Toward an understanding of the short bone phenotype associated with multiple osteochondromas

Abstract

Purpose 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. Methods 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 correlated with length deviations. Results 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 bone with abundant osteochondromas. Conclusions 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.

Heparan sulfate in skeletal development, growth, and pathology: The case of hereditary multiple exostoses

“…However, recent experiments show no change in overall bone volume and no correlation between forearm shortening and the presence of an osteochondroma. This work indicates that HS loss may be important for directing the ratio between peripheral and longitudinal growth (Jones et al, ). Exostoses can also sometimes occur in craniofacial elements such as the mandible (Ruiz and Lara, ).…”

Cell biology of osteochondromas: Bone morphogenic protein signalling and heparan sulphates

“…This gave rise to frequent osteochondromas on the appendicular skeleton, indicating that LOH is the inductive event for osteochondroma [17]. In addition, low-prevalence LOH for Ext1 in physeal chondrocytes was enough to mimic a short-bone phenotype, indicating that LOH drives the short-bone phenotypes associated with MHE [16]. Furthermore, the model indicated that the physeal chondrocyte is the cell of osteochondroma origin, rather than the ossification groove of Ranvier as was previously speculated [17].…”

Skeletal maturity of children with multiple osteochondromas: Is diminished stature due to a systemic influence?

“…More and bigger osteochondromas means more severe MO and thus more influence of the gene dysfunction on the biochemical setup. A mouse study by Jones also does not support the relationship between the volume of osteochondromas and the growth plate influence [ 32 ].…”

“…Several studies have described the systemic influence of the gene defect and its relationship with the growth plate as a possible cause of the short or diminished stature. Jones et al [ 32 ] demonstrated in a mouse genetic model that mice with osteochondromas had shorter femora and tibiae than controls. The volume of the osteochondromas, however, did not correlate with longitudinal shortening.…”