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 induced by ER stress. Creld2 is ubiquitously expressed in multiple tissues, suggesting diverse roles. It is involved in pathways related to cartilage/bone metabolism, energy expenditure, and angiogenesis, and is associated with ER-stress-related diseases such as chronic liver diseases, cardiovascular diseases, kidney diseases, and cancer [1].

Creld2-deficient mice have provided valuable insights. In the liver, Creld2-deficiency leads to a dysregulated unfolded protein response (UPR) and hepatic steatosis during ER stress, 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 skeletal system, 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 multiple tissues. The use of Creld2 knockout (KO) and conditional knockout (CKO) mouse models has revealed its significance in liver metabolism, ischemic heart repair, and skeletal development. These findings contribute to understanding the pathogenesis of related diseases, providing potential targets for disease treatment and prevention in areas such as liver diseases, cardiovascular diseases, and skeletal disorders.

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/