Unsuspected osteochondroma-like outgrowths in the cranial base of Hereditary Multiple Exostoses patients and modeling and treatment with a BMP antagonist in mice

Hereditary Multiple Exostoses (HME) is a rare pediatric disorder caused by loss-of-function mutations in the genes encoding the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2. HME is characterized by formation of cartilaginous outgrowths-called osteochondromas- next to the growth plates of m...

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Bibliographic Details
Published in:PLoS genetics 2017-04, Vol.13 (4), p.e1006742-e1006742
Main Authors: Sinha, Sayantani, Mundy, Christina, Bechtold, Till, Sgariglia, Federica, Ibrahim, Mazen M, Billings, Paul C, Carroll, Kristen, Koyama, Eiki, Jones, Kevin B, Pacifici, Maurizio
Format: Article
Language:English
Subjects:
Aggrecan
AKT protein
Analysis
Animal models
Animals
Antagonists (Biochemistry)
Apert's syndrome
Arthritis
Benign
Biochemistry
Biology and Life Sciences
Bone diseases
Bone morphogenetic proteins
Bone Morphogenetic Proteins - genetics
Bone Morphogenetic Proteins - metabolism
Bone tumors
Cancer
Care and treatment
Cartilage
CAT scans
Cervical Cord - metabolism
Cervical Cord - pathology
Children
Chin
Chondrogenesis - genetics
Colleges & universities
Disease Models, Animal
Ectopic expression
Electronic mail systems
Embryo cells
Embryonic Development - genetics
Enzymes
Exostoses, Multiple Hereditary - diagnostic imaging
Exostoses, Multiple Hereditary - drug therapy
Exostoses, Multiple Hereditary - genetics
Exostoses, Multiple Hereditary - pathology
Genetic aspects
Growth Plate - metabolism
Growth Plate - pathology
Health aspects
Heart diseases
Heparan sulfate
Heparitin Sulfate - biosynthesis
Hereditary diseases
Hereditary multiple exostoses
Humans
Kinases
Lesions
Magnetic Resonance Imaging
Medicine and Health Sciences
Mice
Mice, Knockout
Mutation
N-Acetylglucosaminyltransferases - genetics
Osteoblastogenesis
Osteochondroma
Osteochondroma - diagnostic imaging
Osteochondroma - genetics
Osteochondroma - pathology
Pain
Patients
Pediatrics
Plates (structural members)
Pyrazoles - administration & dosage
Pyrimidines - administration & dosage
Research and Analysis Methods
Rodents
Skeleton
Skin diseases
Skull
Smad1 Protein - genetics
Spine
Stem cells
Surgery
Tomography, Emission-Computed
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Summary:Hereditary Multiple Exostoses (HME) is a rare pediatric disorder caused by loss-of-function mutations in the genes encoding the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2. HME is characterized by formation of cartilaginous outgrowths-called osteochondromas- next to the growth plates of many axial and appendicular skeletal elements. Surprisingly, it is not known whether such tumors also form in endochondral elements of the craniofacial skeleton. Here, we carried out a retrospective analysis of cervical spine MRI and CT scans from 50 consecutive HME patients that included cranial skeletal images. Interestingly, nearly half of the patients displayed moderate defects or osteochondroma-like outgrowths in the cranial base and specifically in the clivus. In good correlation, osteochondromas developed in the cranial base of mutant Ext1f/f;Col2-CreER or Ext1f/f;Aggrecan-CreER mouse models of HME along the synchondrosis growth plates. Osteochondroma formation was preceded by phenotypic alteration of cells at the chondro-perichondrial boundary and was accompanied by ectopic expression of major cartilage matrix genes -collagen 2 and collagen X- within the growing ectopic masses. Because chondrogenesis requires bone morphogenetic protein (BMP) signaling, we asked whether osteochondroma formation could be blocked by a BMP signaling antagonist. Systemic administration with LDN-193189 effectively inhibited osteochondroma growth in conditional Ext1-mutant mice. In vitro studies with mouse embryo chondrogenic cells clarified the mechanisms of LDN-193189 action that turned out to include decreases in canonical BMP signaling pSMAD1/5/8 effectors but interestingly, concurrent increases in such anti-chondrogenic mechanisms as pERK1/2 and Chordin, Fgf9 and Fgf18 expression. Our study is the first to reveal that the cranial base can be affected in patients with HME and that osteochondroma formation is amenable to therapeutic drug intervention.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006742