Creld2, a member of the cysteine-rich epidermal growth factor-like domain (CRELD) protein family, is both an endoplasmic reticulum (ER)-resident protein and a secretory factor. Its expression and secretion are highly induced by ER stress. It is ubiquitously expressed in multiple tissues, suggesting diverse roles. It may be involved in pathways related to ER stress response, and its study using genetic models can help understand its functions [1].

Creld2-deficient mice have provided significant insights. In the liver, Creld2-deficiency leads to a dysregulated unfolded protein response (UPR) and causes hepatic steatosis during ER stress conditions, revealing its role in liver metabolism homeostasis [2]. In the heart, Creld2-deficient mice show impaired de novo microvessel formation in the infarct border zone and develop severe post-infarction heart failure, indicating its importance in ischemic heart repair as an angiogenic growth factor [3]. In the skeleton, cartilage-specific deletion of Creld2 results in disrupted endochondral ossification and short-limbed dwarfism, while deletion in bone causes osteopenia, demonstrating its role in skeletal development [4].

In conclusion, Creld2 plays essential biological functions in liver metabolism, ischemic heart repair, and skeletal development as revealed through gene-knockout mouse models. These models have contributed to understanding its role in diseases such as fatty liver disease, post-infarction heart failure, and skeletal dysplasias.

References:

1. Tang, Qin, Liu, Qinhui, Li, Yanping, Mo, Li, He, Jinhan. 2023. CRELD2, endoplasmic reticulum stress, and human diseases. In Frontiers in endocrinology, 14, 1117414. doi:10.3389/fendo.2023.1117414. https://pubmed.ncbi.nlm.nih.gov/36936176/

2. Kern, Paul, Balzer, Nora R, Blank, Nelli, Bauer, Reinhard, Mass, Elvira. . Creld2 function during unfolded protein response is essential for liver metabolism homeostasis. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 35, e21939. doi:10.1096/fj.202002713RR. https://pubmed.ncbi.nlm.nih.gov/34549824/

3. Wu, Xuekun, Zheng, Linqun, Reboll, Marc R, Polten, Felix, Wollert, Kai C. 2024. Cysteine-rich with EGF-like domains 2 (CRELD2) is an endoplasmic reticulum stress-inducible angiogenic growth factor promoting ischemic heart repair. In Nature cardiovascular research, 3, 186-202. doi:10.1038/s44161-023-00411-x. https://pubmed.ncbi.nlm.nih.gov/39196188/

4. Dennis, Ella P, Edwards, Sarah M, Jackson, Robert M, Piróg, Katarzyna A, Briggs, Michael D. 2020. CRELD2 Is a Novel LRP1 Chaperone That Regulates Noncanonical WNT Signaling in Skeletal Development. In Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 35, 1452-1469. doi:10.1002/jbmr.4010. https://pubmed.ncbi.nlm.nih.gov/32181934/