Abstract
Uremic toxins, such as indoxyl sulfate (IS) and kynurenine, accumulate in the blood in the event of kidney failure and contribute to further bone damage. To maintain the homeostasis of the skeletal system, bone remodeling is a persistent process of bone formation and bone resorption that depends on a dynamic balance of osteoblasts and osteoclasts. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the toxic effects of uremic toxins. IS is an endogenous AhR ligand and is metabolized from tryptophan. In osteoclastogenesis, IS affects the expression of the osteoclast precursor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) through AhR signaling. It is possible to increase osteoclast differentiation with short-term and low-dose IS exposure and to decrease differentiation with long-term and/or high-dose IS exposure. Coincidentally, during osteoblastogenesis, through the AhR signaling pathway, IS inhibits the phosphorylation of ERK, and p38 reduces the expression of the transcription factor 2 (Runx2), disturbing osteoblastogenesis. The AhR antagonist resveratrol has a protective effect on the IS/AhR pathway. Therefore, it is necessary to understand the multifaceted role of AhR in CKD, as knowledge of these transcription signals could provide a safe and effective method to prevent and treat CKD mineral bone disease.
Highlights
Fukagawa et al stated that parathyroid hormone (PTH)-stimulated intracellular cyclic adenosine monophosphate production is suppressed by indoxyl sulfate (IS), which is associated with the inhibition of PTH receptor expression and causes oxidative stress in the bone cells of Chronic kidney disease (CKD) patients [52]
aryl hydrocarbon receptor (AhR) possesses numerous exogenous ligands, such as 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) [67], 3-methylcholanthrene (3-MC) [68], and benzo[a]pyrene (BaP) of polycyclic aromatic hydrocarbons (PAHs) [69], as well as various endogenous ligands, such as IS, indole-3-acid-acetic (IAA) [70], KYN [71], and kynurenine’s metabolites: kynurenic acid [72] and quinolinic acid [73]. Those derived from tryptophan metabolism are of particular importance because they are associated with cardiovascular toxicity; they are shown to be potent AhR ligands [74]
In an in vivo study, Mozar et al stated that IS blocked the differentiation/function of osteoclasts and the activity of bone resorption in a dose-dependent manner after being cultured for five days with more than 200 μM of IS with 3 mM of NaH2 PO4 salt [110]. Their results suggested that osteoclast and osteoblast function was inhibited by IS through the mitogen-activated protein kinase (MAPK) ERK1/2, p38, JNK, and Akt pathways, which result in bone remodeling being destroyed in patients with CKD [110]
Summary
The disease comprises characteristics of laboratory abnormalities, vascular/soft tissue calcification, and bone metabolism deterioration [1] These disorders of the skeleton are the predominant causes of bone loss and fractures in patients with CKD. In the case of CKD, the incidence of fractures [2], morbidity, and mortality are higher than in the general population [3], even among patients with adequate control of calcium, phosphate, and parathyroid hormone (PTH) levels with calcimimetics [4,5] This suggests that, beyond calcitriol, PTH, calcium, and phosphate, uremic toxins could play an important role in the modulation of bone metabolism in CKD. AhR on bone remodeling under the influence of IS in the scenario of CKD and its related signal pathway, hoping to provide a theoretical basis on how to improve bone remodeling in CKD patients
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