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 5 mM. 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.


CONCLUSIONS
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.
Yano
Shozo
S
Department of Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo city, Shimane 693-8501, Japan. syano@med.shimane-u.ac.jp
Yamaguchi
Toru
T
Kanazawa
Ippei
I
Ogawa
Noriko
N
Hayashi
Kumi
K
Yamauchi
Mika
M
Sugimoto
Toshitsugu
T
D016475:3T3 Cells; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D010648:Phenylacetates / Q000633:toxicity*; D010766:Phosphorylation; D014511:Uremia / Q000139:chemically induced*
D010648:Phenylacetates; D000242:Cyclic AMP; D048052:Mitogen-Activated Protein Kinase 3; C025136:phenylacetic acid