The effects of ethylene-1-hydroxy-1, 1-diphosphonate on cellular transformation and organic matrix of the epiphyseal growth plate of the rat--a light microscopic and ultrastructural study.

Abstract

Ethylene-1-hydroxy-1, 1-diphosphonate (EHDP) was administered intraperitoneally to one-day-old rats. In the first experiment, each animal was given 4 injections of EHDP distributed over two consecutive days and corresponding to a total amount of EHDP of 100 mg/kg bwt/day. The animals were sacrificed 12 hours after the last injection. In the second experiment, each animal was given 3 injections, each containing 50 mg of EHDP/kg bwt, with an interval of 6 hours and were thereafter left to survive for 4 days. Animals in the first experiment showed in comparison to normal controls an increased width of the hypertrophic zone; lack of calcified septa within the zone of provisional calcification; persistent atypical chondrocytes in the calcification zone and a large number of matrix vesicles lacking in crystals. The ground substance showed an accumulation of fine precipitates apparently representing undegraded aggregates of proteoglycan macromolecules. Animals in the second experiment formed a new apparently normal epiphyseal growth plate, while the "old" epiphyseal cartilage formed under the influence of EHDP remained largely unresorbed within the metaphysis. Besides the previously described inhibitory effects of diphosphonates on the crystallization of matrix vesicles and the growth of hydroxyapatite crystals, EHDP, at the doses used, was found to have a profound inhibitory effect on the differentiation and migration of the epiphyseal chondrocytes as well as on the degradation of proteoglycan macromolecules. The observed inhibition of vascular invasion appears to be related to inhibition of enzyme degradation of the ground substance, as evidenced by the observation of extracellular lysosomelike bodies in the erosion zone.