SPONTANEOUS CALCIFICATION OF ARTERIES AND CARTILAGE IN MICE LACKING MATRIX GLA PROTEIN

Calcification of the extracellular matrix (ECM) can be physiological o r pathological. Physiological calcification occurs in bone when the so ft ECM is converted into a rigid material capable of sustaining mechan ical force; pathological calcification can occur in arteries(1) and ca rtilage(2) and other soft tissues. No molecular determinant regulating ECM calcification has yet been identified. A candidate molecule is ma trix GLA protein (Mgp), a mineral-binding ECM protein(3) synthesized b y vascular smooth-muscle cells and chondrocytes, two cell types that p roduce an uncalcified ECM, Mice that lack Mgp develop to term but die within two months as a result of arterial calcification which leads to blood-vessel rupture. Chondrocytes that elaborate a typical cartilage matrix can be seen in the affected arteries. Mgp-deficient mice addit ionally exhibit inappropriate calcification of various cartilages, inc luding the growth plate, which eventually leads to short stature, oste openia and fractures. These results indicate that ECM calcification mu st be actively inhibited in soft tissues. To our knowledge, Mgp is the first inhibitor of calcification of arteries and cartilage to be char acterized in vivo.