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Oulun yliopiston väitöskirjat

COLLAGENASE-2 (MATRIX METALLOPROTEINASE-8)IN TONGUE SQUAMOUSCELL CARCINOMA, BONE OSTEOSARCOMA, AND WOUND REPAIR, ACTA UNIVERSITATIS OULUENSISD Medica 1042

ISBN-13:	978-951-42-6103-9
Kieli:	englanti
Kustantaja:	Oulun yliopisto
Oppiaine:	Lääketiede,farmasia
Painosvuosi:	2010
Sidosasu:	pehmeäkantinen
Sivumäärä:	154
Tekijät:	KORPI JAAKKO

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Degradation of extracellular matrix (ECM) and basement membrane (BM) are required both innormal physiological conditions such as wound healing and in pathological tissue remodelling suchas chronic ulcers and cancers. Matrix metalloproteinases (MMPs) are an enzyme family, which cancleave most ECM and BM components. They are associated with physiological and pathologicalprocesses but their exact roles are still largely unknown. The expression of MMP-8 and MMP-26 in acute and chronic human cutaneous wounds usinghistological and cell culture methods were investigated. MMP-8 was expressed in epithelial cells,neutrophils, and other inflammatory cells especially in chronic ulcers while in acute wounds MMP-8 expression was weak or absent. MMP-26 was temporarily present in acute wounds while it wasstrongly expressed in close vicinity to the BM in multiple cell types of most chronic ulcers. In vitrokeratinocyte wound assay showed that MMP-8 and -26 were expressed in migrating cells. Bone formation, collagen metabolism, and inflammation in MMP8-/- mice tooth extractionwounds and also periapical lesion formation were analysed. No differences between wild type orMMP-8-deficient mice in the new bone area or periapical lesion size were found. However, type IIIprocollagen production was increased and inflammatory cell influx was decreased in MMP8-/- mice.In addition, Fas ligand (FasL) production was increased in mandibular alveolar mucosa butdecreased in alveolar bone of MMP-8 deficient mice. MMP-8 was also found to cleave FasL in vitro. A total of 90 human mobile tongue squamous cell carcinoma (SCC) samples were collected.Bryne’s malignancy scores, thickness of the SCCs, expression of microvessel density (CD31 andfactor VIII), cyclooxygenase-2 (COX-2), the laminin-5 (currently termed laminin-332) ã2-chain,integrin ávâ6, estrogen receptor-á (ER-á), estrogen receptor-â (ER-â), and MMPs (-2, -7, -8, -9, -20, and -28) were analysed. The high expression of MMP-8 was associated with a better prognosisfor the patients, particularly in females. In addition, tongue carcinoma formation in MMP8-/- micewas investigated. Tongue SCC developed more often in MMP8-/- female mice than wild typelittermates. In addition, MMP-8 can cleave ER- á and -â and estrogen can induce MMP-8 productionin vitro. A total of 22 biopsies, 10 resection sections, and three lung metastases of 25 osteosarcomapatients samples were stained with MMP-2, -8, -13, -26, and tissue inhibitor of metalloproteinase-1(TIMP-1) using immunohistological methods. Expression of these markers was mostly present insarcoma cells but MMP-8 was not present in lung metastases. In resection sections, chemotherapyaltered MMP-2, -8, and -13 expressions compared to biopsies. However, an association between theexpression and prognosis of osteosarcoma patients could not been found. In conclusion, MMP-8 seems to be an estrogen-related protective factor in tongue SCC and canregulate ECM and BM components and inflammation during wound healing. Further studies areneeded to evaluate the exact function especially of MMP-8 in human osteosarcoma.

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