Yunfei Wang, Ling Wu, Sujing Zong, Pengcui Li, Lixun Chai, Li Guo, Xinping Chen, Shiping Yu, Jian Sun
{"title":"肢体间充质组蛋白脱乙酰酶4对软骨细胞增殖、生长板维持和正常骨形成至关重要。","authors":"Yunfei Wang, Ling Wu, Sujing Zong, Pengcui Li, Lixun Chai, Li Guo, Xinping Chen, Shiping Yu, Jian Sun","doi":"10.1080/03008207.2025.2530045","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of well-ordered chondrocyte proliferation and differentiation leads to distorted architecture of the growth plate, resulting in skeletal dysplasia with impaired longitudinal bone growth. Histone deacetylase 4 (HDAC4) is essential for chondrocyte hypertrophy and endochondral bone formation, but its role in postnatal bone development remains unexplored due to early lethality in Hdac4-ablated mice. Furthermore, a direct in vivo effect of Hdac4 on mesenchymal cell specification and bone development has not been investigated.</p><p><strong>Methods: </strong>We generated <i>Prx1-Cre;Hdac4<sup>fl/fl</sup>, Sp7-Cre;Hdac4<sup>fl/fl</sup>, Acan-CreERT2;Hdac4<sup>fl/fl</sup></i>, and <i>Hdac4<sup>fl/fl</sup></i> transgenic mice, respectively. The genotyping of transgenic mice was performed via conventional PCR. Whole-body radiographs and x-ray analyses of limbs were conducted. Trabecular and cortical bone microstructures of tibias from 21-day-old mice were evaluated using micro-computed tomography. EdU label-retention assay investigated cell proliferation, while histological analyses included H&E, TRAP, and Von Kossa staining. RT-qPCR and Immunohistochemistry to detect the pro-osteogenic function of HDAC4.</p><p><strong>Results: </strong>Hdac4 inactivation in limb mesenchyme cells resulted in limb shortening, premature growth plate closure, abnormal bone morphologies, and loss of the rounded articular surface. HDAC4 was crucial for regulating chondrocyte proliferation and secondary ossification center formation. Micro-computed tomography showed increased trabecular and cortical bone <i>Prx1-Cre;Hdac4<sup>fl/fl</sup></i> mice at 3 weeks, with altered microarchitecture. .</p><p><strong>Conclusion: </strong>Hdac4 in limb mesenchymal cells plays an indispensable role in chondrocyte proliferation, maintenance of the growth plate and formation of secondary ossification centers, its pro-osteogenic role was accomplished through premature differentiation of chondrocytes, along with accelerated cartilage-to-bone conversion.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"1-18"},"PeriodicalIF":2.1000,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Histone deacetylase 4 in limb mesenchyme is essential for chondrocyte proliferation, growth plate maintenance and proper bone formation.\",\"authors\":\"Yunfei Wang, Ling Wu, Sujing Zong, Pengcui Li, Lixun Chai, Li Guo, Xinping Chen, Shiping Yu, Jian Sun\",\"doi\":\"10.1080/03008207.2025.2530045\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Dysregulation of well-ordered chondrocyte proliferation and differentiation leads to distorted architecture of the growth plate, resulting in skeletal dysplasia with impaired longitudinal bone growth. Histone deacetylase 4 (HDAC4) is essential for chondrocyte hypertrophy and endochondral bone formation, but its role in postnatal bone development remains unexplored due to early lethality in Hdac4-ablated mice. Furthermore, a direct in vivo effect of Hdac4 on mesenchymal cell specification and bone development has not been investigated.</p><p><strong>Methods: </strong>We generated <i>Prx1-Cre;Hdac4<sup>fl/fl</sup>, Sp7-Cre;Hdac4<sup>fl/fl</sup>, Acan-CreERT2;Hdac4<sup>fl/fl</sup></i>, and <i>Hdac4<sup>fl/fl</sup></i> transgenic mice, respectively. The genotyping of transgenic mice was performed via conventional PCR. Whole-body radiographs and x-ray analyses of limbs were conducted. Trabecular and cortical bone microstructures of tibias from 21-day-old mice were evaluated using micro-computed tomography. EdU label-retention assay investigated cell proliferation, while histological analyses included H&E, TRAP, and Von Kossa staining. RT-qPCR and Immunohistochemistry to detect the pro-osteogenic function of HDAC4.