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Conference Paper: Genetic control of hypertrophic chondrocyte to osteoblast differentiation in development and skeletal disorders

TitleGenetic control of hypertrophic chondrocyte to osteoblast differentiation in development and skeletal disorders
Authors
KeywordsBiology
Issue Date2016
PublisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/
Citation
The 2016 Annual Meeting of the American Association of Anatomists (AAA) at Experimental Biology (EB) 2016, San Diego, CA., 2-5 April 2016. In FASEB Journal, 2016, v. 80 n. 1 suppl., abstract no. 223.2 How to Cite?
AbstractMaintenance of bone throughout life requires continuous renewal of osteoblasts (Ob). Osteoblasts, originating from the perichondrium, accompany vascular invasion and lay down endochondral bone to replace cartilage. Using a genetic recombination lineage tracing approach in mice, we showed recently that hypertrophic chondrocytes (HCs), rather than being terminally differentiated cells fated to undergo apoptosis, can become osteogenic cells in fetal and postnatal endochondral bones and persist into adulthood. Moreover, the chondrocyte-to-osteoblast transition also occurs in bone repair. However, how the transition of HCs to osteoblasts is controlled molecularly, and the contribution of dysfunction in this process to skeletal dysplasia is not known. Heterozygous human SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia (CD). Complete inactivation of the Sox9 gene in mice results in failure of cartilage formation, presumably because of failure to express SOX9 target genes such as extracellular matrix genes, Col2a1, Col9a1, Col11a2 and aggrecan. Because all the SOX9 mutations are heterozygous, are distributed throughout the gene and appear to cause loss of function, the CD phenotype has been attributed to haploinsufficiency of SOX9. However SOX9 proteins containing an intact HMG box and a truncated activation domain may act as dominant negatives by competition with the wild-type for binding to target genes and interfere with interaction with partner factors via the transactivation domain. The mutant proteins may also gain new function (neomorphic). We aimed to understand the underlying mechanism whereby such mutations in SOX9 cause CD and asked whether the HC to Ob transition is compromised as part of the disease pathogenesis. To address these questions, we generated a conditional mouse model of CD by knocking-in a mouse equivalent of the human CD SOX9 Y440X nonsense mutation (Sox9Y440X), leading to truncation of the protein in the transactivation domain. We found that heterozygous Sox9Y440X/+ mice, display the phenotypic hallmarks of human CD, such as skeletal malformation, inner ear defects, except sex reversal. We compared the phenotypes of mice heterozygous for the Sox9Y440X and for the null allele. We found that Sox9Y440X heterozygous mutants displayed a more severe skeletal phenotype especially with respect to campomelia (bowing of limbs) than in Sox9−/+ mice. Since Sox9 is known to inhibit chondrocyte hypertrophy and osteoblast differentiation, we asked whether the chondrocyte to osteoblast transition is affected in the CD mutants. Molecular phenotyping and lineage tracing experiments implicate abnormality in HH signaling in CD mutants that impacts on the HC to osteoblast transition resulting in abnormal osteogenesis that underlies the campomelia phenotype. (This abstract is from the Experimental Biology 2016 Meeting. There is no full text article associated with this abstract published in The FASEB Journal)
DescriptionSession: Anatomy - The Fate of the Chondrocyte in Development, Regeneration, and Disease
Persistent Identifierhttp://hdl.handle.net/10722/225582
ISSN
2015 Impact Factor: 5.299
2015 SCImago Journal Rankings: 2.775

 

