title: Toward an understanding of the short bone phenotype associated with multiple osteochondromas.
abstract: 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.
authors.affiliation: Sarcoma 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.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jones
authors.forename: Manasi
authors.initials: M
authors.lastname: Datar
authors.forename: Sandhya
authors.initials: S
authors.lastname: Ravichandran
authors.forename: Huifeng
authors.initials: H
authors.lastname: Jin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jurrus
authors.forename: Ross
authors.initials: R
authors.lastname: Whitaker
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004318:Doxycycline; D005097:Exostoses, Multiple Hereditary / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D005269:Femur / Q000473:pathology; D006132:Growth Plate; D057895:Haploinsufficiency; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010641:Phenotype; D013977:Tibia / Q000473:pathology; D000099058:Exostosin 1
chemical_list: D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1; D004318:Doxycycline