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Molybdate impairs glycosaminoglycan sulfation in rat cartilage
1Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Abstract:
The mechanism by which molybdate produces joint and bone deformities is not known. However, we recently reported that molybdate decreases the sulfation of acetaminophen in rat liver. Therefore, the purpose of the present study was to determine the effect of molybdate on the sulfation of glycosaminoglycans (GAGS) and whether manganese-induced joint and bone deformities might be due to this mechanism. Molybdate (15 mmol/kg, po) did not alter total GAG content in patella and articular cartilage of rats assayed 24 hr after administration. Nevertheless, [35S]sulfate uptake into both patella and articular cartilage was decreased dramatically (70 and 50%, respectively) by molybdate. Molybdate did not affect GAG chain elongation, as there was no effect of molybdate on [3H]glucosamine uptake into patella cartilage. These results indicate that molybdate impairs sulfation of GAGs. In an attempt to determine the mechanism of the molybdate-induced decrease in GAG sulfation, the effect of molybdate and sulfate on the incorporation of sulfate into GAGs was examined in vitro using monolayer chondrocyte cultures. Molybdate reduced the sulfation of GAGs in chondrocytes in vitro, but only at concentrations higher than the blood concentration of molybdate given in vivo that decreased GAG sulfation. Molybdate given in vivo decreases plasma sulfate to levels, which when used in vitro, decreases GAG sulfation. Therefore, molybdate treatment decreases sulfate availability and the sulfation of glycosaminoglycans.
Insights
Molybdate significantly impairs glycosaminoglycan sulfation in rats by reducing sulfate availability. This finding offers insight into potential mechanisms behind molybdate-induced joint and bone deformities.
Area of Science:
- Biochemistry
- Skeletal Biology
- Toxicology
Background:
- Molybdate is known to cause joint and bone deformities, but the underlying mechanism remains unclear.
- Previous research indicated molybdate interferes with acetaminophen sulfation in rat liver.
- Glycosaminoglycans (GAGs) are crucial components of cartilage and bone, and their sulfation is vital for skeletal integrity.
Purpose of the Study:
- To investigate the effect of molybdate on glycosaminoglycan (GAG) sulfation.
- To determine if molybdate-induced GAG sulfation impairment contributes to skeletal deformities.
- To elucidate the mechanism by which molybdate affects GAG sulfation.
Main Methods:
- Rats were administered molybdate orally, and GAG content and [35S]sulfate uptake in patella and articular cartilage were measured.
- GAG chain elongation was assessed by measuring [3H]glucosamine uptake.
- In vitro studies using chondrocyte cultures examined the direct effect of molybdate and sulfate concentrations on GAG sulfation.
Main Results:
- Molybdate administration did not alter total GAG content but significantly decreased [35S]sulfate uptake in rat patella and articular cartilage.
- Molybdate did not affect GAG chain elongation, indicating the impairment is specific to sulfation.
- In vitro, molybdate reduced GAG sulfation in chondrocytes, but only at concentrations higher than those observed in vivo; however, in vivo molybdate treatment lowered plasma sulfate levels, which in turn reduced GAG sulfation in vitro.
Conclusions:
- Molybdate impairs the sulfation of glycosaminoglycans (GAGs) in vivo.
- The mechanism involves a decrease in sulfate availability, leading to reduced GAG sulfation.
- This impaired GAG sulfation may be a contributing factor to the joint and bone deformities observed with molybdate exposure.