Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice
<p dir="ltr">Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (...
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| منشور في: |
2021
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| _version_ | 1864513516118999040 |
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| author | Nerea Alonso (1897801) |
| author2 | Sachin Wani (11704868) Lorraine Rose (496764) Rob J. van't Hof (18527778) Stuart H. Ralston (311778) Omar M.E. Albagha (18508167) |
| author2_role | author author author author author |
| author_facet | Nerea Alonso (1897801) Sachin Wani (11704868) Lorraine Rose (496764) Rob J. van't Hof (18527778) Stuart H. Ralston (311778) Omar M.E. Albagha (18508167) |
| author_role | author |
| dc.creator.none.fl_str_mv | Nerea Alonso (1897801) Sachin Wani (11704868) Lorraine Rose (496764) Rob J. van't Hof (18527778) Stuart H. Ralston (311778) Omar M.E. Albagha (18508167) |
| dc.date.none.fl_str_mv | 2021-03-16T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1002/jbmr.4288 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Insertion_Mutation_in_Tnfrsf11a_Causes_a_Paget_s_Disease_Like_Phenotype_in_Heterozygous_Mice_and_Osteopetrosis_in_Homozygous_Mice/25781022 |
| 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 75dup27 MOUSE MODEL OSTEOCLAST PAGET'S DISEASE OF BONE RANK |
| dc.title.none.fl_str_mv | Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (RANK) protein. To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB. Mice heterozygous for the mutation (Tnfrsf11a<sup>75dup27/−</sup>) developed a PDB-like disorder with focal osteolytic lesions in the hind limbs with increasing age. Treatment of these mice with zoledronic acid completely prevented the development of lesions. Studies in vitro showed that RANK ligand (RANKL)-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a<sup>75dup27/−</sup> animals, but that osteoclast survival was increased independent of RANKL stimulation. Surprisingly, Tnfrsf11a<sup>75dup27/75dup27</sup> homozygotes had osteopetrosis at birth, with complete absence of osteoclasts. Bone marrow cells from these mice failed to form osteoclasts in response to RANKL and macrophage colony-stimulating factor (M-CSF) stimulation. This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling. In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..</p><p><br></p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Bone and Mineral Research<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1002/jbmr.4288" target="_blank">https://dx.doi.org/10.1002/jbmr.4288</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_9acce412be59c7189a3c3273cdde1c66 |
| identifier_str_mv | 10.1002/jbmr.4288 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25781022 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous MiceNerea Alonso (1897801)Sachin Wani (11704868)Lorraine Rose (496764)Rob J. van't Hof (18527778)Stuart H. Ralston (311778)Omar M.E. Albagha (18508167)Biological sciencesBiochemistry and cell biology75dup27MOUSE MODELOSTEOCLASTPAGET'S DISEASE OF BONERANK<p dir="ltr">Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (RANK) protein. To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB. Mice heterozygous for the mutation (Tnfrsf11a<sup>75dup27/−</sup>) developed a PDB-like disorder with focal osteolytic lesions in the hind limbs with increasing age. Treatment of these mice with zoledronic acid completely prevented the development of lesions. Studies in vitro showed that RANK ligand (RANKL)-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a<sup>75dup27/−</sup> animals, but that osteoclast survival was increased independent of RANKL stimulation. Surprisingly, Tnfrsf11a<sup>75dup27/75dup27</sup> homozygotes had osteopetrosis at birth, with complete absence of osteoclasts. Bone marrow cells from these mice failed to form osteoclasts in response to RANKL and macrophage colony-stimulating factor (M-CSF) stimulation. This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling. In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..</p><p><br></p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Bone and Mineral Research<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1002/jbmr.4288" target="_blank">https://dx.doi.org/10.1002/jbmr.4288</a></p>2021-03-16T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1002/jbmr.4288https://figshare.com/articles/journal_contribution/Insertion_Mutation_in_Tnfrsf11a_Causes_a_Paget_s_Disease_Like_Phenotype_in_Heterozygous_Mice_and_Osteopetrosis_in_Homozygous_Mice/25781022CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/257810222021-03-16T03:00:00Z |
| spellingShingle | Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice Nerea Alonso (1897801) Biological sciences Biochemistry and cell biology 75dup27 MOUSE MODEL OSTEOCLAST PAGET'S DISEASE OF BONE RANK |
| status_str | publishedVersion |
| title | Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice |
| title_full | Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice |
| title_fullStr | Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice |
| title_full_unstemmed | Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice |
| title_short | Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice |
| title_sort | Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice |
| topic | Biological sciences Biochemistry and cell biology 75dup27 MOUSE MODEL OSTEOCLAST PAGET'S DISEASE OF BONE RANK |