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.Multiple dynamic cellular events underlie de novo bone formation. Osteoblasts develop, synthesize, and deposit extracellular (osteoid) matrix comprising collagen and noncollagenous proteins and participate in osteoid mineralization. Although much has been learned about the cellular and molecular regulation of sequential stages in the bone formation process, e.g., cellular proliferation and differentiation, osteoid deposition, and mineralization, from in vitro (2) and in vivo (20) models, much remains obscure, including, for example, the contribution of systemic versus local regulatory controls.The control of systemic inorganic phosphate (P i ) levels is known to be indispensable for bone formation, especially for osteoid mineralization processes, but the parathyroid hormone (PTH) (decreasing serum P i levels)-vitamin D (increasing serum P i levels) axis does not fully explain systemic P i homeostasis (31). For example, fibroblast growth factor 23 (FGF23) (1) and secreted frizzled-related protein 4 (sFRP-4) (9) were identified and found to display the biological properties of the putative circulating phosphaturic factor "phosphatonin," which may be primarily responsible for a variety of hypophosphatemic disorders. In contrast, osteomalacia/rickets occurs in Hyp and Gy mice (murine homologues of X-linked hypophosphatemia) (18) but not in mice lacking the primary renal sodium-dependent phosphate (NaP i ) transporter, Npt2 (6). Analyses of several Hyp mouse models have also suggested that Hyp osteoblasts may have an intrinsic impairment in mineralization (for example, see reference 13). Moreover, the mineralization defects seen in Fgf23-null mice with hyperphosphatemia (34, 35) and FGF23 tr...
