title: Inhibition of matrix metalloproteinases enhances in vitro repair of the meniscus.
abstract: Damage or injury of the meniscus is associated with onset and progression of knee osteoarthritis (OA). The intrinsic repair capacity of the meniscus is inhibited by inflammatory cytokines, such as interleukin-1 (IL-1). Using an in vitro meniscal repair model system, we examined the hypothesis that inhibition of matrix metalloproteinases (MMPs) in the presence of IL-1 will enhance repair of meniscal lesions. Integrative repair of the meniscus was examined between two concentric explants cultured with IL-1 and various MMP inhibitors for 14 days. Throughout the culture period, we assessed total specific MMP activity in the media. At harvest, biomechanical testing to assess the strength of repair and histologic staining were performed. IL-1 decreased the shear strength of repair, as compared with control explants. In the presence of IL-1, the broad-spectrum MMP inhibitor GM 6001 decreased the MMP activity in the media, increased the shear strength of repair, and enhanced tissue repair in the interface. However, individual MMP inhibitors did not alter the shear strength of repair in either the presence or absence of IL-1. These findings suggest IL-1 may inhibit meniscal repair through upregulation of MMPs, but inhibition of multiple MMPs may be necessary to promote integrative meniscal repair.
authors.affiliation: Department of Surgery, Duke University Medical Center, 375 MSRB, Box 3093, Durham, NC 27710, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: McNulty
authors.forename: J Brice
authors.initials: JB
authors.lastname: Weinberg
authors.forename: Farshid
authors.initials: F
authors.lastname: Guilak
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D008592:Menisci, Tibial / Q000201:enzymology / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013552:Swine; D015854:Up-Regulation
chemical_list: C095170:4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid; D004151:Dipeptides; D006877:Hydroxamic Acids; D007375:Interleukin-1; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D009842:Oligopeptides; D011480:Protease Inhibitors