TIMP3, the Tissue Inhibitor of Metalloproteinase 3, is unique among the four TIMPs due to its extracellular matrix-binding property. It inhibits a broad range of substrates including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAM with thrombospondin motifs (ADAMTSs). TIMP3 also interacts with extracellular proteins, and its mRNA has a long 3' untranslated region targeted by numerous microRNAs. It plays a role in various biological processes and is involved in multiple diseases [4].

Loss of TIMP3 exacerbates thoracic and abdominal aortic aneurysm severity in male and female mice, with increased proteinase activity, smooth muscle cell phenotypic switching, and inflammation. Different patterns of remodeling are seen in the two types of aneurysms. TIMP3 knockdown also compromises the permeability of the human aortic endothelial cell monolayer [2]. In the context of diabetic nephropathy, loss of TIMP3 is a hallmark in human and mouse models, suggesting its pivotal role in this renal disease. Restoration of high TIMP3 activity in the kidney may be a potential therapeutic strategy [1]. In Müller glia, TIMP3 overexpression induces gliosis for retinal repair, and it is mediated by the canonical Wnt/β-catenin pathway [3].

In conclusion, TIMP3 is crucial in maintaining normal physiological functions in various tissues. Studies using gene knockout mouse models have revealed its significant roles in diseases such as aortic aneurysms, diabetic nephropathy, and retinal diseases. These findings provide insights into the mechanisms of these diseases and potential therapeutic targets related to TIMP3.

References:

1. Casagrande, Viviana, Federici, Massimo, Menghini, Rossella. 2021. TIMP3 involvement and potentiality in the diagnosis, prognosis and treatment of diabetic nephropathy. In Acta diabetologica, 58, 1587-1594. doi:10.1007/s00592-021-01766-y. https://pubmed.ncbi.nlm.nih.gov/34181080/

2. Hu, Mei, Meganathan, Ilamaran, Zhu, Jiechun, MacArthur, Rodrick, Kassiri, Zamaneh. 2023. Loss of TIMP3, but not TIMP4, exacerbates thoracic and abdominal aortic aneurysm. In Journal of molecular and cellular cardiology, 184, 61-74. doi:10.1016/j.yjmcc.2023.10.001. https://pubmed.ncbi.nlm.nih.gov/37844423/

3. Hung, Jia-Horung, Tsai, Ping-Hsing, Aala, Wilson Jr F, Hsu, Sheng-Min, Wu, Li-Wha. 2024. TIMP3/Wnt axis regulates gliosis of Müller glia. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 167087. doi:10.1016/j.bbadis.2024.167087. https://pubmed.ncbi.nlm.nih.gov/38369214/

4. Fan, Dong, Kassiri, Zamaneh. 2020. Biology of Tissue Inhibitor of Metalloproteinase 3 (TIMP3), and Its Therapeutic Implications in Cardiovascular Pathology. In Frontiers in physiology, 11, 661. doi:10.3389/fphys.2020.00661. https://pubmed.ncbi.nlm.nih.gov/32612540/