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Indoxyl sulphate inhibits osteoclast differentiation and function

Anaïs Mozar1, Loïc Louvet, Corinne Godin

  • 1INSERM ERI-12, EA4292, Amiens, France.

Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association
|December 6, 2011
PubMed
Abstract

Insights

Indoxyl sulphate (IS), a toxin accumulating in chronic kidney disease (CKD), inhibits osteoclast differentiation and bone resorption. This finding suggests IS contributes to impaired bone remodelling in CKD patients.

Area of Science:

  • Nephrology
  • Endocrinology
  • Bone Biology

Background:

  • Chronic kidney disease (CKD) is associated with impaired bone remodelling.
  • Uremic toxins, such as indoxyl sulphate (IS), are implicated in CKD-related bone abnormalities.
  • Previous studies showed IS induces skeletal resistance to parathyroid hormone in osteoblasts, but its effect on osteoclasts was unknown.

Purpose of the Study:

  • To investigate the direct effect of indoxyl sulphate (IS) on osteoclast (OCL) differentiation and bone-resorbing activity.
  • To assess the influence of inorganic phosphate (Pi) on IS-induced effects on osteoclasts.

Main Methods:

  • Assessed IS effects on OCL differentiation and bone-resorbing activity using monocyte/macrophage models (PBMCs and RAW 264.7 cells).
  • Evaluated IS impact in the presence and absence of 3mM inorganic phosphate (Pi).
  • Analyzed IS-mediated changes in signaling pathways (JNK, Akt, p38, ERK1/2) and AP-1 DNA-binding activity.

Main Results:

  • Indoxyl sulphate (IS) inhibited osteoclast (OCL) differentiation and bone-resorbing activity in a dose-dependent manner.
  • These inhibitory effects were enhanced by the presence of 3mM inorganic phosphate (Pi).
  • IS reduced phosphorylation of key signaling molecules and inhibited AP-1 DNA-binding activity; effects were mediated by IS uptake via organic anion transporters.

Conclusions:

  • Indoxyl sulphate (IS) directly inhibits osteoclast (OCL) function, including differentiation and bone resorption.
  • IS's inhibitory effects on osteoclasts, alongside its known impact on osteoblasts, contribute to impaired bone remodelling in CKD.
  • These findings highlight IS as a significant factor in the bone abnormalities observed in CKD patients.

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