Genetic Ablation of Osteopontin in Osteomalacic Hyp Mice Partially Rescues the Deficient Mineralization Without Correcting Hypophosphatemia

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DOI

  • Betty Hoac, McGill University
  • ,
  • Maja Østergaard
  • Nina K. Wittig
  • Tchilalo Boukpessi, McGill University, School of Dentistry Université de Paris, AP-HP Assistance Publique - Hopitaux de Paris
  • ,
  • Daniel J. Buss, McGill University
  • ,
  • Catherine Chaussain, School of Dentistry Université de Paris, AP-HP Assistance Publique - Hopitaux de Paris
  • ,
  • Henrik Birkedal
  • Monzur Murshed, McGill University, Shriners Hospitals for Children
  • ,
  • Marc D. McKee, McGill University

PHEX is predominantly expressed by bone and tooth-forming cells, and its inactivating mutations in X-linked hypophosphatemia (XLH) lead to renal phosphate wasting and severe hypomineralization of bones and teeth. Also present in XLH are hallmark hypomineralized periosteocytic lesions (POLs, halos) that persist despite stable correction of serum phosphate (Pi) that improves bulk bone mineralization. In XLH, mineralization-inhibiting osteopontin (OPN, a substrate for PHEX) accumulates in the extracellular matrix of bone. To investigate how OPN functions in Hyp mice (a model for XLH), double-null (Hyp;Opn−/−) mice were generated. Undecalcified histomorphometry performed on lumbar vertebrae revealed that Hyp;Opn−/− mice had significantly reduced osteoid area/bone area (OV/BV) and osteoid thickness of trabecular bone as compared to Hyp mice, despite being as hypophosphatemic as Hyp littermate controls. However, tibias examined by synchrotron radiation micro-CT showed that mineral lacunar volumes remained abnormally enlarged in these double-null mice. When Hyp;Opn−/− mice were fed a high-Pi diet, serum Pi concentration increased, and OV/BV and osteoid thickness normalized, yet mineral lacunar area remained abnormally enlarged. Enpp1 and Ankh gene expression were increased in double-null mice fed a high-Pi diet, potentially indicating a role for elevated inhibitory pyrophosphate (PPi) in the absence of OPN. To further investigate the persistence of POLs in Hyp mice despite stable correction of serum Pi, immunohistochemistry for OPN on Hyp mice fed a high-Pi diet showed elevated OPN in the osteocyte pericellular lacunar matrix as compared to Hyp mice fed a control diet. This suggests that POLs persisting in Hyp mice despite correction of serum Pi may be attributable to the well-known upregulation of mineralization-inhibiting OPN by Pi, and its accumulation in the osteocyte pericellular matrix. This study shows that OPN contributes to osteomalacia in Hyp mice, and that genetic ablation of OPN in Hyp mice improves the mineralization phenotype independent of systemic Pi-regulating factors.

Original languageEnglish
JournalJournal of Bone and Mineral Research
Volume35
Issue10
Pages (from-to)2032-2048
Number of pages17
ISSN0884-0431
DOIs
Publication statusPublished - 10 Oct 2020

    Research areas

  • ANIMAL MODELS, BONE MATRIX, CELLS OF BONE, DISEASES AND DISORDERS OF/RELATED TO BONE, GENETIC ANIMAL MODELS, MATRIX MINERALIZATION, NON-COLLAGENOUS PROTEINS, OSTEOCYTES, OSTEOMALACIA AND RICKETS

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