Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3)

Abstract

Tissue inhibitors of metalloproteinases regulate ECM degradation by matrix metalloproteinases (MMPs). We have developed a mouse line deficient for tissue inhibitor of metalloproteinases-3 (TIMP-3), the only TIMP known to reside within the ECM. Homozygous Timp-3-null animals develop spontaneous air space enlargement in the lung that is evident at 2 weeks after birth and progresses with age of the animal. As early as 13 months of age animals become moribund. Lung function, measured by carbon monoxide uptake, is impaired in aged null animals. Lungs from aged null animals have reduced abundance of collagen, enhanced degradation of collagen in the peribronchiolar space, and disorganization of collagen fibrils in the alveolar interstitium, but no increase in inflammatory cell infiltration or evidence of fibrosis in comparison with controls. Using in situ zymography, we show that lungs from aged null animals have heightened MMP activity over wild-type and heterozygotic animals. Finally, TIMP-3-null fibroblast cultures demonstrate enhanced destruction of ECM molecules in vitro. We propose that the deletion of TIMP-3 results in a shift of the TIMP/MMP balance in the lung to favor ECM degradation, culminating in incapacitating illness and a shorter life span.

Development of secondary palate requires strict regulation of ECM remodeling: sequential distribution of RECK, MMP-2, MMP-3, and MMP-9

“…Importantly, the knockout of TIMP genes has little effect on the phenotype of these animals (Caterina et al 2000;Leco et al 2001). However, Nuttall et al (2004) have assessed the transcript patterns of TIMPs and RECK in several organs of mouse embryo and suggest no difference between them; they have shown that RECK transcripts are present in a wide variety of mouse tissues, although RECK is expressed at most sites at a lower level than any of the four TIMPs.…”

Structural Determinants of the ADAM Inhibition by TIMP-3: Crystal Structure of the TACE-N-TIMP-3 Complex

“…Due to its involvement in many physiological processes and inflammatory diseases, regulation of the proteolytic activity of TACE is of utmost importance in the maintenance of the general well-being of the entire physiological system. 9,10 The four mammalian tissue inhibitors of matrix metalloproteinases (TIMP-1 to TIMP-4) were identified originally as powerful inhibitors of the matrix metalloproteinases (MMPs), blocking them non-covalently with 1:1 stoichiometry without much discrimination. However, later it was found that these TIMPs exhibit slightly different inhibition profiles, e.g.…”

Altered Bone Mechanics, Architecture and Composition in the Skeleton of TIMP-3-Deficient Mice

“…Bones from 8-week-old female mice genetically deficient in TIMP-3 (Timp-3 −/− , N = 9) and their wild-type (WT) C57BL6 (N = 6) littermates were analyzed [16]. Only fresh frozen mice were available at the beginning of this study.…”

“…How are these affecting the function of bone? In this study, we analyze the bones from the Timp-3 −/− mouse model [16], measure bone strength in compression and bending, and bone fracture toughness at the whole organ level. To explain changes in the mechanical properties of the Timp-3 −/− bone, we examine its morphology at the microscale length and determine the contribution of TIMP-3 to the bone mineral and collagen arrangement at the tissue level.…”