Regulation of osteoclast differentiation and function by phosphate: potential role of osteoclasts in the skeletal abnormalities in hypophosphatemic conditions.
Mice fed with a low Pi diet exhibited decreased osteoclast number. Hyp mice also showed decreased osteoclasts, and high Pi reversed it. Low Pi reduced osteoclast formation and bone resorption in vitro. Hypophosphatemia may suppress osteoclast differentiation/function, leading to skeletal abnormalities.


BACKGROUND
Skeletal abnormalities seen in hypophosphatemic disorders indicate a critical role of phosphate (Pi) in skeletogenesis. However, the role of osteoclasts in the pathogenesis of the disturbed skeletogenesis is unclear.


METHODS
Mice fed with a low-Pi diet and Hyp mice that are characterized by hypophosphatemia and impaired osteogenesis were studied. Effects of Pi on osteoclast formation and bone resorption were also examined in vitro.


RESULTS
Histomorphometric examination showed that mice on a low-Pi diet exhibited decreased osteoclast number. Furthermore, osteoclast number in Hyp mice was also decreased compared with wildtype (WT) mice. Of note, feeding of Hyp mice with high-Pi diet significantly reversed hypophosphatemia, improved disturbed osteogenesis, and increased osteoclast number. Osteoclast-like cell (OLC) formation and bone resorption in Hyp bone marrow cells was not different from WT bone marrow cells. On the other hand, OLC formation and bone resorption were decreased in conjunction with reduced mRNA expression of RANKL in WT bone marrow cells cultured in the medium containing low Pi (0.5 mM). Recombinant human matrix extracellular phosphoglycoprotein (MEPE), a candidate for phosphatonin, also decreased osteoclast formation, whereas fibroblast growth factor 23 (FGF23), another phosphatonin candidate, showed no effects.


CONCLUSIONS
Our results suggest that Pi controls the differentiation and function of osteoclasts. These actions of Pi on osteoclasts may be associated with the pathogenesis of the skeletal abnormalities in hypophosphatemic disorders.
Hayashibara
Tetsuyuki
T
Department of Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.
Hiraga
Toru
T
Sugita
Atsushi
A
Wang
Liyang
L
Hata
Kenji
K
Ooshima
Takashi
T
Yoneda
Toshiyuki
T
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000209:etiology*; D001842:Bone and Bones / Q000002:abnormalities* / Q000000981:diagnostic imaging; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004032:Diet; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D017674:Hypophosphatemia / Q000150:complications*; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D010710:Phosphates / Q000008:administration & dosage / Q000172:deficiency*; D010750:Phosphoproteins / Q000494:pharmacology; D011859:Radiography; D011994:Recombinant Proteins / Q000494:pharmacology
D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D006023:Glycoproteins; C486579:MEPE protein, human; D010710:Phosphates; D010750:Phosphoproteins; D011994:Recombinant Proteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23