Osteoblast autonomous Pi regulation via Pit1 plays a role in bone mineralization.
The complex pathogenesis of mineralization defects seen in inherited and/or acquired hypophosphatemic disorders suggests that local inorganic phosphate (P(i)) regulation by osteoblasts may be a rate-limiting step in physiological bone mineralization. To test whether an osteoblast autonomous phosphate regulatory system regulates mineralization, we manipulated well-established in vivo and in vitro models to study mineralization stages separately from cellular proliferation/differentiation stages of osteogenesis. Foscarnet, an inhibitor of NaP(i) transport, blocked mineralization of osteoid formation in osteoblast cultures and local mineralization after injection over the calvariae of newborn rats. Mineralization was also down- and upregulated, respectively, with under- and overexpression of the type III NaP(i) transporter Pit1 in osteoblast cultures. Among molecules expressed in osteoblasts and known to be related to P(i) handling, stanniocalcin 1 was identified as an early response gene after foscarnet treatment; it was also regulated by extracellular P(i), and itself increased Pit1 accumulation in both osteoblast cultures and in vivo. These results provide new insights into the functional role of osteoblast autonomous P(i) handling in normal bone mineralization and the abnormalities seen in skeletal tissue in hypophosphatemic disorders.
Yoshiko
Yuji
Y
Department of Oral Growth and Developmental Biology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
Candeliere
G Antonio
GA
Maeda
Norihiko
N
Aubin
Jane E
JE
D016475:3T3 Cells; D000818:Animals; D002113:Calcification, Physiologic; D002478:Cells, Cultured; D017245:Foscarnet / Q000494:pharmacology; D005786:Gene Expression Regulation; D005994:Glycerophosphates / Q000494:pharmacology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D012516:Osteosarcoma / Q000473:pathology; D010758:Phosphorus / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012886:Skull / Q000166:cytology / Q000196:embryology; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000378:metabolism; D050817:Transcription Factor Pit-1 / Q000235:genetics / Q000378:metabolism*
D005994:Glycerophosphates; D006023:Glycoproteins; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D050817:Transcription Factor Pit-1; D010758:Phosphorus; D017245:Foscarnet; C051795:teleocalcin; C031463:beta-glycerophosphoric acid