The Paget's disease of bone risk gene <i>PML</i> is a negative regulator of osteoclast differentiation and bone resorption
<p dir="ltr">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...
Saved in:
| Main Author: | |
|---|---|
| Other Authors: | , , , , |
| Published: |
2022
|
| Subjects: | |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1864513518699544576 |
|---|---|
| author | Sachin Wani (11704868) |
| author2 | Anna Daroszewska (18420849) Donald M. Salter (398595) Rob J. van ‘t Hof (18420852) Stuart H. Ralston (311778) Omar M. E. Albagha (11704871) |
| author2_role | author author author author author |
| author_facet | Sachin Wani (11704868) Anna Daroszewska (18420849) Donald M. Salter (398595) Rob J. van ‘t Hof (18420852) Stuart H. Ralston (311778) Omar M. E. Albagha (11704871) |
| author_role | author |
| dc.creator.none.fl_str_mv | Sachin Wani (11704868) Anna Daroszewska (18420849) Donald M. Salter (398595) Rob J. van ‘t Hof (18420852) Stuart H. Ralston (311778) Omar M. E. Albagha (11704871) |
| dc.date.none.fl_str_mv | 2022-04-26T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1242/dmm.049318 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/The_Paget_s_disease_of_bone_risk_gene_i_PML_i_is_a_negative_regulator_of_osteoclast_differentiation_and_bone_resorption/25662666 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences Bone PML Paget's disease Osteoclasts |
| dc.title.none.fl_str_mv | The Paget's disease of bone risk gene <i>PML</i> is a negative regulator of osteoclast differentiation and bone resorption |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">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.</p><p><br></p><p dir="ltr">This article has an associated First Person interview with the first author of the paper.</p><h2>Other Information</h2><p dir="ltr">Published in: Disease Models & Mechanisms<br>License: <a href="http://creativecommons.org/licenses/by/4.0" target="_blank">http://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1242/dmm.049318" target="_blank">https://dx.doi.org/10.1242/dmm.049318</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_ecfd1eca68de24e8e1c6273fc32250ac |
| identifier_str_mv | 10.1242/dmm.049318 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25662666 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | The Paget's disease of bone risk gene <i>PML</i> is a negative regulator of osteoclast differentiation and bone resorptionSachin Wani (11704868)Anna Daroszewska (18420849)Donald M. Salter (398595)Rob J. van ‘t Hof (18420852)Stuart H. Ralston (311778)Omar M. E. Albagha (11704871)Biological sciencesBiochemistry and cell biologyGeneticsBiomedical and clinical sciencesClinical sciencesBonePMLPaget's diseaseOsteoclasts<p dir="ltr">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.</p><p><br></p><p dir="ltr">This article has an associated First Person interview with the first author of the paper.</p><h2>Other Information</h2><p dir="ltr">Published in: Disease Models & Mechanisms<br>License: <a href="http://creativecommons.org/licenses/by/4.0" target="_blank">http://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1242/dmm.049318" target="_blank">https://dx.doi.org/10.1242/dmm.049318</a></p>2022-04-26T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1242/dmm.049318https://figshare.com/articles/journal_contribution/The_Paget_s_disease_of_bone_risk_gene_i_PML_i_is_a_negative_regulator_of_osteoclast_differentiation_and_bone_resorption/25662666CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/256626662022-04-26T03:00:00Z |
| spellingShingle | The Paget's disease of bone risk gene <i>PML</i> is a negative regulator of osteoclast differentiation and bone resorption Sachin Wani (11704868) Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences Bone PML Paget's disease Osteoclasts |
| status_str | publishedVersion |
| title | The Paget's disease of bone risk gene <i>PML</i> is a negative regulator of osteoclast differentiation and bone resorption |
| title_full | The Paget's disease of bone risk gene <i>PML</i> is a negative regulator of osteoclast differentiation and bone resorption |
| title_fullStr | The Paget's disease of bone risk gene <i>PML</i> is a negative regulator of osteoclast differentiation and bone resorption |
| title_full_unstemmed | The Paget's disease of bone risk gene <i>PML</i> is a negative regulator of osteoclast differentiation and bone resorption |
| title_short | The Paget's disease of bone risk gene <i>PML</i> is a negative regulator of osteoclast differentiation and bone resorption |
| title_sort | The Paget's disease of bone risk gene <i>PML</i> is a negative regulator of osteoclast differentiation and bone resorption |
| topic | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences Bone PML Paget's disease Osteoclasts |