The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption
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 have assessed the candidacy of PML as the predisposing gene for PD...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2022-04-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/15/4/dmm049318 |
| _version_ | 1811257844513636352 |
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| author | Sachin Wani Anna Daroszewska Donald M. Salter Rob J. van ‘t Hof Stuart H. Ralston Omar M. E. Albagha |
| author_facet | Sachin Wani Anna Daroszewska Donald M. Salter Rob J. van ‘t Hof Stuart H. Ralston Omar M. E. Albagha |
| author_sort | Sachin Wani |
| collection | DOAJ |
| description | 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 have 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 that PML expression in blood cells from individuals with PDB was lower than in controls. The differentiation, survival and resorptive activity of osteoclasts prepared from Pml−/− mice was increased compared with wild type. Furthermore, the inhibitory effect of IFN-γ on osteoclast formation from Pml−/− was significantly blunted compared with wild type. Bone nodule formation was also increased in osteoblasts from Pml−/− mice when compared with wild type. Although microCT analysis of trabecular bone showed no differences between Pml−/− mice and wild type, 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 an individual to PDB and identify PML as a novel regulator of bone metabolism. This article has an associated First Person interview with the first author of the paper. |
| first_indexed | 2024-04-12T18:03:53Z |
| format | Article |
| id | doaj.art-00fe2a8aa8354605822d6e6447d01bb6 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-12T18:03:53Z |
| publishDate | 2022-04-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-00fe2a8aa8354605822d6e6447d01bb62022-12-22T03:22:02ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112022-04-0115410.1242/dmm.049318049318The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorptionSachin Wani0Anna Daroszewska1Donald M. Salter2Rob J. van ‘t Hof3Stuart H. Ralston4Omar M. E. Albagha5 Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK 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 have 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 that PML expression in blood cells from individuals with PDB was lower than in controls. The differentiation, survival and resorptive activity of osteoclasts prepared from Pml−/− mice was increased compared with wild type. Furthermore, the inhibitory effect of IFN-γ on osteoclast formation from Pml−/− was significantly blunted compared with wild type. Bone nodule formation was also increased in osteoblasts from Pml−/− mice when compared with wild type. Although microCT analysis of trabecular bone showed no differences between Pml−/− mice and wild type, 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 an individual to PDB and identify PML as a novel regulator of bone metabolism. This article has an associated First Person interview with the first author of the paper.http://dmm.biologists.org/content/15/4/dmm049318bonepmlpaget's diseaseosteoclasts |
| spellingShingle | Sachin Wani Anna Daroszewska Donald M. Salter Rob J. van ‘t Hof Stuart H. Ralston Omar M. E. Albagha The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption Disease Models & Mechanisms bone pml paget's disease osteoclasts |
| title | The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption |
| title_full | The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption |
| title_fullStr | The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption |
| title_full_unstemmed | The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption |
| title_short | The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption |
| title_sort | paget s disease of bone risk gene pml is a negative regulator of osteoclast differentiation and bone resorption |
| topic | bone pml paget's disease osteoclasts |
| url | http://dmm.biologists.org/content/15/4/dmm049318 |
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