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Tetracycline and its analogs have been shown to be of therapeutic benefit in several animal models of disease and in human arthritis The collagenase subfamily of MMP consists of 3 different enzymes: fibroblast collagenase (MMP-1) 3 , neutrophil collagenase (MMP-8) Because of the discrepancy between the ability of doxycycline to prevent the development of experimental osteoarthritis (OA) and the level required to directly inhibit collagenase, we have investigated other modes by which doxycycline could inhibit collagenase activity. We have reported 10 that doxycycline at concentrations as low as 1 µg/ml (2.08 µM) are capable of downregulating the production of MMP-1 and MMP-13. It has also been shown by Jonat and co-workers that 1 µM doxycycline (0.48 µg/ml) will inhibit stromelysin transcriptio

Collagenase specificity in chondrosarcoma metastasis

The treatment of some mesenchymal malignancies has made significant gains over the past few decades with the development of effective systemic therapies. In contrast, the treatment of chondrosarcoma has been limited to surgical resection, with the most significant prognostic indicators being surgical margins and histologic grade. We have reported that MMP-1/TIMP-1 gene expression serves to prognosticate for tumor recurrence in this group of patients. This led to the hypothesis that collagenase activity facilitates cell egression from the cartilaginous matrix. In the current study we examine the specificity of collagenase gene expression in archival human chondrosarcoma samples using semi-quantitative PCR. Messenger RNA was affinity extracted and subject to reverse transcription. The subsequent cDNA was amplified using novel primers and quantitated by densitometry. Ratios of gene expression were constructed and compared to disease-free survival. The data demonstrate that the significance of the MMP-1/TIMP-1 ratio as a predictor of recurrence is confirmed with a larger number of patients. Neutrophil collagenase or MMP-8 was observed in only 5 of 29 samples. Collagenase-3 or MMP-13 was observed in all samples but the level did not correlate with disease-free survival. Since the collagenases have similar activity for fibrillar collagens and cleave the peptide in the same location, post-transcriptional regulatory mechanisms may account for the observed specificity. The determination of the MMP-1/TIMP-1 gene expression ratio not only serves to identify those patients at risk for recurrence but may also serve as a novel therapeutic avenue as an adjunct to surgical resection