1. Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Salaya, Nakhon Pathom, Thailand
2. Department of Orthopaedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
3. International Center for Medical and Radiological Technology, Faculty of Medical Technology, Mahidol University, Salaya, Nakhon Pathom, Thailand
4. Medical Department, Golden Jubilee Medical Center, Faculty of Medicine Siriraj Hospital
5. Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Salaya, Nakhon Pathom, Thailand
Chronic kidney disease (CKD) patients obtained high levels of uremic toxins progressively develop several complications including bone fractures. Protein-bound uremic toxins especially p-cresol and indoxyl sulfate are hardly eliminated due to their high molecular weight. Thus, the abnormality of bone in CKD patient could be potentially resulted from the accumulation of uremic toxins. To determine whether protein-bound uremic toxins have an impact on osteogenesis, mesenchymal stem cells were treated with either p-cresol or indoxyl sulfate under in vitro osteogenic differentiation. The effects of uremic toxins on MSC-osteoblastic differentiation were investigated by evaluation of bone phenotype. The results demonstrated that p-cresol and indoxyl sulfate down-regulated the transcriptional level of collagen type I, deceased alkaline phosphatase activity, and impaired mineralization of MSC-osteoblastic cells. Furthermore, p-cresol and indoxyl sulfate gradually increased senescence-associated beta-galactosidase positive cells while upregulated the expression of p21 which participate in senescent process. Our findings clearly revealed that the presence of uremic toxins dose-dependently influenced a gradual deterioration of osteogenesis. The effects partially mediate through the activation of senescence-associated gene lead to the impairment of osteogenesis. Therefore, the management of cellular senescence triggered by uremic toxins could be considered as an alternative therapeutic approach to prevent bone abnormality in CKD patients.
Keywords: p-cresol, indoxyl sulfate, chronic kidney disease, osteogenesis, cellular senescence, mesenchymal stem cells