CRTAP, or cartilage-associated protein, is a crucial component of the collagen prolyl 3-hydroxylation complex, along with prolyl 3-hydroxylase 1 (P3H1) and peptidyl-prolyl cis-trans isomerase B (PPIB). This complex is essential for the post-translational processing of collagen, which is vital for its proper assembly and function. Collagen processing is related to many biological processes, especially those related to connective tissue development and structure [1,2,4].

In Crtap knockout zebrafish, the fish exhibit typical osteogenesis imperfecta (OI) phenotypes such as reduced size, body disproportion, and altered mineralization. Intracellularly, collagen type I is over-modified and partially retained, causing enlarged endoplasmic reticulum cisternae, and in the extracellular matrix, the abnormal collagen type I assembles into disorganized fibers. This supports the defective chaperone role of the 3-hydroxylation complex as the primary cause of the skeletal phenotype [3]. In Crtap-/- mouse models, mutant Achilles and patellar tendons are thinner and weaker with increased collagen cross-links and reduced collagen fibril size, along with dysregulation in matrix and tendon marker gene expression, and the mice show severe motor impairments and reduced grip strength, indicating tendon and motor phenotypes associated with recessive OI [5].

In conclusion, CRTAP is essential for collagen prolyl 3-hydroxylation and proper collagen processing. The study of Crtap knockout models in zebrafish and mice has significantly contributed to understanding its role in connective tissue-related diseases, particularly osteogenesis imperfecta, by revealing the impact of CRTAP deficiency on collagen structure, function, and related biological processes in vivo.

References:

1. Li, Wenguo, Peng, Junjiang, Yao, Deqiang, Zhao, Jie, Cao, Yu. 2024. The structural basis for the collagen processing by human P3H1/CRTAP/PPIB ternary complex. In Nature communications, 15, 7844. doi:10.1038/s41467-024-52321-6. https://pubmed.ncbi.nlm.nih.gov/39245686/

2. Marini, Joan C, Cabral, Wayne A, Barnes, Aileen M. 2009. Null mutations in LEPRE1 and CRTAP cause severe recessive osteogenesis imperfecta. In Cell and tissue research, 339, 59-70. doi:10.1007/s00441-009-0872-0. https://pubmed.ncbi.nlm.nih.gov/19862557/

3. Tonelli, F, Cotti, S, Leoni, L, Witten, P E, Forlino, A. 2020. Crtap and p3h1 knock out zebrafish support defective collagen chaperoning as the cause of their osteogenesis imperfecta phenotype. In Matrix biology : journal of the International Society for Matrix Biology, 90, 40-60. doi:10.1016/j.matbio.2020.03.004. https://pubmed.ncbi.nlm.nih.gov/32173581/

4. Morello, Roy, Bertin, Terry K, Chen, Yuqing, Boyce, Brendan F, Lee, Brendan. . CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. In Cell, 127, 291-304. doi:. https://pubmed.ncbi.nlm.nih.gov/17055431/

5. Grol, Matthew William, Haelterman, Nele A, Lim, Joohyun, Eyre, David R, Lee, Brendan H. 2021. Tendon and motor phenotypes in the Crtap-/- mouse model of recessive osteogenesis imperfecta. In eLife, 10, . doi:10.7554/eLife.63488. https://pubmed.ncbi.nlm.nih.gov/34036937/