Analysis of chondrodysplasias using transgenic mouse model.

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Type IX collagen is a hybrid extracellular matrix component, with the properties of both a proteoglycan and a collagen. It is found in hyaline cartilage, vitreous humor and embryonic cornea, where it is located along the surfaces of type II-containing collagen fibrils. To investigate the functional role of type IX collagen in cartilage, we have introduced an alphal(IX) gene construct expressing a truncated alphal(IX) chain into mice. The construct was designed with an in frame deletion in the central part of alphal(IX) cDNA and tissue specific expression in cartilages and eyes was obtained by using the type II collagen promoter-enhancer. In mouse tissues the transgene was expressed as shortened alphal(IX) chains that were disulfide-bonded with endogenous polypeptides to form collagenous molecules. Light and electron microscopic examination of the offspring of three different founders revealed pathological changes similar to osteoarthritis in the articular cartilage of knee joints. In addition, mice homozygous for the transgene developed mild chondrodysplasia ; i.e., mild dwarfism, anterior tonguing in the vertebral bodies, and ophthalmopathy. The relative ratio of transgene product to the endogenous alphal(IX) chain was approximately one in homozygotes and less than one in heterozygotes. Therefore, the phenotypic severity correlated well with the level of transgene expression. Given these findings, it is possible that mutations in type IX collagen genes may cause certain forms of chondrodysplasia and osteoarthritis in humans.