Abstract
BackgroundIndoxyl sulfate (IS), an organic anion uremic toxin, promotes the progression of renal dysfunction. Some studies have suggested that IS inhibits osteoclast differentiation and suppresses parathyroid hormone (PTH)-stimulated intracellular cAMP production, decreases PTH receptor expression, and induces oxidative stress in primary mouse calvaria osteoblast cell culture. However, the direct effects of IS on osteoblast apoptosis have not been fully evaluated. Hence, we investigated whether IS acts as a bone toxin by studying whether IS induces apoptosis and inhibits differentiation in the cultured osteoblast cell line MC3T3-E1.MethodsWe assessed the direct effect of IS on osteoblast differentiation and apoptosis in the MC3T3-E1 cell line. We examined caspase-3/7 activity, apoptosis-related proteins, free radical production, alkaline phosphatase activity, and mRNA expression of type 1 collagen and osteonectin. Furthermore, we investigated the uptake of IS via organic anion transport (OAT).ResultsWe found that IS increased caspase activity and induced apoptosis. Production of free radicals increased depending on the concentration of IS. Furthermore, IS inhibited the expression of mRNA type 1 collagen and osteonectin and alkaline phosphatase activity. The expression of OAT, which is known to mediate the cellular uptake of IS, was detected in in the MC3T3-E1 cell line. The inhibition of OAT improved cell viability and suppressed the production of reactive oxygen species. These results suggest that IS is transported in MC3T3-E1 cells via OAT, which causes oxidative stress to inhibit osteoblast differentiation.ConclusionsIS acts as a bone toxin by inhibiting osteoblast differentiation and inducing apoptosis.
Highlights
Indoxyl sulfate (IS), an organic anion uremic toxin, promotes the progression of renal dysfunction
Gene expression of organic anion transport (OAT) in the MC3T3-E1 cell line Because other studies have shown that IS is transported into osteoblasts and renal tubule cells via OAT, gene expression of OAT-1 and OAT-3 was investigated by real time PCR using RNA extracts
After confirming the expression of the OAT gene in the MC3T3-E1 cell line, we investigated whether blocking OAT could prevent IS toxicity
Summary
Indoxyl sulfate (IS), an organic anion uremic toxin, promotes the progression of renal dysfunction. Some studies have suggested that IS inhibits osteoclast differentiation and suppresses parathyroid hormone (PTH)-stimulated intracellular cAMP production, decreases PTH receptor expression, and induces oxidative stress in primary mouse calvaria osteoblast cell culture. The direct effects of IS on osteoblast apoptosis have not been fully evaluated. We investigated whether IS acts as a bone toxin by studying whether IS induces apoptosis and inhibits differentiation in the cultured osteoblast cell line MC3T3-E1. Dahl salt-sensitive hypertensive rats administered IS in combination with a high-salt diet have been found to show an increase in date, the direct effects of IS on osteoblast apoptosis have not been fully evaluated
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