Osteoblast Autonomous Pi Regulation via Pit1 Plays a Role in Bone Mineralization

Abstract

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.