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Toxic Effects of Indoxyl Sulfate on Osteoclastogenesis and Osteoblastogenesis

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出版社

MDPI
DOI: 10.3390/ijms222011265

关键词

aryl hydrocarbon receptor; bone remodeling; indoxyl sulfate; osteoblast; osteoclast

资金

  1. Ministry of Science and Technology (MOST), Taiwan [107-2314-B-030-001-MY3]
  2. Taipei Hospital, Ministry of Health and Welfare, Taiwan [202104]
  3. Taipei Tzu Chi Hospital, Tzu Chi Buddhist Health Foundation [TCRD-TPE-110-02]

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Uremic toxins like IS can affect bone remodeling and cell differentiation through the AhR signaling pathway, which may provide insights into preventing and treating CKD mineral bone disease.
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.

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