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1.  Immunolocalisation studies on six matrix metalloproteinases and their inhibitors, TIMP-1 and TIMP-2, in synovia from patients with osteo- and rheumatoid arthritis. 
OBJECTIVE--To assess the likely importance of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the arthritic process. METHODS--Synovial samples from seven joints with rheumatoid arthritis and three osteoarthritic joints were analysed by indirect immunofluorescence microscopy. Using specific human antisera, we documented the frequencies and distributions of collagenase, stromelysins 1 and 2, matrilysin, gelatinases A and B, TIMP-1, and TIMP-2. RESULTS--Stromelysin 1 was found in all synovia, bound to extracellular matrix, within cells, or both, indicating stromelysin synthesis. Matrilysin was present in only one active inflammatory synovium, and focal synthesis of collagenase and gelatinase A was seen in four synovia. Stromelysin 2 and TIMP-2 were not observed, but TIMP-1 synthesis was seen in five synovia, and in two active synovia the distribution of TIMP-1 positive cells was more widespread than that of MMPs. CONCLUSIONS--The presence of stromelysin 1 in all synovia clearly implicates this enzyme in joint damage. Collagenase, gelatinase A and matrilysin may also have a role in rheumatoid arthritis, but are not significant in osteoarthritis. However, marked regional variations were found in the synthesis of these MMPs, indicating not only that these diseases are episodic but that control of enzyme synthesis is focal. Only TIMP-1 may be considered an inhibitory factor.
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PMCID: PMC1005508  PMID: 7880117
2.  Tissue inhibitor of metalloproteinases and collagenase inhibitory activity in lung secretions from patients with chronic obstructive bronchitis: effect of corticosteroid treatment. 
Thorax  1986;41(10):740-745.
Tissue inhibitor of metalloproteinases (TIMP) and collagenase inhibitory activity were measured in the sputum from nine subjects with chronic bronchitis before and five days after treatment with corticosteroid (oral prednisolone, 40 mg daily). The mean sputum TIMP concentrations for eight of the nine subjects increased from 3.1 (SD 0.87) micrograms/ml to 5.8 (1.9) micrograms/ml (2p less than 0.005). Similarly, the mean collagenase inhibitory activity in the sputum of eight of the nine subjects increased from 1.53 (1.1) U/ml to 2.69 (0.92) U/ml (2p less than 0.05). The TIMP concentrations in sputum exceeded the collagenase inhibitory activity, suggesting that a proportion of the TIMP was inactive. TIMP inactivity was not due to prior complexing with enzyme since the molecular weight of sputum TIMP (27,500) was similar to that described for the purified protein (28,000-28,500). Preliminary studies showed the presence of TIMP in bronchoalveolar lavage samples (range of six specimens 0.45 ng/ml-2.1 micrograms/ml, median 53 ng/ml). Collagenase inhibitory activity was detected in only two of these six lavage samples, suggesting that the TIMP was totally inactive in the other four samples. The significance of the metalloproteinase-inhibitor balance in the pathogenesis of chronic lung disease requires further study.
PMCID: PMC460466  PMID: 3787506
3.  Bacterial antigens induce collagenase and prostaglandin E2 synthesis in human gingival fibroblasts through a primary effect on circulating mononuclear cells. 
Infection and Immunity  1987;55(9):2148-2154.
Our previous work suggests that one mechanism through which connective tissue breakdown might occur in periodontal diseases is the production of metalloproteinases, including collagenase, by gingival fibroblasts. In this study we investigated whether highly purified preparations of lipopolysaccharide (LPS) and lipoteichoic acid (LTA) from a number of putative periodontal pathogens could induce monolayer cultures of human gingival fibroblasts to synthesize collagenase and prostaglandin E2. Using both biochemical assays and immunocytochemical techniques, we found that cells synthesized only very small amounts of collagenase in direct response to LPS or LTA (0.1 to 20.0 micrograms/ml). At the highest dose of both antigens, prostaglandin E2 production was increased. We then studied whether LPS and LTA could signal collagenase production by interacting primarily with a different cell type. Our results show that LPS and LTA were each able to stimulate cultures of human blood mononuclear cells (greater than 95% monocytes) to release collagenase-inducing cytokines. By indirect immunocytochemistry, we found that a large proportion of human gingival fibroblasts was activated to produce collagenase by supernatants from LPS- and LTA-stimulated mononuclear cells, whereas gingival fibroblasts cultured with supernatants from unstimulated mononuclear cells were not. Furthermore, in a population of activated fibroblasts we demonstrated, using a double-labeling technique, that some cells made collagenase and the specific tissue inhibitor of metalloproteinases (TIMP) simultaneously. As yet, the collagenase-inducing signals remain poorly characterized but the interleukins-1 and tumor necrosis factors seem likely candidates.
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PMCID: PMC260671  PMID: 3040590

Results 1-3 (3)