Paget's disease of bone (PDB) is characterized by focal increases in bone remodelling. Genome-wide association studies identified a susceptibility locus for PDB tagged by rs5742915 which is located within the PML gene. Here we assessed the candidacy of PML as the predisposing gene for PDB at this locus. We found that the PDB-risk allele of rs5742915 was associated with lower PML expression and PML expression in blood cells from patients with PDB was lower than in controls. The differentiation, survival and resorptive activity of osteoclasts prepared from Pml−/− mice was increased compared to WT. Furthermore, the inhibitory effect of IFN-γ on osteoclast formation from Pml−/− was significantly blunted compared with WT. Bone nodule formation was also increased in osteoblasts from Pml−/− mice as compared with WT. While microCT analysis of trabecular bone showed no differences between Pml−/− mice and WT, bone histomorphometry showed that Pml−/− mice had high bone turnover with increased indices of bone resorption and increased mineral apposition rate. These data indicate that reduced expression of PML predisposes to PDB and identify PML as a novel regulator of bone metabolism.
Reduced expression of PML predisposes to Paget's disease of bone by increasing osteoclast differentiation and bone resorption
- Award Group:
- Funder(s): European Research Countil
- Award Id(s): 311723-GENEPAD
- Funder(s):
Currently Viewing Accepted Manuscript - Newer Version Available
Sachin Wani, Anna Daroszewska, Donald M. Salter, Rob J. van 't Hof, Stuart H. Ralston, Omar M. E. Albagha; Reduced expression of PML predisposes to Paget's disease of bone by increasing osteoclast differentiation and bone resorption. Dis Model Mech 2022; dmm.049318. doi: https://doi.org/10.1242/dmm.049318
Download citation file:
Advertisement
Valuing peer review at Disease Models & Mechanisms
We would like to thank our peer reviewers who contributed their time and expertise in 2023. In her latest Editorial, Editor-in-Chief Liz Patton has outlined why we continue to value our peer reviewers dedication.
Subject collection: Building advocacy into research
DMM’s new series - Building advocacy into research - features interviews, ‘The Patient’s Voice’, with patients and advocates for a range of disease types, with the aim of supporting the highest quality research for the benefit of all patients affected by disease.
Travelling Fellowships for early-career researchers
DMM and its sister journals offer Travelling Fellowships of up to £3,000 to graduate students and post-doctoral researchers wishing to make collaborative visits to other laboratories. Find out more about our Travelling Fellowships and read stories from previous grant recipients.
Read & Publish Open Access publishing: what authors say
We have had great feedback from authors who have benefitted from our Read & Publish agreement with their institution and have been able to publish Open Access with us without paying an APC. Read what they had to say.
The Forest of Biologists
Our Publisher Claire Moulton recently visited the two Woodland Trust UK sites where we are planting new native trees for published Research and Review papers and protecting ancient woodland on behalf of our peer reviewers.
Other journals from
The Company of Biologists