P-Cresyl Sulfate Induces Osteoblast Dysfunction Through Activating JNK and P38 MAPK Pathways

Recent data suggest that several uremic toxins may contribute to the development of bone abnormalities in chronic kidney disease. p-Cresyl sulfate (PCS), the sulfate conjugate of p-cresol, is a protein-bound uremic toxin associated with the progression of chronic kidney disease, cardiovascular risk, and mortality. However, the effects of PCS on bone metabolism remain unclear. In the present study, we evaluated the toxic effects of PCS on primary mouse osteoblasts, compared with an extensively studied uremic toxin indoxyl sulfate (IS). Pre-treatment of osteoblasts with PCS at 0.125 mM and above significantly decreased parathyroid hormone (PTH)-induced cAMP production in a dose-dependent manner. PCS also induced a significant increase in intracellular production of reactive oxygen species (ROS) at 0.25 mM and above, but not at lower concentrations. PCS at 0.125 mM (a concentration that did not induce significant ROS increase) decreased cell viability by augmenting DNA fragmentation and reducing cell proliferation. Inhibition of JNK and p38 mitogen-activated protein kinase (MAPK) abolished the PCS-induced increase in DNA fragmentation and decrease in cAMP production in osteoblastic cells. Compared with PCS, IS induced ROS production at 0.05 mM but did not reduce cAMP production from 0.05 to 0.5 mM. IS induced decrease in cell viability and increase in DNA fragmentation at 0.5mM only. These results suggest that PCS damages osteoblastic cells through not only increasing ROS production but also activating JNK/p38 MAPKs, which is different from the mechanism of injury by IS. These damages of osteoblasts induced by PCS may play a critical role in impairing bone metabolism in patients with chronic kidney disease in whom PCS accumulates.