DC FieldValueLanguage
dc.contributor.authorCheah, KSE-
dc.contributor.authorAu, TYK-
dc.contributor.authorWynn, S-
dc.contributor.authorTan, T-
dc.contributor.authorYip, KHR-
dc.contributor.authorChan, D-
dc.date.accessioned2016-05-20T08:09:06Z-
dc.date.available2016-05-20T08:09:06Z-
dc.date.issued2016-
dc.identifier.citationThe 2016 Annual Meeting of the American Association of Anatomists (AAA) at Experimental Biology (EB) 2016, San Diego, CA., 2-5 April 2016. In FASEB Journal, 2016, v. 80 n. 1 suppl., abstract no. 223.2-
dc.identifier.issn0892-6638-
dc.identifier.urihttp://hdl.handle.net/10722/225582-
dc.descriptionSession: Anatomy - The Fate of the Chondrocyte in Development, Regeneration, and Disease-
dc.description.abstractMaintenance of bone throughout life requires continuous renewal of osteoblasts (Ob). Osteoblasts, originating from the perichondrium, accompany vascular invasion and lay down endochondral bone to replace cartilage. Using a genetic recombination lineage tracing approach in mice, we showed recently that hypertrophic chondrocytes (HCs), rather than being terminally differentiated cells fated to undergo apoptosis, can become osteogenic cells in fetal and postnatal endochondral bones and persist into adulthood. Moreover, the chondrocyte-to-osteoblast transition also occurs in bone repair. However, how the transition of HCs to osteoblasts is controlled molecularly, and the contribution of dysfunction in this process to skeletal dysplasia is not known. Heterozygous human SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia (CD). Complete inactivation of the Sox9 gene in mice results in failure of cartilage formation, presumably because of failure to express SOX9 target genes such as extracellular matrix genes, Col2a1, Col9a1, Col11a2 and aggrecan. Because all the SOX9 mutations are heterozygous, are distributed throughout the gene and appear to cause loss of function, the CD phenotype has been attributed to haploinsufficiency of SOX9. However SOX9 proteins containing an intact HMG box and a truncated activation domain may act as dominant negatives by competition with the wild-type for binding to target genes and interfere with interaction with partner factors via the transactivation domain. The mutant proteins may also gain new function (neomorphic). We aimed to understand the underlying mechanism whereby such mutations in SOX9 cause CD and asked whether the HC to Ob transition is compromised as part of the disease pathogenesis. To address these questions, we generated a conditional mouse model of CD by knocking-in a mouse equivalent of the human CD SOX9 Y440X nonsense mutation (Sox9Y440X), leading to truncation of the protein in the transactivation domain. We found that heterozygous Sox9Y440X/+ mice, display the phenotypic hallmarks of human CD, such as skeletal malformation, inner ear defects, except sex reversal. We compared the phenotypes of mice heterozygous for the Sox9Y440X and for the null allele. We found that Sox9Y440X heterozygous mutants displayed a more severe skeletal phenotype especially with respect to campomelia (bowing of limbs) than in Sox9−/+ mice. Since Sox9 is known to inhibit chondrocyte hypertrophy and osteoblast differentiation, we asked whether the chondrocyte to osteoblast transition is affected in the CD mutants. Molecular phenotyping and lineage tracing experiments implicate abnormality in HH signaling in CD mutants that impacts on the HC to osteoblast transition resulting in abnormal osteogenesis that underlies the campomelia phenotype. (This abstract is from the Experimental Biology 2016 Meeting. There is no full text article associated with this abstract published in The FASEB Journal)-
dc.languageeng-
dc.publisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/-
dc.relation.ispartofThe FASEB Journal-
dc.subjectBiology-
dc.titleGenetic control of hypertrophic chondrocyte to osteoblast differentiation in development and skeletal disorders-
dc.typeConference_Paper-
dc.identifier.emailCheah, KSE: hrmbdkc@hku.hk-
dc.identifier.emailAu, TYK: tiffany_au@hku.hk-
dc.identifier.emailChan, D: chand@hku.hk-
dc.identifier.authorityCheah, KSE=rp00342-
dc.identifier.authorityChan, D=rp00540-
dc.identifier.hkuros257758-
dc.identifier.hkurosROS 257761-
dc.identifier.volume80-
dc.identifier.issue1 suppl.-
dc.publisher.placeUnited States-

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