Down-regulation of islet amyloid polypeptide expression induces death of human annulus fibrosus cells via mitochondrial and death receptor pathways

作者：Wu, Xinghuo; Wang, Kun; Hua, Wenbin; Li, Shuai; Liu, Xianzhe; Liu, Wei; Song, Yu; Zhang, Yukun; Shao, Zengwu; Yang, Cao^*

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2017, 1863(6): 1479-1491.

DOI：10.1016/j.bbadis.2017.04.016

• Islet amyloid polypeptide
• Apoptosis
• Disc degeneration
• Extracellular matrix metabolism
• Annulus fibrosus

Islet amyloid polypeptide (IAPP) exerts its biological effects by participating in the regulation of glucose metabolism and cell apoptosis. The main goal of the present study was to investigate the expression of IAPP in degenerated intervertebral disc tissue and IAPP's modulation of extracellular matrix (ECM) catabolic and anabolic genes in human AF cells. We found that the expression of IAPP, the calcitonin receptor, and receptor activity modifying protein decreased considerably in AF cells during the progression of intervertebral disc degeneration (IDD). Meanwhile, transfection with pLV-siIAPP decreased the expression of IAPP and its receptors and reduced glucose uptake and the expression of aggrecan, Col2Al, and BG. Down-regulation of IAPP also induced a significant increase in reactive oxygen species generation in AF cells, along with a decrease in matrix metalloproteinases and an increase in the concentration of cellular Ca2+ ultimately leading to death. Further analysis revealed that siIAPP intervention promoted the release of cytochrome c from mitochondria, resulting in the activation of Caspase-3 and Caspase-9. In contrast, significantly decreased expression of Caspase-3 and Caspase-9 was observed in AF cells transfected with pLV-IAPP. The concentrations of Fas and FasL proteins were significantly decreased in AF cells transfected with PLV-IAPP, while activation of the Fas/FasL system and cell death were induced by siIAPP intervention. Mechanistically, AMPK/Akt-mTOR signaling pathways were involved. In conclusion, down-regulation of LAPP expression induces the death of human AF cells via mitochondrial and death receptor pathways, potentially offering a novel therapeutic target for the treatment of IDD.

• 出版日期2017-6
• 单位华中科技大学