Systemic levels of interleukin-6 and matrix metalloproteinase-9 in patients with multiple myeloma may be useful as prognostic indexes of bone disease
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Aikaterini Sfiridaki
Abstract
Multiple myeloma is characterized by accelerated production of the proteolytic enzyme matrix metalloproteinase (MMP)-9. We hypothesized that myeloma-produced MMP-9 may influence the rate of bone turnover in a paracrine manner. Thus, we examined the correlations of MMP-9 levels, disease severity, and bone turnover rate as evaluated by markers of bone formation and resorption.
Thirty-seven newly diagnosed multiple myeloma patients (nine of Durie-Salmon stage I, 12 of stage II and 16 of stage III) and 12 age-matched controls were studied. Serum MMP-9 levels were significantly higher at stage II compared to stage I (188.78±91.27 vs. 59.25±33.09 ng/mL, p<0.004). Additionally, free urine pyridinolines (F-Pyd), free urine deoxy-pyridinolines (F-Dpd) and urine N-telopeptide fragment (NTx) were elevated, their level correlating with disease stage (p<0.001, p<0.03, p<0.001, respectively), as were bone marrow infiltration and serum interleukin-6 (IL-6) levels (p<0.0001, p<0.01, respectively). MMP-9 levels were lower in patients compared with controls (p<0.001), whereas IL-6 and bone resorption marker levels were higher in patients than in controls (p<0.001 in all cases). Significant correlation was found between infiltration, MMP-9, free urine pyd, free urine dpd and NTx for each stage of the disease (p<0.03, p<0.003, p<0.002, p<0.003 and p<0.001, respectively). Levels of MMP-9 and of IL-6 in multiple myeloma correlate well with bone turnover rate and may be useful in disease evaluation.
References
1. Bataille R, Chappard D, Basle M. Excessive bone resorption in human plasmacytomas: direct induction by tumour cells in vivo. Br J Haematol 1995; 90: 721–4. 10.1111/j.1365-2141.1995.tb05609.xSearch in Google Scholar
2. Alexandrakis MG, Passam FH, Malliaraki N, Katachanakis C, Kyriakou DS, Margioris AN. Evaluation of bone disease in multiple myeloma: a correlation between biochemical markers of bone metabolism and other clinical parameters in untreated multiple myeloma patients. Clin Chim Acta 2002; 325: 51–7. 10.1016/S0009-8981(02)00246-2Search in Google Scholar
3. Mundy GR. Myeloma bone disease. Eur J Cancer 1998; 34: 246–51. 10.1016/S0959-8049(97)10133-2Search in Google Scholar
4. Alexandrakis MG, Kyriakou DS, Passam FH, Malliaraki N, Vlachonikolis IG, Karkavitsas N. Urinary N-telopeptidelevels in multiple myeloma patients, correlation with Tc-99m-sestaMIBI scintigraphy and other biochemical markers of disease activity. Hematol Oncol 2003; 21: 17–24. 10.1002/hon.700Search in Google Scholar PubMed
5. Ray JM, Stetler-Stevenson WG. The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur Respir J 1994; 7: 2062–72. 10.1183/09031936.94.07112062Search in Google Scholar
6. Vacca A, Ribatti D, Presta M, Minischetti M, Iurlaro M, Ria R, et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 1999; 93: 3064–73. 10.1182/blood.V93.9.3064.409k07_3064_3073Search in Google Scholar
7. Barille S, Akhoundi C, Collette M, Mellerin MP, Rapp MJ, Harousseau JL, et al. Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells. Blood 1997; 90: 1649–55. 10.1182/blood.V90.4.1649Search in Google Scholar
8. Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 1993; 73: 161–95. 10.1152/physrev.1993.73.1.161Search in Google Scholar PubMed
9. Stetler-Stevenson WG, Aznavoorian S, Liotta LA. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol 1993; 9: 541–73. 10.1146/annurev.cb.09.110193.002545Search in Google Scholar PubMed
