The uraemic toxin phenylacetic acid inhibits osteoblastic proliferation and differentiation: an implication for the pathogenesis of low turnover bone in chronic renal failure

Background. A relatively high level of serum parathyroid hormone (PTH) is required to maintain normal bone turnover in patients with chronic kidney disease (CKD). Uraemic toxins could cause an impaired response to PTH in bone and result in low turnover bone disease. Since phenylacetic acid (PAA) has been identified as one of the uraemic toxins in patients with CKD and has an inhibiting property of monocyte function, we examined if PAA might inhibit osteoblastic functions in vitro. Methods. Using mouse osteoblastic MC3T3-E1 cells, we performed BrdU incorporation, real-time PCR, Western blot and stainings to see the effect of PAA. Results. PAA significantly inhibited proliferation in a dose-dependent manner ranging between 0.5 and 5mM. PAA reduced osteocalcin mRNA level, alkaline phosphatase activity and osteoblastic mineralization. PAA pre-treatment also decreased both PTH-induced cAMP production and extracellular signal-regulated kinase (ERK) phosphorylation. Conclusion. PAA, a newly identified uraemic toxin, affects osteoblastic functions such as proliferation, differentiation, mineralization and responsiveness to PTH, indicating that this molecule could play an important role in the pathogenesis of low turnover bone in CKD.