MMP28 in Idiopathic Pulmonary Fibrosis: Beyond the Extracellular Matrix

Among the host of molecular mediators that have been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) are a family of extracellular matrix-degrading enzymes jointly termed matrix metalloproteinases (MMPs). Their defining function--to degrade the extracellular matrix--suggests a protective, antifibrotic action in IPF. However, such an intuitive notion is difficult to reconcile with consistently observed elevated levels of various MMPs in the lung tissues of patients with IPF, and with elevated levels of circulating MMP7 accurately predicting IPF outcomes. Extensive evidence suggests that although some MMPs indeed prevent or limit fibrotic responses, many of them, paradoxically, have profibrotic activities. The mechanisms that control nuclear versus cytoplasmic versus extracellular localization of MMP28 still need to be deciphered. Moreover, the similar as well as distinct functional effects of differentially localized MMP28 (nuclear, cytoplasmic, or extracellular) require detailed characterization. Such information may form the basis for the development of innovative approaches to therapeutically modulate the levels and functional effects of MMP28 in IPF.