Localization of degradative enzymes and their inhibitors in the degenerate human intervertebral disc.
The histological and biochemical changes that occur in the extracellular matrix of the intervertebral disc (IVD) during ageing and degeneration have been investigated extensively. However, the mechanisms behind these changes are not fully understood. A number of studies have suggested the involvement of matrix metalloproteinases (MMPs) and ADAMTS in IVD degeneration, but few have localized the site of production of these enzymes to the cells of the degenerate disc. This study uses immunohistochemical techniques to localize and quantify the production of degrading enzymes (MMPs 1, 3, and 13, and ADAMTS 4) and their inhibitors (TIMPS 1, 2, and 3) within non-degenerate and degenerate discs of varying severity of degeneration. In all discs investigated, the cells that produced the enzymes and their inhibitors were the chondrocyte-like cells of the nucleus pulposus and inner annulus fibrosus (AF), with little immunopositivity in the outer AF. Non-degenerate discs showed low numbers of cells expressing the degradative enzymes MMP 1 and ADAMTS 4, suggesting a role for these enzymes in normal homeostasis. No MMP 3 or MMP 13 immunopositivity was observed in non-degenerate discs. In degenerate discs, the number of cells immunopositive for MMPs 1, 3, 13 and ADAMTS 4 increased with the severity of degeneration. This increase in degrading enzymes was also accompanied by increases in the number of cells immunopositive for TIMPs 1 and 2 but not TIMP 3. This study highlights that although the expression of a number of MMPs increases with degeneration, this is accompanied by an increase in their inhibitors. However, the increase in the number of cells immunoreactive for ADAMTS 4 with increasing degeneration was not paralleled by a rise in its inhibitor TIMP 3. This finding indicates that the aggrecanases, rather then the MMPs, are a possible therapeutic target for the inhibition of disc degeneration.
Injury Repair and Rehabilitation Research Group, Laboratory Medicine Academic Group, Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Christine Lyn
CL
Le Maitre
Anthony J
AJ
Freemont
Judith Alison
JA
Hoyland
D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007403:Intervertebral Disc / Q000201:enzymology* / Q000378:metabolism / Q000601:surgery; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D008875:Middle Aged; D011348:Procollagen N-Endopeptidase; D013122:Spinal Diseases / Q000201:enzymology* / Q000378:metabolism / Q000601:surgery; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
D019714:Tissue Inhibitor of Metalloproteinases; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human