Increased PHOSPHO1 and alkaline phosphatase expression during the anabolic bone response to intermittent parathyroid hormone delivery

Dean A. Houston, Louise A. Stephen, Soher N. Jayash, Katherine Myers, Kirsty Little, Mark Hopkinson, Andrew A. Pitsillides, Vicky E. MacRae, Jose Luis Millan, Katherine A. Staines, Colin Farquharson

Research output: Contribution to journalArticlepeer-review

Abstract

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‐day iPTH (80 µg/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 the femora of WT mice following iPTH administration but remained unchanged in the femora of Phospho1−/− mice. After 28 days of iPTH administration, the anabolic response in the femora of WT was greater than that noted in Phospho1−/− mice. Specifically, cortical and trabecular bone volume/total volume, 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 PHOSPHO1, this suggests that the osteoanabolic effects of iPTH are at least partly mediated via bone mineralisation processes.
Original languageEnglish
Number of pages13
JournalCell Biochemistry and Function
DOIs
Publication statusPublished - 20 Dec 2022

Bibliographical note

Funding Information:
We thank the staff of the Biological Research Facility (BRF), University of Edinburgh who provided expert animal support. We are also grateful to the Biotechnology and Biological Sciences Research Council (BBSRC) for Institute Strategic Programme Grant Funding (BB/J004316/1) to C. F., L. A. S., S. N. J. and V. E. M. and for Doctoral Training Partnership funding to D. A. H. (BB/J01446X/1). For the purpose of open access, the author has applied a CC BY public copyright to any Author Accepted Manuscript version arising from this submission.

Publisher Copyright:
© 2022 The Authors. Cell Biochemistry and Function published by John Wiley & Sons Ltd.

Keywords

  • RESEARCH ARTICLE
  • RESEARCH ARTICLES
  • bone mineralisation
  • intermittent PTH
  • phosphatase
  • PHOSPHO1
  • SMPD3
  • TNAP

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