Indoxyl sulfate, a uremic toxin in chronic kidney disease, suppresses both bone formation and bone resorption

Abnormalities of bone turnover are commonly observed in patients with chronic kidney disease (CKD), and the low-turnover bone disease is considered to be associated with low serum parathyroid hormone (PTH) levels and skeletal resistance to PTH. Indoxyl sulfate is a representative uremic toxin that accumulates in the blood of CKD patients. Recently, we have reported that indoxyl sulfate exacerbates low bone turnover induced by parathyroidectomy in adult rats, and suggested that indoxyl sulfate directly induces low bone turnover through inhibition of bone formation by mechanisms unrelated to skeletal resistance to PTH. To define the direct action of indoxyl sulfate in bone turnover, we examined the effects of indoxyl sulfate on bone formation and bone resorption in vitro. In cultures of mouse primary osteoblasts, indoxyl sulfate suppressed the expression of osterix, osteocalcin and BMP2 mRNAs, and clearly inhibited the formation of mineralized bone nodules. Therefore, indoxyl sulfate directly acts on osteoblastic cells to suppress bone formation. On the other hand, indoxyl sulfate suppressed interleukin (IL)-1-induced osteoclast formation in co-cultures of bone marrow cells and osteoblasts, and IL-1-induced bone resorption in calvarial organ cultures. In cultures of osteoblasts, indoxyl sulfate suppressed the mRNA expression of RANKL, the receptor activator of NF-κB ligand, which is a pivotal factor for osteoclast differentiation. Moreover, indoxyl sulfate acted on osteoclast precursor, bone-marrow derived macrophages and RAW264.7 cells, and suppressed RANKL-dependent differentiation into mature osteoclasts. Indoxyl sulfate may induce low-turnover bone disease in CKD patients by its direct action on both osteoblasts and osteoclast precursors to suppress bone formation and bone resorption. This article is protected by copyright. All rights reserved.