Increased PHOSPHO1 and Alkaline Phosphatase expression during the anabolic bone response to intermittent parathyroid hormone delivery: Control of PHOSPHO1 and TNAP expression by iPTH

Dean Houston, Louise Stephen, Soher Nagi Jayash, Katherine Myers, Kirsty Little, Mark Hopkinson , Andrew Pitsillides, Vicky MacRae, jose luis millan, Katherine A. Staines, Colin Farquharson

Research output: Contribution to journalArticlepeer-review


The administration of intermittent parathyroid hormone (iPTH) is anabolic to the skeleton. Recent studies with cultured osteoblasts have revealed that the expression of PHOSPHO1, a bone-specific phosphatase essential for the initiation of mineralisation, is regulated by PTH. Therefore, this study sought to determine whether the bone anabolic response to iPTH involves modulation of expression of Phospho1 and of other enzymes critical for bone matrix mineralisation. To mimic iPTH treatment, primary murine osteoblasts were challenged with 50 nM PTH for 6 h in every 48 h period for 8 days (4 cycles), 14 days (7 cycles) and 20 days (10 cycles) in total. The expression of both Phospho1 and Smpd3 was almost completely inhibited after 4 cycles, whereas 10 cycles were required to stimulate a similar response in Alpl expression. To explore the in vivo role of PHOSPHO1 in PTH-mediated osteogenesis, the effects of 14- and 28- days iPTH (80µg/kg/day) administration was assessed in male wild-type (WT) and Phospho1-/- mice. The expression of Phospho1, Alpl, Smpd3, Enpp1, Runx2 and Trps1 expression was enhanced in femora of WT mice following iPTH administration but remained unchanged in femora of Phospho1-/- mice. After 28-days of iPTH administration the anabolic response in femora of WT was greater than that noted in Phospho1-/- mice. Specifically, cortical and trabecular BV/TV, as well as cortical thickness were increased in femora of iPTH-treated WT but not in iPTH-treated Phospho1-/- mice. Trabecular bone osteoblast number was also increased in iPTH-treated WT mice but not in iPTH-treated Phospho1-/- mice. The increased levels of Phospho1, Alpl, Enpp1 and Smpd3 in WT mice in response to iPTH administration is consistent with their contribution to the potent anabolic properties of iPTH in bone. Furthermore, as the anabolic response to iPTH was attenuated in mice deficient in PHOSPHO this suggests that the osteoanabolic effects of iPTH are at least partly mediated via bone mineralisation processes.
Significance Statement: Intermittent administration of PTH (iPTH) is recognised to increase osteoblast number and promote bone formation. A critical component of this anabolic response is the mineralisation of the osteoid matrix but the effects iPTH on the expression of mineralisation regulating enzymes is unclear. This study’s principal finding was that iPTH administration increased the expression of Phospho1, Alpl, Enpp1 and Smpd3 in vivo which was consistent with a bone anabolic PTH regimen. The data also disclosed that in the absence of PHOSPHO1, the iPTH anabolic response was dampened, suggesting that amplified Phospho1 expression is a prerequisite for a full iPTH mediated bone anabolic response.
Original languageEnglish
Pages (from-to)1-13
JournalCell Biochemistry and Function
Early online date20 Dec 2022
Publication statusE-pub ahead of print - 20 Dec 2022


  • Bone mineralisation
  • intermittent PTH
  • phosphatase
  • TNAP
  • SMPD3


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