GENETIC DETERMINATION OF CARTILAGINOUS METAPLASIA IN MOUSE AORTA

Calcification frequently occurs in atherosclerotic plaques in humans, but the cellular and genetic factors contributing to this pathological trait are unknown. We previously reported that the arterial calcifica tion among inbred strains is genetically determined, and we now report that cartilaginous metaplasia, associated with the presence of arteri al chondrocytes that express type II collagen, may underlie this calci fication. Both uncalcified and calcified cartilaginous metaplasia were often colocalized with aortic atheromatous lesions and calcification, and clear genetic differences were observed in the occurrence of aort ic cartilaginous metaplasia among inbred strains. Analysis of a geneti c cross between strains C57BL/6J (exhibiting aortic cartilaginous meta plasia) and C3H/HeJ (no aortic cartilaginous metaplasia) revealed a re cessive inheritance pattern; thus, F-1 mice were entirely devoid of ca rtilaginous metaplasia, in common with the C3H/HeJ parental strain. An alyses of an F-2 cross and a set of recombinant inbred strains derived from parental strains C57BL/6J and C3H/HeJ were consistent with a maj or gene effect exhibiting incomplete penetrance. The occurrence of aor tic calcification was correlated with the occurrence of cartilaginous metaplasia in these genetic crosses, suggesting a link between the tra its. Finally, we observed widespread calcified cartilaginous metaplasi a within spontaneous atherosclerotic lesions in mice targeted for a nu ll mutation in the apoE gene, suggesting that cartilaginous metaplasia is a potential pathway for artery wall calcification associated with the atherosclerotic plaque.