Molecular and cellular characterizations of human cherubism: disease aggressiveness depends on osteoclast differentiation
Abstract Background Cherubism is a rare autosomal dominant disorder of the jaws caused by mutation of the SH3BP2 gene. The bone is replaced by a fibrous granuloma containing multinucleated giant cells. Cells of the cherubism granuloma have never been systematically analyzed. Hence, the aim of this s...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-09-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13023-018-0907-2 |
| _version_ | 1818340444863463424 |
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| author | Natacha Kadlub Quentin Sessiecq Marion Mandavit Aurore Coulomb L’Hermine Cecile Badoual Louise Galmiche Ariane Berdal Vianney Descroix Arnaud Picard Amélie E. Coudert |
| author_facet | Natacha Kadlub Quentin Sessiecq Marion Mandavit Aurore Coulomb L’Hermine Cecile Badoual Louise Galmiche Ariane Berdal Vianney Descroix Arnaud Picard Amélie E. Coudert |
| author_sort | Natacha Kadlub |
| collection | DOAJ |
| description | Abstract Background Cherubism is a rare autosomal dominant disorder of the jaws caused by mutation of the SH3BP2 gene. The bone is replaced by a fibrous granuloma containing multinucleated giant cells. Cells of the cherubism granuloma have never been systematically analyzed. Hence, the aim of this study was to characterize the cells in human cherubism granulomas, to determine the osteoclastic characteristics of the multinucleated giant cells and to investigate the potential role of TNF-α in human cherubism. Results Seven granulomas were analyzed in pathology, molecular biology and immunohistochemistry. Granulomas were composed mainly of macrophages or osteoclasts within a fibroblastic tissue, with few lymphoid cells. Myeloid differentiation and nuclear NFATc1 localization were both associated with disease aggressiveness. OPG and RANKL immunohistochemical expression was unexpected in our specimens. Five granuloma cells were cultured in standard and osteoclastogenic media. In culture, cherubism cells were able to differentiate into active osteoclasts, in both osteoclastogenic and standard media. IL-6 was the major cytokine present in the culture supernatants. Conclusion Multinucleated giant cells from cherubism granulomas are CD68 positive cells, which differentiate into macrophages in non-aggressive cherubism and into osteoclasts in aggressive cherubism, stimulated by the NFATc1 pathway. This latter differentiation appears to involve a disturbed RANK-L/RANK/OPG pathway and be less TNF-α dependent than the cherubism mouse model. |
| first_indexed | 2024-12-13T15:43:00Z |
| format | Article |
| id | doaj.art-936658526b28474982965083221e5b5e |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-13T15:43:00Z |
| publishDate | 2018-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-936658526b28474982965083221e5b5e2022-12-21T23:39:46ZengBMCOrphanet Journal of Rare Diseases1750-11722018-09-0113111610.1186/s13023-018-0907-2Molecular and cellular characterizations of human cherubism: disease aggressiveness depends on osteoclast differentiationNatacha Kadlub0Quentin Sessiecq1Marion Mandavit2Aurore Coulomb L’Hermine3Cecile Badoual4Louise Galmiche5Ariane Berdal6Vianney Descroix7Arnaud Picard8Amélie E. Coudert9INSERM, UMRS 1138 Equipe 5, Laboratoire de Physiopathologie Orale Moléculaire, Centre de Recherche de CordeliersCHU de Bordeaux, Service de Chirurgie MaxillofacialeINSERM U 970, Equipe 10, PARCC, faculté Paris DescartesAPHP, Hôpital Armand Trousseau, Service d’Anatomopathologie et cytologieUniversité Paris DescartesUniversité Paris DescartesINSERM, UMRS 1138 Equipe 5, Laboratoire de Physiopathologie Orale Moléculaire, Centre de Recherche de CordeliersINSERM, UMRS 1138 Equipe 5, Laboratoire de Physiopathologie Orale Moléculaire, Centre de Recherche de CordeliersINSERM, UMRS 1138 Equipe 5, Laboratoire de Physiopathologie Orale Moléculaire, Centre de Recherche de CordeliersINSERM, UMRS 1138 Equipe 5, Laboratoire de Physiopathologie Orale Moléculaire, Centre de Recherche de CordeliersAbstract Background Cherubism is a rare autosomal dominant disorder of the jaws caused by mutation of the SH3BP2 gene. The bone is replaced by a fibrous granuloma containing multinucleated giant cells. Cells of the cherubism granuloma have never been systematically analyzed. Hence, the aim of this study was to characterize the cells in human cherubism granulomas, to determine the osteoclastic characteristics of the multinucleated giant cells and to investigate the potential role of TNF-α in human cherubism. Results Seven granulomas were analyzed in pathology, molecular biology and immunohistochemistry. Granulomas were composed mainly of macrophages or osteoclasts within a fibroblastic tissue, with few lymphoid cells. Myeloid differentiation and nuclear NFATc1 localization were both associated with disease aggressiveness. OPG and RANKL immunohistochemical expression was unexpected in our specimens. Five granuloma cells were cultured in standard and osteoclastogenic media. In culture, cherubism cells were able to differentiate into active osteoclasts, in both osteoclastogenic and standard media. IL-6 was the major cytokine present in the culture supernatants. Conclusion Multinucleated giant cells from cherubism granulomas are CD68 positive cells, which differentiate into macrophages in non-aggressive cherubism and into osteoclasts in aggressive cherubism, stimulated by the NFATc1 pathway. This latter differentiation appears to involve a disturbed RANK-L/RANK/OPG pathway and be less TNF-α dependent than the cherubism mouse model.http://link.springer.com/article/10.1186/s13023-018-0907-2CherubismRANKLTNF-αOsteoclastNFATc1Auto-inflammatory bone disease |
| spellingShingle | Natacha Kadlub Quentin Sessiecq Marion Mandavit Aurore Coulomb L’Hermine Cecile Badoual Louise Galmiche Ariane Berdal Vianney Descroix Arnaud Picard Amélie E. Coudert Molecular and cellular characterizations of human cherubism: disease aggressiveness depends on osteoclast differentiation Orphanet Journal of Rare Diseases Cherubism RANKL TNF-α Osteoclast NFATc1 Auto-inflammatory bone disease |
| title | Molecular and cellular characterizations of human cherubism: disease aggressiveness depends on osteoclast differentiation |
| title_full | Molecular and cellular characterizations of human cherubism: disease aggressiveness depends on osteoclast differentiation |
| title_fullStr | Molecular and cellular characterizations of human cherubism: disease aggressiveness depends on osteoclast differentiation |
| title_full_unstemmed | Molecular and cellular characterizations of human cherubism: disease aggressiveness depends on osteoclast differentiation |
| title_short | Molecular and cellular characterizations of human cherubism: disease aggressiveness depends on osteoclast differentiation |
| title_sort | molecular and cellular characterizations of human cherubism disease aggressiveness depends on osteoclast differentiation |
| topic | Cherubism RANKL TNF-α Osteoclast NFATc1 Auto-inflammatory bone disease |
| url | http://link.springer.com/article/10.1186/s13023-018-0907-2 |
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