Loss of STAT3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development.
Studies with genetically modified mice have implicated the transcriptional regulator STAT3 as a key modulator of bone development. STAT3-OKO knockout mouse lines were generated in two genetic backgrounds, pure C57BL/6 (STAT3-OKO-BL) and mixed C57BL/6, CD1 (STAT3-OKO-M). Both lines exhibited defectiv...
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0315078 |
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| author | Rebecca K Davidson Kylie Corry Amos Orlofsky Ping Li Caleb E Russell Amy Zhang Mariana Moraes de Lima Perini Carlie N Priddy Andrew V Nguyen Jiliang Li |
| author_facet | Rebecca K Davidson Kylie Corry Amos Orlofsky Ping Li Caleb E Russell Amy Zhang Mariana Moraes de Lima Perini Carlie N Priddy Andrew V Nguyen Jiliang Li |
| author_sort | Rebecca K Davidson |
| collection | DOAJ |
| description | Studies with genetically modified mice have implicated the transcriptional regulator STAT3 as a key modulator of bone development. STAT3-OKO knockout mouse lines were generated in two genetic backgrounds, pure C57BL/6 (STAT3-OKO-BL) and mixed C57BL/6, CD1 (STAT3-OKO-M). Both lines exhibited defective postnatal bone development resulting in reduced body weight and shortened femurs that displayed low bone mineral density as well as cortical widening and thinning in the diaphyseal region. Remarkably, each of these defects displayed sexual dimorphism that was dependent on genetic background: the phenotype was entirely male-specific in STAT3-OKO-M but not in STAT3-OKO-BL, in which defects were similar in both sexes. However, both lines exhibited a male-specific bone defect in mineralization, and also in bone mechanical properties related to bone quality, such as yield stress and ultimate stress. On the other hand, bone mechanical properties such as ultimate force, that may reflect density and macrostructure rather than bone quality, showed male-specific defects only in STAT3-OKO-M. These findings suggest that STAT3 may regulate multiple sex-dependent mechanisms in bone development that control either mineralization or bone accrual, and that the sex-dependence of at least some of these mechanisms is affected by genetic background. Finally, we used CRISPR/Cas9 to generate STAT3-deficient preosteoblastic cells from immortalized wild-type bone marrow stem cells and showed that the defective osteoblastic differentiation of STAT3-ablated cells was associated with reduced gene expression of Wnt3a and Wnt5a, consistent with other studies that identify Wnt signaling pathways as potential effector mechanisms for STAT3-mediated regulation of bone development. |
| format | Article |
| id | doaj-art-e6e376b8a100421fb0c8197a4e0754dd |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-e6e376b8a100421fb0c8197a4e0754dd2025-08-20T03:02:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-011912e031507810.1371/journal.pone.0315078Loss of STAT3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development.Rebecca K DavidsonKylie CorryAmos OrlofskyPing LiCaleb E RussellAmy ZhangMariana Moraes de Lima PeriniCarlie N PriddyAndrew V NguyenJiliang LiStudies with genetically modified mice have implicated the transcriptional regulator STAT3 as a key modulator of bone development. STAT3-OKO knockout mouse lines were generated in two genetic backgrounds, pure C57BL/6 (STAT3-OKO-BL) and mixed C57BL/6, CD1 (STAT3-OKO-M). Both lines exhibited defective postnatal bone development resulting in reduced body weight and shortened femurs that displayed low bone mineral density as well as cortical widening and thinning in the diaphyseal region. Remarkably, each of these defects displayed sexual dimorphism that was dependent on genetic background: the phenotype was entirely male-specific in STAT3-OKO-M but not in STAT3-OKO-BL, in which defects were similar in both sexes. However, both lines exhibited a male-specific bone defect in mineralization, and also in bone mechanical properties related to bone quality, such as yield stress and ultimate stress. On the other hand, bone mechanical properties such as ultimate force, that may reflect density and macrostructure rather than bone quality, showed male-specific defects only in STAT3-OKO-M. These findings suggest that STAT3 may regulate multiple sex-dependent mechanisms in bone development that control either mineralization or bone accrual, and that the sex-dependence of at least some of these mechanisms is affected by genetic background. Finally, we used CRISPR/Cas9 to generate STAT3-deficient preosteoblastic cells from immortalized wild-type bone marrow stem cells and showed that the defective osteoblastic differentiation of STAT3-ablated cells was associated with reduced gene expression of Wnt3a and Wnt5a, consistent with other studies that identify Wnt signaling pathways as potential effector mechanisms for STAT3-mediated regulation of bone development.https://doi.org/10.1371/journal.pone.0315078 |
| spellingShingle | Rebecca K Davidson Kylie Corry Amos Orlofsky Ping Li Caleb E Russell Amy Zhang Mariana Moraes de Lima Perini Carlie N Priddy Andrew V Nguyen Jiliang Li Loss of STAT3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development. PLoS ONE |
| title | Loss of STAT3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development. |
| title_full | Loss of STAT3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development. |
| title_fullStr | Loss of STAT3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development. |
| title_full_unstemmed | Loss of STAT3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development. |
| title_short | Loss of STAT3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development. |
| title_sort | loss of stat3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development |
| url | https://doi.org/10.1371/journal.pone.0315078 |
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