Mechanical destabilization induced by controlled annular incision of the intervertebral disc dysregulates metalloproteinase expression and induces disc degeneration

• Published in: Spine (Philadelphia, Pa. 1976) Vol. 37; no. 1; p. 18
• Main Authors: Melrose, James, Shu, Cindy, Young, Cara, Ho, Ronald, Smith, Margaret M, Young, Allan A, Smith, Susan S, Gooden, Ben, Dart, Andrew, Podadera, Juan, Appleyard, Richard C, Little, Christopher B
• Format: Journal Article
• Language: English
• Published: United States 01.01.2012
• Subjects: ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAMTS4 Protein; Animals; Collagen - genetics; Collagen - metabolism; Disease Models, Animal; Gene Expression; Gene Expression Profiling; Intervertebral Disc - injuries; Intervertebral Disc - metabolism; Intervertebral Disc - pathology; Intervertebral Disc Degeneration - etiology; Intervertebral Disc Degeneration - metabolism; Intervertebral Disc Degeneration - pathology; Lumbar Vertebrae - pathology; Lumbar Vertebrae - physiopathology; Lumbar Vertebrae - surgery; Magnetic Resonance Imaging; Male; Metalloproteases - genetics; Metalloproteases - metabolism; Orchiectomy; Procollagen N-Endopeptidase - genetics; Procollagen N-Endopeptidase - metabolism; Proteoglycans - genetics; Proteoglycans - metabolism; RNA, Messenger - metabolism; Sheep; Stress, Mechanical
• ISSN: 1528-1159
• DOI: 10.1097/BRS.0b013e31820cd8d5

An investigation of mechanical destabilization of the lumbar ovine intervertebral disc (IVD) inducing IVD degeneration (IVDD) as determined by multiparameter outcome measures (magnetic resonance imaging [MRI], IVD composition, biomechanical testing, gene profiling, immunohistochemistry, and immunoblotting). To assess the effect of IVD mechanical destabilization on matrix protein and metalloproteinase gene expression to investigate the pathophysiological mechanisms of lumbar IVDD. Several earlier studies have used annular transection to induce IVDD in sheep, but none have optimized or validated the most appropriate lesion size. The annulus fibrosus (AF) incision inducing maximal change in IVD biomechanics was applied to L1-L2, L3-L4, and L5-L6 discs in vivo to compare with a sham procedure at 3 months post operation. IVDs were evaluated by MRI, biomechanics, histopathology, proteoglycan and collagen content, gene expression, and aggrecan proteolysis by Western blotting. Significant changes were observed in lesion (6 × 20 mm(2)) compared with sham IVDs at 3 months post operation: reduced disc height on MRI; increased neutral zone in biomechanical testing; depleted proteoglycan and collagen content in the nucleus pulposus (NP) and lesion half of the AF but not in the contralateral AF; increased messenger RNA for collagen I and II, aggrecan, versican, perlecan, matrix metalloproteinase (MMP)-1 & 13, and ADAMTS-5, in the lesion-site AF and NP but not in the contralateral AF. ADAMTS-4 messenger RNA was increased in the lesion-site AF but decreased in the NP. Despite an upregulation in MMPs, there was no change in MMP- or ADAMTS-generated aggrecan neoepitopes in any region of the IVD in lesion or sham discs. Lumbar IVDD was reproducibly induced with a 6 × 20 mm(2) annular lesion, with focal dysregulation of MMP gene expression, cell cloning in the inner AF, loss of NP aggrecan, and disc height. Loss of aggrecan from the NP was not attributable to increased proteolysis in the interglobular domain by MMPs or ADAMTS.