Timp3, short for Tissue Inhibitor of Metalloproteinase 3, is unique among the four TIMPs due to its extracellular matrix-binding property. It broadly inhibits matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAM with thrombospondin motifs (ADAMTSs). Besides its metalloproteinase-inhibitory role, it can interact with extracellular proteins, having multifarious functions. Its mRNA has a long 3' untranslated region targeted by numerous microRNAs. Timp3 is involved in various biological processes and is of great importance in many diseases [7].

Loss of Timp3 exacerbates thoracic and abdominal aortic aneurysm in mice, increasing proteinase activity, smooth muscle cell phenotypic switching, and inflammation [1]. In a mouse model of laser-induced retinal damage, increased Timp3 levels were associated with Müller glia gliosis, enhancing retinal repair through the canonical Wnt/β-catenin pathway [2]. Mice deficient in Timp3 have elevated TNF levels and severe liver inflammation, highlighting its role in regulating this inflammatory cytokine [3]. In cervical cancer, downregulation of Timp3 promotes the malignant phenotype, tumorigenesis, and metastasis of cells via the PI3K/AKT pathway [4]. In thyroid carcinoma, TIMP3-high expression is associated with down-modulation of inflammation-related gene sets and reduced protumoral hematopoietic cells fraction [5]. In mechanical loading-induced chondrocyte degeneration, Timp3/TGF-β1 axis plays a vital role [6].

In conclusion, Timp3 is crucial in multiple biological processes and diseases. Gene knockout mouse models have revealed its roles in vascular diseases like aortic aneurysm, retinal diseases such as gliosis, inflammation regulation, and cancer progression. Understanding Timp3's functions through these models provides insights into disease mechanisms and potential therapeutic strategies for related diseases.