</p><p><strong>Results: </strong>Hdac4 inactivation in limb mesenchyme cells resulted in limb shortening, premature growth plate closure, abnormal bone morphologies, and loss of the rounded articular surface. HDAC4 was crucial for regulating chondrocyte proliferation and secondary ossification center formation. Micro-computed tomography showed increased trabecular and cortical bone <i>Prx1-Cre;Hdac4<sup>fl/fl</sup></i> mice at 3 weeks, with altered microarchitecture. .</p><p><strong>Conclusion: </strong>Hdac4 in limb mesenchymal cells plays an indispensable role in chondrocyte proliferation, maintenance of the growth plate and formation of secondary ossification centers, its pro-osteogenic role was accomplished through premature differentiation of chondrocytes, along with accelerated cartilage-to-bone conversion.</p>\",\"PeriodicalId\":10661,\"journal\":{\"name\":\"Connective Tissue Research\",\"volume\":\" \",\"pages\":\"1-18\"},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2025-07-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Connective Tissue Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/03008207.2025.2530045\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Connective Tissue Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/03008207.2025.2530045","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Histone deacetylase 4 in limb mesenchyme is essential for chondrocyte proliferation, growth plate maintenance and proper bone formation.
Background: Dysregulation of well-ordered chondrocyte proliferation and differentiation leads to distorted architecture of the growth plate, resulting in skeletal dysplasia with impaired longitudinal bone growth. Histone deacetylase 4 (HDAC4) is essential for chondrocyte hypertrophy and endochondral bone formation, but its role in postnatal bone development remains unexplored due to early lethality in Hdac4-ablated mice. Furthermore, a direct in vivo effect of Hdac4 on mesenchymal cell specification and bone development has not been investigated.
Methods: We generated Prx1-Cre;Hdac4fl/fl, Sp7-Cre;Hdac4fl/fl, Acan-CreERT2;Hdac4fl/fl, and Hdac4fl/fl transgenic mice, respectively. The genotyping of transgenic mice was performed via conventional PCR. Whole-body radiographs and x-ray analyses of limbs were conducted. Trabecular and cortical bone microstructures of tibias from 21-day-old mice were evaluated using micro-computed tomography. EdU label-retention assay investigated cell proliferation, while histological analyses included H&E, TRAP, and Von Kossa staining. RT-qPCR and Immunohistochemistry to detect the pro-osteogenic function of HDAC4.
Results: Hdac4 inactivation in limb mesenchyme cells resulted in limb shortening, premature growth plate closure, abnormal bone morphologies, and loss of the rounded articular surface. HDAC4 was crucial for regulating chondrocyte proliferation and secondary ossification center formation. Micro-computed tomography showed increased trabecular and cortical bone Prx1-Cre;Hdac4fl/fl mice at 3 weeks, with altered microarchitecture. .
Conclusion: Hdac4 in limb mesenchymal cells plays an indispensable role in chondrocyte proliferation, maintenance of the growth plate and formation of secondary ossification centers, its pro-osteogenic role was accomplished through premature differentiation of chondrocytes, along with accelerated cartilage-to-bone conversion.
期刊介绍：
The aim of Connective Tissue Research is to present original and significant research in all basic areas of connective tissue and matrix biology.
The journal also provides topical reviews and, on occasion, the proceedings of conferences in areas of special interest at which original work is presented.
The journal supports an interdisciplinary approach; we present a variety of perspectives from different disciplines, including
Biochemistry
Cell and Molecular Biology
Immunology
Structural Biology
Biophysics
Biomechanics
Regenerative Medicine
The interests of the Editorial Board are to understand, mechanistically, the structure-function relationships in connective tissue extracellular matrix, and its associated cells, through interpretation of sophisticated experimentation using state-of-the-art technologies that include molecular genetics, imaging, immunology, biomechanics and tissue engineering.
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