MATRIX METALLOPROTEINESES AND THEIR TISSUE INHIBITORS IN PRIMARY BONE TUMOR PATIENTS: CLINICAL AND PATHOLOGIC CORRELATIONS

DOI: https://doi.org/10.29296/24999490-2018-05-08

N.E. Kushlinskii, I.S. Chernomaz, E.S. Gershtein, I.V. Boulytcheva, M.D. Aliev, Yu.N. Soloviev N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe highway, 24, Moscow, 115478, Russian Federation E-mail: [email protected]

Introduction. The search of molecular markers for early diagnostics, prognosis, and identification of new objects for molecular-targeted therapy of primary bone tumors remains one of the most important tasks despite the significant achievements in the treatment of bone sarcomas, especially osteosarcoma. Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) involved in the degradation of practically all extracellular matrix components occupy one of the key positions among potential biological markers of various tumors. Aim of the study. Comparative evaluation of MMP-2, 7, 9 and TIMP-1, 2 levels in blood serum of primary bone neoplasms’ patients and practically healthy persons, and analysis of associations between these markers and principal clinical and pathologic characteristics of bone tumors. Material and methods. 105 patients with malignant bone tumors (50 – osteosarcoma, 41 – chondrosarcoma, 11 – chordoma, 4 – Ewing sarcoma), 27 borderline giant cell bone tumor (GCBT), and 13 benign bone tumor patients were examined. Control group comprised 42 persons. MMP-2, 7, 9 and TIMP-1, 2 serum levels were measured by standard ELISA kits (R&D, USA). Results. Substantial and significant increase of matrilysin (MMP-7) serum concentration was demonstrated not only in patients with malignant sarcomas but also in those with borderline GCBT and benign and tumor-like bone lesions when compared to control. The increase of MMP-7 level did not depend on neoplasm’s character and histological type of bone sarcomas. A significant increase of TIMP-2 level was also observed in sarcomas and GCBT patients, while TIMP-1 was increased in relation to control only in patients with benign bone neoplasms. Meanwhile, serum levels of gelatinases either were unchanged (MMP-9) or decreased (MMP-2) as compared to healthy control. Gelatinases, but not MMP-7 serum levels in bone sarcoma patients were associated with the levels of RANK/RANKL/OPG system – the key regulator of bone homeostasis components. This observation corresponds to contemporary views on the role of these proteinases in RANK/RANKL/OPG processing. Conclusion. Considerable increase of MMP-7 serum concentration associated with the neoplasm character and histological type of bone sarcomas, as well as an increase of serum TIMP-2 in GCBT and malignant bone tumor patients are observed. MMP-2, 9 and TIMP-1 concentrations in the sera of bone tumor patients either stayed unchanged or decreased as compared to control. Thus, MMPs and TIMPs investigated in this study cannot be regarded as specific diagnostic markers for bone tumors. Further investigations and follow-up of patients enclosed in this study are required for the assessment of MMPs/TIMPs role in disease prognosis and evaluation of treatment efficiency.
Keywords: 
bone tumors, MMP-7, MMP-2, MMP-9, TIMP-1, TIMP-2, blood serum
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