Alterations of ADAMTSs and TIMP-3 in human nucleus pulposus cells subjected to compressive load: Implications in the pathogenesis of human intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) pertains to the loss of extracellular matrix (ECM), particularly the early loss of aggrecan, the turnover of which is regulated by ADAMTSs. Amongst the etiological factors of IDD, mechanical stress plays an important role in the physiological and pathological processes of nucleus pulposus (NP) cells. However, the role of ADAMTSs and their inhibitor in human NP cells under mechanical stress has not been elucidated to date. The purpose of this study was to investigate the role of ADAMTSs and TIMP-3 in NP cells under mechanical stress. Human NP cells isolated from non-degenerative and degenerative discs were subjected to dynamic compressive load. The expression of ADAMTSs, aggrecan, and TIMP-3 was detected by quantitative real-time PCR and/or Western blot. Consequently, the gene expression of ADAMTS-1, 4, and 5 increased significantly in loaded NP cells compared with not-loaded cells from either non-degenerative or degenerative discs, whereas the gene expression of aggrecan decreased significantly. Moreover, Western blot indicated increased protein levels of ADAMTSs-1, 4, and 5. However, the expression of TIMP-3 altered insignificantly. Together, this study is the first addressing the underlying mechanisms of compressive load as a contributing factor to IDD in terms of ADAMTSs. Our results suggest that compressive load leads to the increase in ADAMTS-1, 4, and 5 that contributes to the decrease of aggrecan and IDD via TIMP-3 independent machinery.