CCN1, also known as CYR61 (cysteine-rich angiogenic inducer 61), belongs to the CCN family of matricellular proteins. It plays critical roles in regulating proliferation, differentiation, apoptosis, angiogenesis, and fibrosis. CCN1 is positively regulated by TGF-β and the hippo/YAP/TAZ mechanotransduction pathway [1,2]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions.

In KO/CKO mouse models, fibroblast-specific CCN1 deletion led to progressive skin thinning, reduced collagen-related enzyme expression, and resistance to bleomycin-induced skin fibrosis, suggesting CCN1 is essential for skin fibrosis [5]. In esophageal adenocarcinoma, CCN1 induced apoptosis by upregulating TRAIL and its death receptors, but TNF antagonized CCN1's apoptosis-inducing capability [3]. In autoimmune hepatitis, CCN1-deficient mice (CCN1 fl/fl Cre+) showed attenuated inflammation, and CCN1 promoted inflammation in vitro by inducing IL-6 production via the α6β1/PI3K/Akt/NF-κB pathway [4].

In conclusion, CCN1 is crucial in multiple biological processes, especially in fibrosis, apoptosis, and inflammation-related diseases. The use of KO/CKO mouse models has revealed its roles in skin fibrosis, esophageal adenocarcinoma, and autoimmune hepatitis, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Zhu, Yin, Almuntashiri, Sultan, Han, Yohan, Somanath, Payaningal R, Zhang, Duo. 2020. The Roles of CCN1/CYR61 in Pulmonary Diseases. In International journal of molecular sciences, 21, . doi:10.3390/ijms21217810. https://pubmed.ncbi.nlm.nih.gov/33105556/

2. Leask, Andrew. . Et tu, CCN1…. In Journal of cell communication and signaling, 14, 355-356. doi:10.1007/s12079-020-00573-4. https://pubmed.ncbi.nlm.nih.gov/32705539/

3. Dang, Tong, Chang, Zhiheng, Meng, Jing, Wang, Pei, Chai, Jianyuan. 2021. TNF antagonizes CCN1 in apoptosis in esophageal adenocarcinoma. In Cytokine, 149, 155728. doi:10.1016/j.cyto.2021.155728. https://pubmed.ncbi.nlm.nih.gov/34634651/

4. Jiang, Renquan, Tang, Jifeng, Zhang, Xuehao, Lin, Jinpiao, Ou, Qishui. 2022. CCN1 Promotes Inflammation by Inducing IL-6 Production via α6β1/PI3K/Akt/NF-κB Pathway in Autoimmune Hepatitis. In Frontiers in immunology, 13, 810671. doi:10.3389/fimmu.2022.810671. https://pubmed.ncbi.nlm.nih.gov/35547732/

5. Quesnel, Katherine, Shi-Wen, Xu, Hutchenreuther, James, Stratton, Richard J, Leask, Andrew. 2019. CCN1 expression by fibroblasts is required for bleomycin-induced skin fibrosis. In Matrix biology plus, 3, 100009. doi:10.1016/j.mbplus.2019.100009. https://pubmed.ncbi.nlm.nih.gov/33543008/