10. Niesvizky R, Warrell RP Jr. Pathophysiology and management of bone disease in multiple myeloma. Cancer Invest 1997; 15: 85–90. 10.3109/07357909709018921Search in Google Scholar PubMed
11. Kelly T, Borset M, Abe E, Gaddy-Kurten D, Sanderson RD. Matrix metalloproteinases in multiple myeloma. Leuk Lymphoma 2000; 37: 273–81. 10.3109/10428190009089428Search in Google Scholar PubMed
12. Van Valckenborgh E, Bakkus M, Munaut C, Noel A, St Pierre Y, Asosingh K, et al. Upregulation of matrix metalloproteinase-9 in murine 5T33 multiple myeloma cells by interaction with bone marrow endothelial cells. Int J Cancer 2002; 101: 512–8. 10.1002/ijc.10642Search in Google Scholar
13. Vande Broek I, Asosingh K, Allegaert V, Leleu X, Facon T, Vanderkerken K, et al. Bone marrow endothelial cells increase the invasiveness of human multiple myeloma cells through upregulation of MMP-9: evidence for a role of hepatocyte growth factor. Leukemia 2004; 18: 976–82. 10.1038/sj.leu.2403331Search in Google Scholar
14. Westermarck J, Kahari VM. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 1999; 13: 781–92. 10.1096/fasebj.13.8.781Search in Google Scholar
15. Derksen PW, de Gorter DJ, Meijer HP, Bende RJ, van Dijk M, Lokhorst HM, et al. The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma. Leukemia 2003; 17: 764–74. 10.1038/sj.leu.2402875Search in Google Scholar
16. Abildgaard N, Glerup H, Rungby J, Bendix-Hansen K, Kassem M, Brixen K, et al. Biochemical markers of bone metabolism reflect osteoclastic and osteoblastic activity in multiple myeloma. Eur J Haematol 2000; 64: 121–9. 10.1034/j.1600-0609.2000.90074.xSearch in Google Scholar
17. Corso A, Arcaini L, Mangiacavalli S, Astori C, Orlandi E, Lorenzi A, et al. Biochemical markers of bone disease in asymptomatic early stage multiple myeloma. A study on their role in identifying high risk patients. Haematologica 2001; 86: 394–8. Search in Google Scholar
18. Fonseca R, Trendle MC, Leong T, Kyle RA, Oken MM, Kay NE, et al. Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients. Br J Haematol 2000; 109: 24–9. 10.1046/j.1365-2141.2000.01960.xSearch in Google Scholar
19. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975; 36: 842–54. 10.1002/1097-0142(197509)36:3<842::AID-CNCR2820360303>3.0.CO;2-USearch in Google Scholar
20. Anderson KC, Lust JA. Role of cytokines in multiple myeloma. Semin Hematol 1999; 36(1 Suppl 3): 14–20. Search in Google Scholar
21. Dhodapkar MV, Kelly T, Theus A, Athota AB, Barlogie B, Sanderson RD. Elevated levels of shed syndecan-1 correlate with tumour mass and decreased matrix metalloproteinase-9 activity in the serum of patients with multiple myeloma. Br J Haematol 1997; 99: 368–71. 10.1046/j.1365-2141.1997.3893203.xSearch in Google Scholar
22. Kaushal GP, Xiong X, Athota AB, Rozypal TL, Sanderson RD, Kelly T. Syndecan-1 expression suppresses the level of myeloma matrix metalloproteinase-9. Br J Haematol 1999; 104: 365–73. 10.1046/j.1365-2141.1999.01180.xSearch in Google Scholar
23. Stetler-Stevenson WG, Liotta LA, Kleiner DE Jr. Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J 1993; 7: 1434–41. 10.1096/fasebj.7.15.8262328Search in Google Scholar
24. Tanaka A, Matsuda H. IgE crosslinkage of Fcepsilonreceptor I induces both production and activation of matrix metalloproteinase-9 in mast cells. Cell Immunol 2004; 228: 66–75. 10.1016/j.cellimm.2004.03.009Search in Google Scholar PubMed
25. Tchougounova E, Lundequist A, Fajardo I, Winberg JO, Abrink M, Pejler G. A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J Biol Chem 2005; 280: 9291–6. 10.1074/jbc.M410396200Search in Google Scholar PubMed
