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The longitudinal degradation mechanism of extracellular matrix (ECM) in the interbertebral disc remains unclear. Our objective was to elucidate catabolic and anabolic gene expression profiles and their balances in intervertebral disc degeneration using a static compression model.    Methods  Forty-eight 12-week-old male Sprague-Dawley rat tails were instrumented with an Ilizarov-type device with springs and loaded statically at 1.3 MPa for up to 56 days. Experimental loaded and distal-unloaded control discs were harvested and analyzed by real-time reverse transcription-polymerase chain reaction (PCR) messenger RNA quantification for catabolic genes [ matrix metalloproteinase  ( MMP ) -1a ,  MMP-2 ,  MMP-3 ,  MMP-7 ,  MMP-9 ,  MMP-13 ,  a disintegrin and metalloproteinase with thrombospondin motifs  ( ADAMTS ) -4 , and  ADAMTS-5 ], anti-catabolic genes [ tissue inhibitor of metalloproteinases  ( TIMP ) -1 ,  TIMP-2 , and  TIMP-3 ], ECM genes [ aggrecan-1 ,  collagen type 1-α1 , and  collagen type 2-α1 ], and pro-inflammatory cytokine genes [ tumor necrosis factor  ( TNF ) -α ,  interleukin  ( IL ) -1α ,  IL-1β , and  IL-6 ]. Immunohistochemistry for MMP-3, ADAMTS-4, ADAMTS-5, TIMP-1, TIMP-2, and TIMP-3 was performed to assess their protein expression level and distribution. The presence of MMP- and aggrecanase-cleaved aggrecan neoepitopes was similarly investigated to evaluate aggrecanolytic activity.    Results  Quantitative PCR demonstrated up-regulation of all  MMPs  and  ADAMTS-4  but not  ADAMTS-5. TIMP-1  and  TIMP-2  were almost unchanged while  TIMP-3  was down-regulated. Down-regulation of  aggrecan-1  and  collagen type 2-α1  and up-regulation of  collagen type 1-α1  were observed. Despite  TNF-α  elevation,  ILs  developed little to no up-regulation. Immunohistochemistry showed, in the nucleus pulposus, the percentage of immunopositive cells of MMP-cleaved aggrecan neoepitope increased from 7 through 56 days with increased MMP-3 and decreased TIMP-1 and TIMP-2 immunopositivity. The percentage of immunopositive cells of aggrecanase-cleaved aggrecan neoepitope increased at 7 and 28 days only with decreased TIMP-3 immunopositivity. In the annulus fibrosus, MMP-cleaved aggrecan neoepitope presented much the same expression pattern. Aggrecanase-cleaved aggrecan neoepitope increased at 7 and 28 days only with increased ADAMTS-4 and ADAMTS-5 immunopositivity.    Conclusions  This rat tail sustained static compression model mimics ECM metabolic imbalances of MMPs, aggrecanases, and TIMPs in human degenerative discs. A dominant imbalance of MMP-3/TIMP-1 and TIMP-2 relative to ADAMTS-4 and ADAMTS-5/TIMP-3 signifies an advanced stage of intervertebral disc degeneration.

arthritis research and therapy

Rat tail static compression model mimics extracellular matrix metabolic imbalances of matrix metalloproteinases, aggrecanases, and tissue inhibitors of metalloproteinases in intervertebral disc degeneration