A. Hiltunen et al., RETARDED CHONDROGENESIS IN TRANSGENIC MICE WITH A TYPE-II COLLAGEN DEFECT RESULTS IN FRACTURE-HEALING ABNORMALITIES, Developmental dynamics, 200(4), 1994, pp. 340-349
We have examined the biological and biomechanical consequences of defe
ctive type II collagen production for fracture repair employing a gene
tically engineered mouse line Del1 which was generated by microinjecti
on of a 39-kb mouse pro alpha 1(II) collagen gene construct containing
a deletion of exon 7 and intron 7 (Metsaranta et al. [1992] J. Cell B
iol, 118:203-212). Standardized tibial fractures were produced in tran
sgenic Del1 mice and their nontransgenic littermates were used as cont
rols, The fracture callus tissues were analyzed at days 7, 9, 14, 28,
and 42 using radiography, histomorphometry, biomechanical testing, and
Northern analysis of mRNAs for several tissue-specific matrix compone
nts. Deficient production of cartilage in Del1 mice resulted in reduce
d radiographic callus size, smaller cross-sectional area, and impaired
biomechanical properties when compared with fractures of nontransgeni
c control mice. The differences were most evident in 14-day fracture c
alluses. Consequently mRNAs for cartilage-specific type IX and X colla
gens and aggrecan were also reduced in Del1 calluses. Levels of type I
I collagen mRNAs were unaffected since the mutated transgene produced
additional type II collagen mRNA molecules. Further abnormalities in t
he fracture repair process of Del1 mice were observed in callus remode
ling. In the control animals a typical feature of external callus remo
deling was reduction of callus size during endochondral ossification b
etween days 14 and 28. Such reduction was not observed in the transgen
ic mice. Histological examination of fracture calluses suggested also
a reduction in trabecular surface area, which was found to be even mor
e pronounced in metaphyseal bone of Del1 mice. Despite these differenc
es the biomechanical properties of the calluses in the two groups beca
me similar by day 28 of fracture healing. The results thus suggest tha
t reduced chondrogenesis due to the presence of mutated transgenes in
Del1 mice not only causes a temporary impairment in biomechanical prop
erties of healing fractures but also affects later stages of callus re
modeling. (C) 1994 Wiley-Liss, Inc.