Indoxyl sulphate inhibits osteoclast differentiation and function

Abstract

Background. Patients with chronic kidney disease (CKD) develop various bone abnormalities characterized by impaired bone remodelling. Recent data suggest that accumulation of the uraemic toxin indoxyl sulphate (IS) may be one of the factors involved in bone abnormalities in CKD patients. Indeed, it was recently reported that IS induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells. However, it is not yet known whether IS also affects osteoclast cells.Methods.In the present study, we assessed the direct effect of IS at uraemic concentrations and in the presence (to reach the 3 mM concentration) or absence of added inorganic phosphate (Pi) on osteoclast (OCL) differentiation and bone-resorbing activity in two well-established cellular models of monocyte/macrophage (peripheral blood mononuclear cells and the RAW 264.7 cell line).Results.We found that IS inhibits both OCL differentiation and bone-resorbing activity in a dose-dependent manner and that these effects were enhanced in the presence of Pi at 3mM concentration. IS induced a gradual inhibition of JNK, Akt, p38, ERK1/2 phosphorylation and AP-1 DNA-binding activity. The effects of IS on OCL differentiation and AP-1 were prevented by probenecid, a competitive inhibitor of organic anion transporters, suggesting that IS's effects occur subsequently to its intake.Conclusion.Our findings strongly suggest that IS not only inhibits osteoblast function but also has an inhibitory effect on OCL function and thus could affect bone remodelling in CKD patients. © 2011 The Author.