Tissue inhibitor of matrix metalloproteinase-3 levels in the extracellular matrix of lung, kidney, and eye increase with age.

Tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) is an important regulator of matrix metalloproteinase activity in many types of disease, including atherosclerosis, neoplasia, and inflammatory conditions. Among TIMPs, TIMP-3 uniquely binds the extracellular matrix (ECM). We performed IHC staining on 17 tissue microarrays containing >1500 samples to determine the location of ECM TIMP-3 staining in a variety of predominantly vascular tissues. We found a unique pattern of TIMP-3 staining in the ECM of renal arterioles, small pulmonary vessels and parenchyma, and Bruch's membrane in the retina. There was no staining in larger caliber arteries including coronary and internal mammary arteries. TIMP-3 protein accumulation was found to be an age-dependent phenomenon, with staining appearing in all three tissues in early adulthood and becoming more robust among the elderly. These findings may help to explain the late onset of the TIMP-3-associated ocular diseases Sorsby fundus dystrophy and age-related macular degeneration and suggest a similar phenomenon could be at work in other age-related conditions.