Ccn4, also known as WNT1-Inducible Signaling Pathway Protein 1 (WISP1), is a highly conserved, secreted cysteine-rich matricellular protein. It has diverse functions in cell proliferation, migration, invasion, angiogenesis, wound healing, repair, and apoptosis. Ccn4 is involved in multiple pathways related to metabolism such as those of protein kinase B (Akt), mechanistic target of rapamycin (mTOR), and is of great biological importance in the development and progression of numerous diseases including cancer, fibrosis, metabolic and inflammatory disorders [1,2].

In an ApoE mouse model, Ccn4 deficiency led to increased apoptosis and occlusion of the brachiocephalic artery as well as increased plaque in the aortic root, while overexpression reduced occlusion, apoptosis, macrophage number, and lipid core size, indicating its role in atherosclerotic plaque progression [3]. In a mouse aneurysm model using apolipoprotein-E knockout (ApoE-/-) mice, deletion of Ccn4 significantly reduced aneurysm severity, aortic area, and aneurysm grade score, likely due to reduced macrophage infiltration and cell apoptosis [4].

In conclusion, Ccn4 plays essential roles in multiple biological processes and is involved in diseases like atherosclerosis and aneurysm. Gene knockout mouse models have been crucial in revealing these functions, highlighting Ccn4 as a potential therapeutic target for such diseases.

References:

1. Singh, Kirti, Oladipupo, Sunday S. 2024. An overview of CCN4 (WISP1) role in human diseases. In Journal of translational medicine, 22, 601. doi:10.1186/s12967-024-05364-8. https://pubmed.ncbi.nlm.nih.gov/38937782/

2. Maiese, Kenneth. . Prospects and Perspectives for WISP1 (CCN4) in Diabetes Mellitus. In Current neurovascular research, 17, 327-331. doi:10.2174/1567202617666200327125257. https://pubmed.ncbi.nlm.nih.gov/32216738/

3. Williams, Helen, Simmonds, Steven, Bond, Andrew, Johnson, Jason, George, Sarah. 2024. CCN4 (WISP-1) reduces apoptosis and atherosclerotic plaque burden in an ApoE mouse model. In Atherosclerosis, 397, 118570. doi:10.1016/j.atherosclerosis.2024.118570. https://pubmed.ncbi.nlm.nih.gov/39276419/

4. Williams, Helen, Wadey, Kerry S, Frankow, Aleksandra, Johnson, Jason L, George, Sarah J. 2021. Aneurysm severity is suppressed by deletion of CCN4. In Journal of cell communication and signaling, 15, 421-432. doi:10.1007/s12079-021-00623-5. https://pubmed.ncbi.nlm.nih.gov/34080128/