Concentrations of Metalloproteinased-9 (MMP-9), Metalloproteinases -1 and-2 Tissue Inhibitors (TIMP-1, TIMP-2), Tumor Necrosis Factor-α (TNF-α), Hepatocyte Growth Factor (HGF), Dickkopf Related Proten 1 (DKK-1) and Emmprin (CD147) Expression Are Increased in Patients with Myeloma Multiplex and MMP-9 Correlates with advanced Stage of Disease

Metalloproteinases (MMP) belong to the group of metallodependent proteolitic enzymes included into endopeptidases being characteristic for the ability of extracelullar matrix degradation. Gelatinases: A(MMP-2) and B (MMP-9) take part in neoplasms metastatic process. MMP activity is controlled both by their tissue inhibitors (TIMP) and activator (emmprin). Multiple myeloma (MM) is a lymphocytes B proliferative disease which is accompanied by osteolytic lesions and extramedullar spread. There are few reports concerning the assessment of MMP-2, MMP-9, TIMP-1, TIMP-2, TNF-α, HGF, DKK-1 concentrations as well as emmprin expression on bone marrow mesenchymal stem cells (BMSC) in patients suffering from multiple myeloma.

The goal of the study was to assess MMP-2, MMP-9, TIMP-1,TIMP-2, TNF-α, HGF, DKK-1 concentrations in marrow plasma, in culture supernatant as well as emmprin expression on BMSC in multiple myeloma patients. The survey also comprised metalloproteinases, their inhibitors and cytokines influence on myeloma development and progress and included the trial whether these parameters are related to clinical stage of myeloma.

Forty patients were enrolled in the study: 18 males and 22 females aged 48–81 years (mean age-52.4 years) with de novo diagnosed multiple myeloma. According to ISS (International Staging System) 7 patients were at stage I, 19 patients were at stage II and 14 patients were at stage III. Control group consisted of 11 healthy persons matched with age and sex. Bone marrow was collected before the treatment. Bone marrow mesenchymal stem cells (BMSCs) revealing antigen CD166 expression were derived in incubation process on Mesencult culture. Concentrations: MMP-2 and TIMP-2, MMP-9, TIMP-1, TNF-α, HGF and DKK-1 were measured in marrow plasma and culture supernatant with ELISA test. Emmprin expression on CD166+ cells was assessed by FACS analysis.

Mean concentrations of MMP-9, TIMP-1 and TIMP-2 in both marrow plasma and culture supernatant were significantly higher in multiple myeloma patients in comparison with control group. Mean concentration of TNF-α, HGF and DKK-1 assessed in culture supernatant were significantly higher in patients than in control group. In turn, MMP-2 mean concentration in marrow plasma did not differ significantly between patients and control groups. MMP-9/TIMP-1 ratio for marrow plasma and supernatant was significantly higher in MM group. MMP-2/TIMP-2 ratio for culture supernatant was higher in patients in comparison with healthy persons. Besides, in patients at the higher stage of the disease progress (II+III), MMP-9 concentration estimated in marrow plasma was higher than in patients placed at the disease advance low stage (I). CD147 expression on BMSC cells of myeloma patients was significantly higher than the one on BMSC collected from healthy persons. It also correlated with MMP-2 and TIMP-2 concentrations and MMP-2/TIMP-2 ratio in culture supernatant.

Concentrations of MMP-9, MMP-2, TIMP-1, TIMP-2, TNF-α, HGF and DKK-1 and emmprin expression are increased in myeloma patients and concentration of MMP-9 correlates with advanced stage of disease.

No relevant conflicts of interest to declare.