Generalized connective tissue disease in Crtap-/- mouse

Dustin Baldridge, Jennifer Lennington, Mary Ann Weis, Erica P. Homan, Ming Ming Jiang, Elda Munivez, Douglas R. Keene, William R. Hogue, Shawna Pyott, Peter H. Byers, Deborah Krakow, Daniel H. Cohn, David R. Eyre, Brendan Lee, Roy Morello

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Mutations in CRTAP (coding for cartilage-associated protein), LEPRE1 (coding for prolyl 3-hydroxylase 1 [P3H1]) or PPIB (coding for Cyclophilin B [CYPB]) cause recessive forms of osteogenesis imperfecta and loss or decrease of type I collagen prolyl 3-hydroxylation. A comprehensive analysis of the phenotype of the Crtap-/- mice revealed multiple abnormalities of connective tissue, including in the lungs, kidneys, and skin, consistent with systemic dysregulation of collagen homeostasis within the extracellular matrix. Both Crtap-/- lung and kidney glomeruli showed increased cellular proliferation. Histologically, the lungs showed increased alveolar spacing, while the kidneys showed evidence of segmental glomerulosclerosis, with abnormal collagen deposition. The Crtap-/- skin had decreased mechanical integrity. In ddition to the expected loss of proline 986 3-hydroxylation in α1(I) and α1(II) chains, there was also loss of 3Hyp at proline 986 in α2(V) chains. In contrast, at two of the known 3Hyp sites in α1(IV) chains from Crtap-/- kidneys there were normal levels of 3- hydroxylation. On a cellular level, loss of CRTAP in human OI fibroblasts led to a secondary loss of P3H1, and vice versa. These data suggest that both CRTAP and P3H1 are required to maintain a stable complex that 3-hydroxylates canonical proline sites within clade A (types I, II, and V) collagen chains. Loss of this activity leads to a multi-systemic connective tissue disease that affects bone, cartilage, lung, kidney, and skin.

Original languageEnglish
Article numbere10560
JournalPloS one
Volume5
Issue number5
DOIs
StatePublished - 2010

Fingerprint

Dive into the research topics of 'Generalized connective tissue disease in Crtap-/- mouse'. Together they form a unique fingerprint.

Cite this