The influence of uremic toxins on low bone turnover disease in chronic kidney disease

^aSchool of Medicine, Tzu Chi University, Hualien, Taiwan, ^bDepartment of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan, ^cDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan, ^dDivision of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ^eDivision of Nephrology, Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, New Taipei, Taiwan, ^fTaipei Medical University‑Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan, ^gDepartment of Pediatrics, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, ^hDepartment of Pediatrics, Tri‑Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ⁱDepartment of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, ^jSchool of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan, ^kDivision of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, New Taipei, Taiwan, ^lDivision of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan

 

 

ABSTRACT

 

Uremic toxins play a crucial role in the development of low bone turnover disease in chronic kidney disease (CKD) through the induction of oxidative stress. This oxidative stress disrupts the delicate balance between bone formation and resorption, resulting in a decline in both bone quantity and quality. Reactive oxygen species (ROS) activate nuclear factor kappa‑B and mitogen‑activated protein kinase signaling pathways, promoting osteoclastogenesis. Conversely, ROS hinder osteoblast differentiation by facilitating the binding of Forkhead box O proteins (FoxOs) to β‑catenin, triggering apoptosis through FoxOs‑activating kinase phosphorylation. This results in increased osteoblastic receptor activator of nuclear factor kappa‑B ligand (RANKL) expression and decreased nuclear factor erythroid 2‑related factor 2 levels, compromising antioxidant defenses against oxidative damage. As CKD progresses, the accumulation of protein‑bound uremic toxins such as indoxyl sulfate (IS) and p‑cresyl sulfate (PCS) intensifies oxidative stress, primarily affecting osteoblasts. IS and PCS directly inhibit osteoblast viability, induce apoptosis, decrease alkaline phosphatase activity, and impair collagen 1 and osteonectin, impeding bone formation. They also reduce cyclic adenosine 3',5'-monophosphate (cAMP) production and lower parathyroid hormone (PTH) receptor expression in osteoblasts, resulting in PTH hyporesponsiveness. In summary, excessive production of ROS by uremic toxins not only reduces the number and function of osteoblasts but also induces PTH hyporesponsiveness, contributing to the initiation and progression of low bone turnover disease in CKD.

 

Keywords: Chronic kidney disease, Low bone turnover disease, Oxidative stress, Uremic toxins