Effects of suppressing bioavailability of insulin-like growth factor on age-associated intervertebral disc degeneration.
Effects of suppressing bioavailability of insulin-like growth factor on age-associated intervertebral disc degeneration.
复制标题
作者：
Kritschil R;Zhang Z;Lei C;Zhong J;Dong Q;Lee J;Conover CA;Sowa G;Vallejo AN;Vo N
抑制胰岛素样生长因子-1（IGF-1）信号通路可减少年龄相关疾病并延长物种寿命，使IGF-1通路成为衰老的关键调节因子。先前的体外椎间盘细胞研究已经报道了外源性添加IGF-1对基质产生的促合成代谢作用。然而，抑制IGF-1信号对年龄相关性椎间盘退变（IDD）的总体影响尚不清楚。在此，使用PAPPA −/−小鼠检查了抑制IGF-1信号传导对体内年龄相关IDD的影响。这些动物具有妊娠相关血浆蛋白A（PAPPA）的靶向缺失，PAPPA是切割抑制性IGF结合蛋白的主要蛋白酶，该抑制性IGF结合蛋白控制IGF-1用于细胞信号传导的生物利用度。与年龄匹配的野生型（Wt）同窝仔相比，在23月龄PAPPA −/−小鼠的椎间盘中观察到基质蛋白聚糖（PG）和聚集蛋白聚糖水平降低。与Wt同窝小鼠相比，在老年PAPPA −/−小鼠椎间盘中也观察到聚集蛋白聚糖溶解和两种关键分解代谢标志物基质金属蛋白酶-3和具有血小板反应蛋白基序-4的去整合素和金属蛋白酶表达减少。抑制IGF-1信号转导可能会使细胞代谢向维持而不是生长和减少细胞衰老转变。沿着这条线，通过p53和核纤层蛋白B1标记物评估，老年PAPPA −/−小鼠的椎间盘也表现出较低的细胞衰老。总的来说，这些数据揭示了在年龄老化过程中PAPPA/IGF-1信号传导对椎间盘基质稳态的复杂调节，即IGF-1生物利用度降低有利于减少椎间盘细胞衰老和基质分解，但也不利于减少椎间盘PG基质分解。在IGF-1被认为是治疗IDD的治疗性生长因子之前，该途径需要进一步的机制阐明。
Suppression of the insulin‐like growth factor‐1 (IGF‐1) signaling pathway reduces age‐related disorders and increases lifespan across species, making the IGF‐1 pathway a key regulator of aging. Previous in vitro intervertebral disc cell studies have reported the pro‐anabolic effect of exogenously adding IGF‐1 on matrix production. However, the overall effects of suppressing IGF‐1 signaling on age‐related intervertebral disc degeneration (IDD) is not known. Here, the effects of suppressing IGF‐1 signaling on age‐related IDD in vivo were examined using PAPPA −/− mice. These are animals with targeted deletion of pregnancy‐associated plasma protein A (PAPPA), the major protease that cleaves inhibitory IGF binding proteins that control bioavailability of IGF‐1 for cell signaling. Compared to age‐matched wild‐type (Wt) littermates, reduced levels of matrix proteoglycan (PG) and aggrecan were seen in discs of 23‐month old PAPPA −/− mice. Decreased aggrecanolysis and expression of two key catabolic markers, matrix metalloproteinase‐3 and a disintegrin and metalloproteinase with thrombospondin motifs‐4, were also observed in discs of old PAPPA −/− mice compared to Wt littermates. Suppressing IGF‐1 signaling has been implicated to shift cellular metabolism toward maintenance rather than growth and decreasing cellular senescence. Along this line, discs of old PAPPA −/− mice also exhibited lower cellular senescence, assessed by p53 and lamin B1 markers. Collectively, the data reveal complex regulation of disc matrix homeostasis by PAPPA/IGF‐1 signaling during chronologic aging, that is, reduced IGF‐1 bioavailability confers the benefit of decreasing disc cellular senescence and matrix catabolism but also the disadvantage of decreasing disc PG matrix anabolism. This pathway requires further mechanistic elucidation before IGF‐1 could be considered as a therapeutic growth factor for treating IDD.
登录
查看更多内容
影响因子：
5.3
作者：
Ngo K;Patil P;McGowan SJ;Niedernhofer LJ;Robbins PD;Kang J;Sowa G;Vo N
通讯作者：
Vo N
影响因子：
3.5
作者：
Gubbi S;Quipildor GF;Barzilai N;Huffman DM;Milman S
通讯作者：
Milman S
影响因子：
3.9
作者：
LUYTEN, FP;HASCALL, VC;REDDI, AH
通讯作者：
REDDI, AH
DOI：
10.1016/0304-4165(86)90306-5
发表时间：
1986-09-04
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
FARNDALE, RW;BUTTLE, DJ;BARRETT, AJ
通讯作者：
BARRETT, AJ
影响因子：
7.3
作者：
Le Maitre, CL;Richardson, SMA;Hoyland, JA
通讯作者：
Hoyland, JA