疾病期间观察到的不同表型。
Intervertebral disc degeneration presents a wide spectrum of clinically degenerative disc phenotypes; however, the contribution of genetic background to the degenerative outcomes has not been established. We characterized the spinal phenotype of 3 mouse strains with varying cartilage-regenerative potential at 6 and 23 months: C57BL/6, LG/J and SM/J. All strains showed different aging phenotypes. Importantly, LG/J mice showed an increased prevalence of dystrophic disc calcification in caudal discs with aging. Quantitative-histological analyses of LG/J and SM/J caudal discs evidenced accelerated degeneration compared to BL6, with cellular disorganization and cell loss together with fibrosis of the NP, respectively. Along with the higher grades of disc degeneration, SM/J, at 6M, also differed the most in terms of NP gene expression compared to other strains. Moreover, although we found common DEGs between BL6 and LG/J aging, most of them were divergent between the strains. Noteworthy, the common DEGs altered in both LG/J and BL6 aging were associated with inflammatory processes, response to stress, cell differentiation, cell metabolism and cell division. Results suggested that disc calcification in LG/J resulted from a dystrophic calcification process likely aggravated by cell death, matrix remodelling, changes in calcium/phosphate homeostasis and cell transformation. Lastly, we report 7 distinct phenotypes of human disc degeneration based on transcriptomic profiles, that presented similar pathways and DEGs found in aging mouse strains. Together, our results suggest that disc aging and degeneration depends on the genetic background and involves changes in various molecular pathways, which might help to explain the diverse phenotypes seen during disc disease.