Differential regulation of matrix degrading enzymes in a TNFα-induced model of nucleus pulposus tissue degeneration

Intervertebral disc degeneration occurs commonly and is linked to persistent back pain and the development of disc herniation. The mechanisms responsible for tissue catabolism have not yet been fully elucidated. Previously we characterized an in vitro model of TNFα-induced nucleus pulposus degeneration, which demonstrates decreased expression of matrix macromolecules, increased expression of matrix degrading enzymes, and the activation of aggrecanase-mediated proteoglycan degradation [Seguin, C.A., Pilliar, R.M., Roughley, P.J., and Kandel, R.A. 2005. Tumor necrosis factor-alpha modulates matrix production and catabolism in nucleus pulposus tissue. Spine 30: 1940–1948]. This study explores the intracellular pathways activated during TNFα-induced matrix degradation. We demonstrate that in nucleus pulposus cells, the p38 and JNK pathways regulate induction of MMP-1 and -3; p38, JNK, and NF-κB regulate the induction of MMP-13; and ERK regulates the up-regulation of MT1-MMP mRNA in response to TNFα. Induction of ADAMTS-4 and -5 mRNA occurred downstream of NF-κB activation. Depletion of tissue proteoglycans was mediated by ERK and NF-κB-dependent “aggrecanase” activity, suggesting MT1-MMP and ADAMTS-4 and -5 as effectors of TNFα-induced tissue catabolism.