26. Theoharides TC, Conti P. Mast cells: the Jekyll and Hyde of tumor growth. Trends Immunol 2004; 25: 235–41. 10.1016/j.it.2004.02.013Search in Google Scholar PubMed
27. Alexandrakis MG, Passam FH, Dambaki C, Pappa CA, Stathopoulos EN. The relation between bone marrow angiogenesis and the proliferation index Ki-67 in multiple myeloma. J Clin Pathol 2004; 57: 856–60. 10.1136/jcp.2003.013110Search in Google Scholar PubMed PubMed Central
28. Vacca A, Ribatti D, Roccaro AM, Ria R, Palermo L, Dammacco F. Bone marrow angiogenesis and plasma cell angiogenic and invasive potential in patients with active multiple myeloma. Acta Haematol 2001; 106: 162–9. 10.1159/000046612Search in Google Scholar PubMed
29. Alexandrakis MG, Passam FH, Pappa CA, Dambaki C, Sfakiotaki G, Alegakis AK, et al. Expression of proliferating cell nuclear antigen (PCNA) in multiple myeloma: its relationship to bone marrow microvessel density and other factors of disease activity. Int J Immunopathol Pharmacol 2004; 17: 49–56. 10.1177/039463200401700107Search in Google Scholar PubMed
30. Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002; 128: 344–50. 10.1159/000063858Search in Google Scholar PubMed
©2005 by Walter de Gruyter Berlin New York
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Articles in the same Issue
- The future of clinical laboratories: more testing or knowledge services?
- Apolipoprotein A5 and triglyceridemia. Focus on the effects of the common variants
- Genotyping of the 19-bp insertion/deletion polymorphism in the 5′ flank of β-hydroxylase gene by dissociation analysis of allele-specific PCR products
- APOE genotypes and dyslipidemias in a sample of the Portuguese population
- Serum proteins profile as an indicator of malignancy: multivariate logistic regression and ROC analyses
- Mean fluorescence intensity rate is a useful marker in the detection of paroxysmal nocturnal hemoglobinuria clones
- Alterations of glycosaminoglycan metabolism in the development of diabetic complications in relation to metabolic control
- Erythrocyte zinc content in critically ill patients
- Systemic levels of interleukin-6 and matrix metalloproteinase-9 in patients with multiple myeloma may be useful as prognostic indexes of bone disease
- Analysis of the applicability of artificial neural networks for studying blood plasma: determination of magnesium ion concentration as a case study
- The effect of long-term storage on measured plasma lactate concentrations and prospective lactate results from a multicenter trial of antiretroviral therapy
- Evaluation of renal function in intensive care: plasma cystatin C vs. creatinine and derived glomerular filtration rate estimates
- Multicentre physiological reference values for some urinary component-to-creatinine (creatininium) concentration ratios
- Diagnostic and analytical performance of a screening panel for allergy
- Preliminary evaluation of the Iris IQ™ 200 automated urine analyser
- The Asp298 but not the C-786 genotype of the endothelial nitric oxide synthase is reduced with age in healthy Swiss men
- Identification of preanalytical mistakes in the stat section of the clinical laboratory
- Congress of Clinical Chemistry and Laboratory Medicine 2nd Annual Conference of the German United Society for Clinical Chemistry and Laboratory Medicine (DGKL) together with the Austrian Society for Laboratory Medicine and Clinical Chemistry (ÖGLMKC) Jena, Germany, October 6–8, 2005
- SIBioC 2005 37th National Congress of the Italian Society of Clinical Biochemistry and Clinical Molecular Biology Rome, Italy, October 11–14, 2005
