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Toward an Understanding of the Short Bone Phenotype Associated with Multiple Osteochondromas

Institution:
1Sarcoma Services, Department of Orthopaedics and Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
2Department of Human Genetics, Howard Hughes Medical Institute, University of Utah, 15 North 2030 East Room 5440, Salt Lake City, UT, USA.
3Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, USA.
4School of Computing, University of Utah, Salt Lake City, UT, USA.
Publisher:
John Wiley & Sons, Inc.
Publication Date:
Apr-2013
Journal:
J Orthop Res
Volume Number:
31
Issue Number:
4
Pages:
651-7
Citation:
J Orthop Res. 2013 Apr;31(4):651-7.
PubMed ID:
23192691
PMCID:
PMC3683979
Keywords:
osteochondroma, exostosis, skeletal dysplasias, mouse genetic models, shape analysis
Appears in Collections:
NA-MIC
Sponsors:
P41 RR012553/RR/NCRR NIH HHS/United States
P41 GM103545/GM/NIGMS NIH HHS/United States
K08 CA138764/CA/NCI NIH HHS/United States
R01 GM021168/GM/NIGMS NIH HHS/United States
U54 EB005149/EB/NIBIB NIH HHS/United States
Generated Citation:
Jones K.B., Datar M., Ravichandran S., Jin H., Jurrus E., Whitaker R., Capecchi M.R. Toward an Understanding of the Short Bone Phenotype Associated with Multiple Osteochondromas. J Orthop Res. 2013 Apr;31(4):651-7. PMID: 23192691. PMCID: PMC3683979.
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Individuals with multiple osteochondromas (MO) demonstrate shortened long bones. Ext1 or Ext2 haploinsufficiency cannot recapitulate the phenotype in mice. Loss of heterozygosity for Ext1 may induce shortening by steal of longitudinal growth into osteochondromas or by a general derangement of physeal signaling. We induced osteochondromagenesis at different time points during skeletal growth in a mouse genetic model, then analyzed femora and tibiae at 12 weeks using micro-CT and a point-distribution-based shape analysis. Bone lengths and volumes were compared. Metaphyseal volume deviations from normal, as a measure of phenotypic widening, were tested for correlation with length deviations. Mice with osteochondromas had shorter femora and tibiae than controls, more consistently when osteochondromagenesis was induced earlier during skeletal growth. Volumetric metaphyseal widening did not correlate with longitudinal shortening, although some of the most severe shortening was in bones with abundant osteochondromas. Loss of heterozygosity for Ext1 was sufficient to drive bone shortening in a mouse model of MO, but shortening did not correlate with osteochondroma volumetric growth. While a steal phenomenon seems apparent in individual cases, some other mechanism must also be capable of contributing to the short bone phenotype, independent of osteochondroma formation. Clones of chondrocytes lacking functional heparan sulfate must blunt physeal signaling generally, rather than stealing growth potential focally.

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