Pu. Rani et al., Restoration of normal bone development by human homologue of collagen typeII (COL2A1) gene in col2a1 null mice, DEV DYNAM, 214(1), 1999, pp. 26-33
Development of the vertebrate skeleton is a highly complex process in which
collagen type II plays a vital role in the formation of long bones via end
ochondral ossification. Collagen type II, which is encoded by a single COL2
A1/Col2a1 gene, is the most abundant structural protein in the cartilage ma
trix, where it undergoes complex interactions with several other proteins,
The sequence of mature collagen type II chains, each with about 1,100 amino
acids, is conserved between different mammalian species, There are 37 amin
o acid positions that are different between mouse and human collagen type I
I. Previously, we have demonstrated that transgenic mice, in which Col2a1 g
ene is knocked out, exhibit a lethal phenotype due to the absence of endoch
ondral bone formation. To investigate whether the biological role of collag
en type II is conserved between the species, human COL2A1 gene was expresse
d in Col2a1 null mice by crossing with transgenic mice in which human COL2A
1 gene was integrated. The collagen type II from human gene rescued the let
hal phenotype in null mice, indicating that the biological function of coll
agen type II is conserved between human and mouse. The animals exhibited no
rmal endochondral bone formation and a normal growth plate in tibio-tarsal
joint, Chondrocytes isolated from the cartilage of these mice secreted huma
n protein, suggesting that the animals incorporated heterologous protein to
form cartilage which is essentially "humanized." The animals reached puber
ty and produced normal progeny. A completely normal phenotype in newborns i
ndicates that human COL2A1 gene is expressed properly both temporally and s
patially. These animals may be useful to generate models to study the effec
t of COL2A1 mutations on skeletal development in humans by introducing muta
ted gene constructs either into embryos or by crossing with transgenic anim
als with COL2A1 mutations. Dev Dyn 1999;214:26-33. (C) 1999 Wiley-Liss, Inc
.