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PROLONGED AGGRECANOLYTIC ACTIVATION OF MATRIX METALLOPROTEINASES (MMPS) RELATIVE TO AGGRECANASES IN A RAT TAIL COMPRESSION LOADING‐INDUCED DISC DEGENERATION MODEL: GP16.

Yurube, Takashi; Nishida, Kotaro; Suzuki, Teppei; Kakutani, Kenichiro; Maeno, Koichiro; Takada, Toru; Kurosaka, Masahiro; Doita, Minoru

Spine Journal Meeting Abstracts: October 2011 - Volume - Issue - [no page #]
GENERAL POSTERS
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Kobe University Graduate School of Medicine, Orthopaedic Surgery, Kobe, Japan

INTRODUCTION: Precise cellular pathobiology remains unclear because of few wellestablished animal model researches. Furthermore, aggrecanolytic potentials of degradative enzymes have not been fully focused. Our objective was, using a rat tail static compression loading‐induced model we validated, to elucidate catabolismrelated gene alterations and their aggrecanolytic activities throughout the disc degeneration cascade.

METHODS: Forty‐eight 12‐week‐old Sprague‐Dawley rat tails were attached with an Ilizarov‐type device and loaded statically at 1.3 MPa for up to 56 days. Loaded and distal‐unloaded control discs were harvested for real‐time RT‐PCR genequantification: catabolism [MMP‐1a, ‐2, ‐3, ‐7, ‐9, ‐13, ADAMTS‐4, and ‐5], anabolism [TIMP‐1, ‐2, and ‐3], extracellular matrix [aggrecan‐1, collagen type 1‐α1, and type 2‐α1], and pro‐inflammatory cytokine [TNF‐α IL‐1α, ‐1β, and ‐6]. Immunohistochemistry for MMP‐3, ADAMTS‐4, ‐5, TIMP‐1, ‐2, and ‐3 was performed. The presence of MMPand aggrecanase‐cleaved aggrecan products was investigated.

RESULTS: Most catabolic genes, particularly MMP‐3, showed significant mRNA upregulations from 7 days. TIMP‐1 and ‐2 were unchanged while TIMP‐3 was significantly down‐regulated throughout. Up‐regulation of collagen type 1‐α1 and down‐regulations of aggrecan‐1 and collagen type 2‐α1 were confirmed. Despite TNFα‐ elevation, ILs demonstrated no drastic up‐regulation. Immunohistochemistry exhibited more predominant expressions for MMP‐3 than ADAMTS‐4/‐5 as well as TIMP‐1/‐2 than ‐3. Aggrecan fragments were detected with a longer duration of immunopositivity generated by MMPs than by aggrecanases.

DISCUSSION: Static compression revealed pathological imbalances of increased MMP and ADAMTS relative to TIMP enzymes and their different working phases. Earlier aggrecanase activation associated with TIMP‐3 down‐regulation and later MMP activation represented by MMP‐3 up‐regulation might play crucial roles in the disc degeneration.

© 2011 Lippincott Williams & Wilkins, Inc.