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Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in tuberculosis pathogenesis and cavitation. In particular, MMP-7 is induced by hypoxia and highly expressed around pulmonary cavities of Mycobacterium tuberculosis–infected C3HeB/FeJ mice. In this study, we evaluated whether administration of cipemastat, an orally available potent inhibitor of MMP-7, could reduce pulmonary cavitation in M. tuberculosis–infected C3HeB/FeJ mice. We demonstrate that, compared with untreated controls, cipemastat treatment paradoxically increases the frequency of cavitation (32% vs 7%; P = .029), immunopathology, and mortality. Further studies are needed to understand the role of MMP inhibitors as adjunctive treatments for pulmonary tuberculosis.

Renal fibrosis is characterised by an excessive accumulation of extracellular matrix (ECM) proteins. Evidence suggests that this results from both increased ECM synthesis and a reduced degradation. Here, we determine changes in the matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) in relation to ECM production and the progression of renal fibrosis in subtotally nephrectomized (SNx) rats. Groups of 4–6 SNx or sham-operated male Wistar rats were sacrificed between days 7 and 120 following surgery. Total RNA was analysed by Northern blotting. Messenger RNA for collagens I (+710%), III (+674%), and IV (+358%) were significantly (p < 0.05) raised by day 7 and remained elevated over the 120 days. Significant (p < 0.05) increase in fibronectin, laminin and heparan sulfate proteoglycan mRNAs occurred latter at days 60 (+224%), 120 (+210%), and 120 (+256%), respectively. Increases (p < 0.05) in mRNA for MMP-1 (+360%) and MMP-2 (+239%) occurred from day 7 with MMP-1 reaching +881% by day 120. MMP-3 and -9 showed no change. Zymography on day 90 remnant kidneys showed mRNA changes were translated into active MMP-1 (+1,700%) and MMP-2 (+440%), p < 0.05. TIMP-1 mRNA was also raised (+548%, p < 0.05) by day 7 and remained elevated, while TIMP-2 mRNA levels only reached significance by day 120 (+165%). In contrast, TIMP-3 mRNA was decreased by day 30 (p > 0.05) and dropped to 27% of control by day 120. However, Western blot analysis of TIMPs 1 and 3 at day 90 showed a 5- and 4-fold increase respectively, while TIMP-2 levels were not significantly altered. Measurements of overall collagenase activities in remnant kidney homogenates were reduced. Using collagen I and IV substrates, proteolytic activity in remnant kidneys dropped to 40 and 27% of controls (p < 0.01), respectively. This data suggests that reduced MMP activity may contribute towards renal scarring, however this is not a result of reduced MMP transcription or activation, but likely to be due to the inhibition by TIMPs.

The development of the collagenase inhibitor, cipemastat (Ro 32-3555), required the synthesis of both carbon-14 labelled and deuteriated material for the measurement of the parent drug and drug-related material in biological fluids. In addition, labelled metabolites were needed for both in vitro metabolism and analytical studies. This paper describes the synthesis of labelled forms of cipemastat and its amide (Ro 32-4778) and glucuronide (Ro 32-6414) metabolites. Copyright © 2001 John Wiley & Sons, Ltd.

The osteoclast is a unique cell that cycles between bone resorption and migration. In this study, we used KB-R7785, an inhibitor of matrix metalloproteinases (MMPs), to investigate the role of MMPs in this cycle. Osteoclasts prepared from neonatal rabbits were processed to measure: (1) migration on hydroxyapatite (HA)-coated dishes, (2) the formation of an actin band, which is a large collection of podosomes, (3) the life span of podosomes, and (4) lacunar resorption on ivory slices. KB-R7785 significantly decreased the area of the tracks formed by osteoclasts on HA-coated dishes. The percentage of actin/podosome band formation, expressed as: (total length of the actin band/circumference of the osteoclast) × 100, was significantly increased after the addition of KB-R7785, which implies that podosome disassembly in osteoclasts was decreased by the inhibition of MMPs. Time-lapse cinemicrography demonstrated that the addition of KB-R7785 increased the life span of podosomes. Several indexes (number of resorption pits, total resorption area, and mean resorption area) of osteoclast resorption activity were significantly decreased by KB-R7785, while the average depth of resorption was increased. These results indicate that decreased podosome disassembly caused by an MMP inhibitor suppresses the migration of osteoclasts and, ultimately, inhibits osteoclastic bone resorption.

The clinical efficacy of anti-TNF-alpha therapies have highlighted the apparently central role that TNF-alpha plays in the pathology of rheumatoid arthritis, particularly the inflammatory component. Recent identification of a metalloproteinase from the metzincin superfamily responsible for the production of the soluble form of this cytokine, has generated a large amount of pharmaceutical interest and presents the prospect of a metalloproteinase inhibitor as an anti-inflammatory drug. However, the traditional focus of metzincin inhibitor research has been the identification of inhibitors of matrix metalloproteinases; enzymes associated with matrix destruction, a feature common to both rheumatoid arthritis and osteoarthritis. Inhibitors of this class of metalloproteinase are now in clinical evaluation in patients. This review summarises the current development status of metalloproteinase inhibitors in arthritic diseases and discusses some of the issues that have arisen during their progress to become clinical treatments for these diseases.