Endochondral bone formation in toothless (osteopetrotic) rats: failures ofchondrocyte patterning and type X collagen expression

The pacemaker of endochondral bone growth is cell division and hypertrophy of chondrocytes. The developmental stages of chondrocytes, characterized by the expression of collagen types II and X, are arranged in arrays across t he growth zone. Mutations in collagen II and X genes as well as the absence of their gene products lead to different, altered patterns of chondrocyte stages which remain aligned across the growth plate (GP). Here we analyze G P of rats bearing the mutation toothless (tl) which, apart from bone defect s, develop a progressive, severe chondrodystrophy during postnatal weeks 3 to 6. Mutant GP exhibited disorganized, non-aligned chondrocytes and minera lized metaphyseal bone but without cartilage mineralization or cartilaginou s extensions into the metaphysis. Expression of mRNA coding for collagen ty pes II (Col II) and X (Col X) was examined in the tibial GP by in situ hybr idization. Mutant rats at 2 weeks exhibited Col II RNA expression and some hypertrophied chondrocytes (HC) but no Col X RNA was detected. By 3rd week, HC had largely disappeared from the central part of the mutant GP and Col II RNA expression was present but weak and in 2 separate bands. Peripherall y the GP contained HC but without Col X RNA expression. This abnormal patte rn was exacerbated by the fourth week. Bone mineralized but cartilage in th e GP did not. These data suggest that the t/mutation involves a regulatory function for chondrocyte maturation, including Col X RNA synthesis and mine ralization, and that the GP abnormalities are related to the Col X deficien cy. The differences in patterning in the tl rat GP compared to direct Col X mutations may be explained by compensatory effects.