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The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption

Sachin Wani1, Anna Daroszewska2, Donald M Salter1

  • 1Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.

Disease Models & Mechanisms
|March 1, 2022
PubMed

Insights

Reduced expression of the PML gene is linked to Paget's disease of bone (PDB). This study reveals PML as a key regulator of bone metabolism, impacting osteoclast activity and bone turnover in PDB.

Area of Science:

  • Genetics
  • Bone Biology
  • Molecular Medicine

Background:

  • Paget's disease of bone (PDB) involves localized bone remodeling.
  • A genome-wide association study identified a PDB susceptibility locus within the PML gene (rs5742915).

Purpose of the Study:

  • To investigate the role of the PML gene in Paget's disease of bone.
  • To determine if reduced PML expression predisposes individuals to PDB.

Main Methods:

  • Assessed the association between the PDB-risk allele (rs5742915) and PML expression.
  • Measured PML expression in blood cells from PDB patients and controls.
  • Utilized Pml-/- mice to study osteoclast and osteoblast function.
  • Analyzed bone turnover using microCT and histomorphometry.

Main Results:

  • The PDB-risk allele correlated with lower PML expression.
  • PML expression was reduced in blood cells of PDB patients compared to controls.
  • Pml-/- mice exhibited increased osteoclast differentiation, survival, and resorptive activity.
  • Pml-/- mice showed enhanced bone nodule formation and high bone turnover with increased resorption and mineral apposition rate.
  • The inhibitory effect of IFN-γ on osteoclast formation was blunted in Pml-/- mice.

Conclusions:

  • Reduced PML expression is a predisposing factor for Paget's disease of bone.
  • PML is identified as a novel regulator of bone metabolism, influencing osteoclast and osteoblast activity.
  • These findings provide new insights into the molecular mechanisms underlying PDB.
Keywords:
BoneOsteoclastsPMLPaget's disease

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