0
Articles   |    
Association between Ratio of Matrix Metalloproteinase-1 to Tissue Inhibitor of Metalloproteinase-1 and Local Recurrence, Metastasis, and Survival in Human Chondrosarcoma*
KEITH R. BEREND, M.D.†; ALISON P. TOTH, M.D.†; JOHN M. HARRELSON, M.D.†; LESTER J. LAYFIELD, M.D.†; LLOYD A. HEY, M.D.†; SEAN P. SCULLY, M.D., PH.D.†, DURHAM, NORTH CAROLINA
View Disclosures and Other Information
Investigation performed at the Division of Orthopaedic Surgery, Laboratory of Cell and Molecular Biology; the Division of Diagnostic Pathology; and the Center for Clinical Effectiveness, Duke University Medical Center, Durham
J Bone Joint Surg Am, 1998 Jan 01;80(1):11-7
5 Recommendations (Recommend) | 3 Comments | Saved by 3 Users Save Case

Abstract

Chondrosarcoma, a malignant cartilage-forming mesenchymal tumor, displays a wide range of clinical behavior that can be difficult to predict with histological analysis. Matrix metalloproteinases contribute to the processes of local invasion and metastasis by controlling the ability of a tumor to transverse tissue boundaries. The specificity of matrix metalloproteinase-1 (interstitial collagenase) for fibrillar collagen may be central to those processes. Matrix metalloproteinase-2 facilitates invasion by degradation of such basement-membrane structures as type-IV collagen. The balance between the activity of tissue inhibitors of metalloproteinase and the activity of matrix metalloproteinase determines the proteolytic activity and may, in part, determine the overall invasiveness and potential for metastasis. The measurement of the ratio of matrix metalloproteinase to tissue inhibitor of metalloproteinase may have prognostic value for determining whether individual chondrosarcomas are locally invasive or will metastasize. Furthermore, there may be a specific pattern of expression of matrix metalloproteinase and tissue inhibitor of metalloproteinase in chondrosarcomas that is related to local invasion and probability of metastasis.Sixteen paraffin-embedded archival specimens of tumors were examined. Six twenty-micrometer-thick sections were cut from each tumor, and the amounts of cDNA formed from the mRNA were determined with reverse transcription-polymerase chain reaction with use of novel primers for matrix metalloproteinase-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2. The amounts of cDNA for the matrix metalloproteinases and their inhibitors were determined by chemiluminescence and band densitometry. The ratio of the amount of cDNA for matrix metalloproteinase-1 to that for its tissue inhibitor and the ratio of the amount of cDNA for matrix metalloproteinase-2 to that for its tissue inhibitor were calculated, and the results were compared with use of the Student t test, enabling log-rank analysis of Kaplan-Meier survival curves. These ratios as well as the age and gender of the patient; the grade, size, and location of the tumor; the type of adjuvant therapy; and the operative margins were examined for significance with use of stepwise logistic-regression analysis.The patients who had recurrent disease had a significantly higher (p < 0.003) ratio of matrix metalloproteinase-1 to tissue inhibitor of metalloproteinase-1 (mean, 0.939; range, 0.647 to 1.101) than the patients who were free of disease (mean, 0.703; range, 0.629 to 0.772). Moreover, there was a striking difference between the Kaplan-Meier survival curve associated with a high ratio (more than 0.8) and that associated with a low ratio (p = 0.0015). The mean ratio of matrix metalloproteinase-2 to tissue inhibitor of metalloproteinase-2 was 1.814 (range, 1.206 to 3.77) in the patients who had recurrent disease compared with 1.473 (range, 1.073 to 2.390) in those who were free of disease; this difference was not found to be significant, with the numbers available. Analysis of the survival curves indicated that a worse prognosis was associated with a high ratio, but again this relationship was not found to be significant. Regression analysis revealed that a high ratio of matrix metalloproteinase-1 to its tissue inhibitor was a moderately significant independent predictor of a poor outcome (a = 0.07).CLINICAL RELEVANCE: A high ratio of matrix metalloproteinase-1 to tissue inhibitor of metalloproteinase-1 in human chondrosarcoma may be indicative of a more invasive and aggressive tumor and a worse prognosis. The data presented here suggest that concentrations of matrix metalloproteinase-1, with substrate specificity for fibrillar collagens, may be important in the pathogenesis of local invasiveness and metastasis in human chondrosarcoma. The methods described in the present report may be useful for prognostically stratifying the survival of patients who have chondrosarcoma and for identifying a mechanism for the selection of adjuvant therapy in the future.

Figures in this Article
    Sign In to Your Personal ProfileSign In To Access Full Content
    Not a Subscriber?
    Get online access for 30 days for $35
    New to JBJS?
    Sign up for a full subscription to both the print and online editions
    Register for a FREE limited account to get full access to all CME activities, to comment on public articles, or to sign up for alerts.
    Register for a FREE limited account to get full access to all CME activities
    Have a subscription to the print edition?
    Current subscribers to The Journal of Bone & Joint Surgery in either the print or quarterly DVD formats receive free online access to JBJS.org.
    Forgot your password?
    Enter your username and email address. We'll send you a reminder to the email address on record.

     
    Forgot your username or need assistance? Please contact customer service at subs@jbjs.org. If your access is provided
    by your institution, please contact you librarian or administrator for username and password information. Institutional
    administrators, to reset your institution's master username or password, please contact subs@jbjs.org

    References

    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
    CME Activities Associated with This Article
    Submit a Comment
    Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
    Comments are moderated and will appear on the site at the discretion of JBJS editorial staff.

    * = Required Field
    (if multiple authors, separate names by comma)
    Example: John Doe





    Related Content
    The Journal of Bone & Joint Surgery
    JBJS Case Connector
    Topic Collections
    Related Audio and Videos
    PubMed Articles
    Clinical Trials
    Readers of This Also Read...
    JBJS Jobs
    03/05/2014
    OK - The University of Oklahoma
    03/19/2014
    VA - VIRGINIA COMMONWEALTH UNIVERSITY MEDICAL CENTER
    04/16/2014
    OH - OhioHealth Research and Innovation Institute (OHRI)