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Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus

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Clinical Orthopaedics and Related Research®

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.

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Acknowledgments

We thank Rebecca Wilusz for technical assistance and Franklin Moutos for assistance with manuscript preparation.

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Authors and Affiliations

  1. Department of Surgery, Duke University Medical Center, 375 MSRB, Box 3093, Durham, NC, 27710, USA

    Amy L. McNulty PhD & Farshid Guilak PhD

  2. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    J. Brice Weinberg MD

  3. VA Medical Center, Durham, NC, USA

    J. Brice Weinberg MD

  4. Department of Biomedical Engineering, Duke University, Durham, NC, USA

    Farshid Guilak PhD

Authors
  1. Amy L. McNulty PhD
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  2. J. Brice Weinberg MD
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  3. Farshid Guilak PhD
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Corresponding author

Correspondence to Farshid Guilak PhD.

Additional information

One or more of the authors have received funding from the Arthritis Foundation (ALM, FG), VA Rehabilitation Research Service Award (JBW), and NIH Grants AR50245 (FG), AG15768 (FG), AR48182 (FG), AR48852 (FG), and AR55434 (ALM).

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McNulty, A.L., Weinberg, J.B. & Guilak, F. Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus. Clin Orthop Relat Res 467, 1557–1567 (2009). https://doi.org/10.1007/s11999-008-0596-6

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