title: Increased MMP-2 activity during intervertebral disc degeneration is correlated to MMP-14 levels.
abstract: Intervertebral disc (IVD) degeneration is associated with the increased expression of several matrix metalloproteinases (MMPs), in particular MMP-2. However, little is known about the actual activity of MMP-2 in healthy and degenerated discs, or what mechanisms are involved in its activation. A major activation pathway involves complex formation with MMP-14 and a tissue inhibitor of metalloproteinases-2 (TIMP-2). In a series of 56 human IVDs, obtained at autopsy and graded according to the Thompson score (I-V), we analysed whether MMP-2 activity was increased in different stages of IVD degeneration and to what extent activation was related to the production of MMP-14 and TIMP-2. MMP-2 activation and production were quantified by gelatin zymography. Immunohistochemical staining of MMP-14 and TIMP-2 was quantified with a video overlay-based system. A positive correlation was observed between the amount of active MMP-2 and pro-MMP-2 and degeneration grade (p < 0.001, correlation coefficient (CC) 0.557; and p < 0.001, CC 0.556, respectively). MMP-2 activity correlated positively with MMP-14 and less strongly with TIMP-2 (p = 0.001, CC 0.436; and p = 0.03, CC 0.288, respectively). Moreover, immunopositivity for MMP-14 correlated to degeneration grade (p = 0.002, CC 0.398). IVD degeneration was associated with the activity of MMP-2 and the correlation of its activation with MMP-14 production suggests MMP-14 activates MMP-2 during degeneration. As MMP-14 is capable of activating several other enzymes that are also thought to be involved in IVD degeneration, it may be a key mediator of the degenerative process.
authors.affiliation: Department of Orthopaedics, University Medical Centre, Utrecht, The Netherlands.
authors.forename: J P H J
authors.initials: JP
authors.lastname: Rutges
authors.forename: J A
authors.initials: JA
authors.lastname: Kummer
authors.forename: F C
authors.initials: FC
authors.lastname: Oner
authors.forename: A J
authors.initials: AJ
authors.lastname: Verbout
authors.forename: R J M
authors.initials: RJ
authors.lastname: Castelein
authors.forename: H J A
authors.initials: HJ
authors.lastname: Roestenburg
authors.forename: W J A
authors.initials: WJ
authors.lastname: Dhert
authors.forename: L B
authors.initials: LB
authors.lastname: Creemers
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004247:DNA / Q000032:analysis; D004789:Enzyme Activation; D006801:Humans; D007403:Intervertebral Disc / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008875:Middle Aged; D012720:Severity of Illness Index; D013122:Spinal Diseases / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
chemical_list: D019716:Tissue Inhibitor of Metalloproteinase-2; D004247:DNA; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14