Collagenase-2 (matrix metalloproteinase-8) in tongue squamous cell carcinoma, bone osteosarcoma, and wound repair

Abstract Degradation of extracellular matrix (ECM) and basement membrane (BM) are required both in normal physiological conditions such as wound healing and in pathological tissue remodelling such as chronic ulcers and cancers. Matrix metalloproteinases (MMPs) are an enzyme family, which can cleave most ECM and BM components. They are associated with physiological and pathological processes but their exact roles are still largely unknown. The expression of MMP-8 and MMP-26 in acute and chronic human cutaneous wounds using histological 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 was strongly expressed in close vicinity to the BM in multiple cell types of most chronic ulcers. In vitro keratinocyte wound assay showed that MMP-8 and -26 were expressed in migrating cells. Bone formation, collagen metabolism, and inflammation in MMP8-/- mice tooth extraction wounds and also periapical lesion formation were analysed. No differences between wild type or MMP-8-deficient mice in the new bone area or periapical lesion size were found. However, type III procollagen production was increased and inflammatory cell influx was decreased in MMP8-/- mice. In addition, Fas ligand (FasL) production was increased in mandibular alveolar mucosa but decreased 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 and factor VIII), cyclooxygenase-2 (COX-2), the laminin-5 (currently termed laminin-332) γ2-chain, integrin αvβ6, estrogen receptor-α (ER-α), estrogen receptor-β (ER-β), and MMPs (-2, -7, -8, -9, -20, and -28) were analysed. The high expression of MMP-8 was associated with a better prognosis for the patients, particularly in females. In addition, tongue carcinoma formation in MMP8-/- mice was investigated. Tongue SCC developed more often in MMP8-/- female mice than wild type littermates. In addition, MMP-8 can cleave ER- α and -β and estrogen can induce MMP-8 production in vitro. A total of 22 biopsies, 10 resection sections, and three lung metastases of 25 osteosarcoma patients 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 in sarcoma cells but MMP-8 was not present in lung metastases. In resection sections, chemotherapy altered MMP-2, -8, and -13 expressions compared to biopsies. However, an association between the expression 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 can regulate ECM and BM components and inflammation during wound healing. Further studies are needed to evaluate the exact function especially of MMP-8 in human osteosarcoma