Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients.
Multiple hereditary exostoses (MHE) is an autosomal dominant skeletal disorder caused by mutations in one of the two EXT genes and characterized by multiple osteochondromas that generally arise near the ends of growing long bones. Defective endochondral ossification is likely to be involved in the formation of osteochondromas. In order to investigate potential changes in chondrocyte proliferation and/or differentiation during this process, osteochondroma samples from MHE patients were obtained and used for genetic, morphological, immunohistological, and in situ hybridization studies. The expression patterns of IHH (Indian hedgehog) and FGFR3 (Fibroblast Growth Factor Receptor 3) were similar with transcripts expressed throughout osteochondromas. Expression of PTHR1 (Parathyroid Hormone Receptor 1) transcripts was restricted to a narrow zone of prehypertrophic chondrocytes. Numerous cells forming osteochondromas although resembling prehypertrophic chondrocytes, stained positively with an anti-proliferating cell nuclear antigen (PCNA) antibody. In addition, ectopic expression of collagen type I and abnormal presence of osteocalcin (OC), osteopontin (OP), and bone sialoprotein (BSP) were observed in the cartilaginous osteochondromas. These data indicate that most chondrocytes involved in the growth of osteochondromas can proliferate, and that some of them exhibit bone-forming cell characteristics. We conclude that in MHE, defective heparan sulfate biosynthesis caused by EXT mutations maintains the proliferative capacity of chondrocytes and promotes phenotypic modification to bone-forming cells.
Benoist-Lasselin
Catherine
C
INSERM U393, Hôpital des Enfants Malades, and Université Paris, France.
de Margerie
Emmanuel
E
Gibbs
Linda
L
Cormier
Sarah
S
Silve
Caroline
C
Nicolas
Gisèle
G
LeMerrer
Martine
M
Mallet
Jean-Francois
JF
Munnich
Arnold
A
Bonaventure
Jacky
J
Zylberberg
Louise
L
Legeai-Mallet
Laurence
L
D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D019902:Chondrocytes / Q000473:pathology* / Q000648:ultrastructure; D024042:Collagen Type I / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005097:Exostoses, Multiple Hereditary / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D058574:Integrin-Binding Sialoprotein; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D015675:Osteocalcin / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012795:Sialoglycoproteins / Q000378:metabolism
D014408:Biomarkers, Tumor; D024042:Collagen Type I; C546871:IBSP protein, human; D058574:Integrin-Binding Sialoprotein; D018809:Proliferating Cell Nuclear Antigen; D012795:Sialoglycoproteins; D015675:Osteocalcin; D004247:DNA