Tissue Inhibitor of Metalloprotease 4 (TIMP-4) is a member of the Tissue Inhibitors of Metalloproteinases (TIMPs) family, which are natural inhibitors of matrix metalloproteinases (MMPs). MMPs are enzymes responsible for the degradation of the extracellular matrix (ECM), playing a crucial role in tissue remodeling and various physiological processes. TIMP-4, like other TIMPs, regulates the activity of MMPs, thereby influencing ECM composition and integrity .
Human TIMP-4 is a non-glycosylated polypeptide consisting of 195 amino acids. It shares a high degree of sequence homology with other TIMPs, particularly TIMP-2, with which it is 51% identical at the amino acid level . TIMP-4 is expressed in a variety of tissues, including the heart, kidney, pancreas, colon, testes, brain, and adipose tissue . This restricted expression pattern suggests that TIMP-4 has specific physiological roles in these tissues.
TIMP-4 is primarily known for its ability to inhibit MMPs, thereby regulating ECM remodeling. However, recent studies have shown that TIMP-4 also has MMP-independent functions. It can influence cell proliferation, apoptosis, and other cellular processes . For instance, TIMP-4 has been implicated in the regulation of smooth muscle cell (SMC) proliferation and lipid metabolism, which are critical factors in the development of atherosclerosis .
The dysregulation of TIMP-4 has been associated with various diseases, including cancer and cardiovascular diseases. Overproduction of MMPs, which TIMP-4 inhibits, is often linked to cancer progression and metastasis . In cardiovascular diseases, TIMP-4 plays a protective role by preventing the degradation of ECM components and maintaining vascular integrity . For example, the loss of TIMP-4 has been shown to promote atherosclerotic plaque deposition in the abdominal aorta, independent of plasma cholesterol levels .
Given its role in regulating MMP activity and its involvement in various diseases, TIMP-4 has potential therapeutic applications. By modulating TIMP-4 levels, it may be possible to develop treatments for conditions characterized by excessive ECM degradation, such as cancer and atherosclerosis . Further research is needed to fully understand the mechanisms by which TIMP-4 exerts its effects and to develop targeted therapies.