Matrix metalloproteinases (MMPs) are implicated in multiple sclerosis where one of their roles may be to facilitate the transmigration of circulating leukocytes into the CNS. Studies have focused on only a few MMPs, and much remains unknown of which of the 23 MMP family members is/are critical to the multiple sclerosis disease process. Using quantitative real time polymerase chain reactions, we have systematically analysed the expression of all 23 MMP members in subsets of leukocytes isolated from the blood of normal individuals. We found a distinctive pattern of MMP expression in different cellular populations: MMP-11, MMP-26 and MMP-27 were enriched in B cells, while MMP-15, MMP-16, MMP-24 and MMP-28 were prominent in T lymphocytes. Of interest is the enrichment of a majority of MMP members in monocytes: MMP-1, MMP-3, MMP-9, MMP-10, MMP-14, MMP-19 and MMP-25. MMP-2 and MMP-17 were also significantly represented in monocytes, although B cells had significant amounts of these MMPs. In correspondence with their strong expression of many MMP members, monocytes migrated more rapidly across a model of the blood-brain barrier in culture than T or B lymphocytes. Finally, we found higher levels of two of the monocyte-expressed MMPs in multiple sclerosis patients compared with normal individuals: MMP-2 and MMP-14. Tissue inhibitor of metalloproteinases (TIMP)-2 was also elevated in monocytes from multiple sclerosis patients, providing a mechanism for the reported activation of MMP-2 by MMP-14 and TIMP-2. These results emphasize that monocytes are prominent contributors of the neuroinflammation in multiple sclerosis through a mechanism that involves their high MMP expression and that they identify specific MMP members as targets for novel therapeutics in the disease.

IntroductionMycobacterium tuberculosis infects one-third of the world's population (1) and is transmitted by the aerosol route. Although the mechanisms whereby M. tuberculosis evades the host immune response are increasingly well understood (2), those by which M. tuberculosis engages the immune response to drive tissue destruction and hence transmission are relatively poorly characterized (3). The events underlying this immunopathology are not well defined, in part because the mouse, one of the most useful models in which to study M. tuberculosis immunology, does not develop lung pathology similar to that of humans (4, 5). In humans, M. tuberculosis subverts the host immune response to drive proteolytic destruction of the extracellular matrix scaffold. The current paradigm of tuberculosis (TB) pathology proposes that caseation leads directly to cavitation (2, 4, 6). However, this model overlooks that fact that destruction of lung extracellular matrix must be driven by proteases. Fibrillar collagens provide the lung's tensile strength and are highly resistant to enzymatic degradation (7,8). Only collagenolytic MMPs can cleave these helical collagens at neutral pH (9).MMPs are a family of zinc-dependent proteases that can collectively degrade all components of the extracellular matrix (8). MMP activity is tightly regulated at the level of transcription and activation by proteolytic cleavage. MMPs are specifically inhibited by tissue inhibitor of metalloproteinases (TIMPs) (9). Excessive MMP activity is implicated in diverse pulmonary pathologies characterized by extracellular matrix destruction (8). However, despite the potentially key role of MMPs in lung matrix destruction in human TB, the central mechanisms resulting in tissue damage have not been defined.

Abstract-Cytokine and extracellular matrix (ECM) homeostasis are distinct systems that are each dysregulated in heart failure. Here we show that tissue inhibitor of metalloproteinase (TIMP)-3 is a critical regulator of both systems in a mouse model of left ventricular (LV) dilation and dysfunction. Timp-3 Ϫ/Ϫ mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB). Timp-3 deficiency resulted in increased TNF␣ converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-␣ (TNF␣) processing. In addition, TNF␣ production increased in timp-3 Ϫ/Ϫ -AB myocardium. A significant elevation in gelatinase and collagenase activities was observed 1 week after AB, with localized ECM degradation in timp-3 Ϫ/Ϫ -AB myocardium. Timp-3 Ϫ/Ϫ / tnf␣ Ϫ/Ϫ mice were generated and subjected to AB for comparative analyses with timp-3 Ϫ/Ϫ -AB mice. This revealed the critical role of TNF␣ in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNF␣, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNF␣, or limiting MMP activity with a synthetic MMP inhibitor (PD166793), each partially attenuated LV dilation and cardiac dysfunction in timp-3 Ϫ/Ϫ -AB mice. Notably, combining TNF␣ ablation with MMP inhibition completely rescued heart disease in timp-3 Ϫ/Ϫ -AB mice. This study provides a basis for anti-TNF␣ and MMP inhibitor combination therapy in heart disease. Ⅲ matrix metalloproteinase Ⅲ tumor necrosis factor-␣ C ardiovascular disease is the major cause of death in the Western world and is predicted to be the leading cause of mortality worldwide by 2020. 1 A close relationship between the severity of cardiac dysfunction, development of heart failure, and cardiac expression of tumor necrosis factor-␣ (TNF␣) has been demonstrated. 2,3 TNF␣ is a pleiotropic cytokine and is found elevated in patients with dilated cardiomyopathy (DCM), 4,5 ischemic heart disease, and congestive heart failure (CHF). 3 Based on the potential importance of TNF␣ in heart disease, anti-TNF␣ therapy has been attempted in patients with heart failure although significant benefits of this therapy remain to be demonstrated. 6,7 This suggests that other factors play key roles in the progression of heart failure. Maladaptive extracellular matrix (ECM) remodeling is a common feature of ventricular remodeling in patients with DCM and CHF. 8 Matrix metalloproteinases (MMPs) are the primary ECM remodeling enzymes, 9 and a disintegrin and metalloproteinase, ADAM-17/TACE (TNF␣ converting enzyme) converts membrane bound TNF␣ to its soluble form. 10,11 Furthermore, TNF␣ signaling is known to induce the transcription of metalloproteinases, 9,12 evoking a potentially important but overlooked interaction between TNF␣ signaling and ECM remodeling. Whether a direct relatio...