Nutrition and Somatomedin. VIM. The “Somatomedin Inhibitor” in Diabetic Rat Serum is a General Inhibitor of Growing Cartilage

Serum somatomedin activity appears to reflect the presence of both somatomedins and “somatomedin inhibitor,” a factor(s) that blunts cartilage stimulation by somatomedins. Although poor growth in uncontrolled diabetes is associated with an increase in inhibitor, suggesting a possible physiologic role, little is known of the interactions between this factor and somatomedins. We examined such interactions by measuring the effects of serum from normal rats (NRS, enriched in somatomedins) and serum from streptozo-tocin-diabetic rats (DRS, enriched in inhibitor) on costal cartilage from hypophysectomized rats. A 48-h exposure of cartilage to NRS resulted in an uptake of sulfate and uridine 125 ± 36% and 59 ± 14% (m ± SEM) above buffer levels, respectively, but addition of DRS to NRS produced sulfate and uridine uptake of 66 ± 3% and 95 ± 2% below buffer, respectively, indicating that chondroitin sulfate and RNA synthesis were both affected. Significant inhibition of uridine uptake (an early cartilage process) occurred as little as 4 h after exposure to DRS, while inhibition of sulfate uptake (a later process) was not found until 20 h. The decrease in isotope uptake following 24 h of exposure to DRS persisted over the next 24 h despite transfer of cartilage to fresh DRS-free medium and addition of NRS during the second 24-h period. When cartilage was incubated with a fixed concentration of DRS and increasing concentrations of NRS, Lineweaver-Burk analysis of both sulfate and uridine uptake indicated that NRS/DRS interactions were noncompetitive. These results indicate that the inhibitory factor in DRS affects different cartilage processes, produces profound, long-lasting decreases in cartilage activity, and has noncompetitive interactions with somatomedins in NRS. We conclude that somatomedin inhibitor in the serum of diabetic rats is a general inhibitor of growing cartilage that not only blocks stimulation by somatomedins, but also inhibits cartilage metabolism directly.