Multiple hereditary exostoses (MHE) is an autosomal dominant bone disorder caused by heterozygous mutations of EXT1 or EXT2, which jointly encode a glycosyltransferase essential for heparan sulfate biosynthesis. MHE is the most common genetic bone dysplasia and thought to affect several thousand Americans. During the current funding cycle, we elucidated a long- standing puzzle concerning the genetic mechanism of MHE. Specifically, we demonstrated that loss of heterozygosity modeled via stochastic conditional knockout results in the recapitulation of essentially all human MHE phenotypes. Based on this achievement and novel questions revealed by these studies, we will explore further this debilitating disease, with goals of understanding its complete pathogenic mechanism and identifying novel biomarkers and potential therapeutic targets. We propose the following aims. 1. Determine the origin of osteochondroma: While our studies elucidated the genetic mechanisms of osteochondromatogenesis, the cellular mechanisms by which a small number of Ext1 null cells develop into osteochondromas remains almost entirely elusive. One of the critical issues is whether osteochondromas are originated either from growth plate chondrocytes or from the perichondrium. We will perform perichondrium-specific Ext1 knockout and the analysis of perichondrial progenitor cells lacking Ext1 to address this issue. 2. Determine the affected signaling pathway that is critical for osteochondromatogenesis: Another critical issue is what is the defective signaling pathway directly responsible for osteochondromatogenesis. Based on strong preliminary evidence, we will focus on the BMP pathway and determine whether aberrant BMP signaling is the main molecular culprit underlying the disease. 3. Genome-wide analysis of osteochondroma transcriptome: We will perform a state-of-the-art bioinformatics study to determine transcriptomic changes that define osteochondroma. By applying the weighted gene coexpression network analysis on RNA microarray data sets, we will identify molecular signatures that distinguish osteochondroma from normal chondrocytes and potential genetic biomarkers to predict the future severity and recurrence of osteochondroma in MHE patients.

Public Health Relevance

Multiple hereditary exostoses (MHE) is a highly debilitating genetic bone disorder affecting several thousands of people in the US, which is caused by genetic defects in heparan sulfate synthesis. This research seeks to elucidate the pathogenic mechanisms of MHE and to identify molecular signatures that correlate with the severity of the disease. This research is highly relevant to public health because it seeks to identify biomarkers and potential therapeutic targets for MHE. Additionally, this research can provide novel insight into other bone diseases, such as solitary osteochondroma, fibrodysplasia ossificans progressiva (FOP), and osteoporosis, in which heparan sulfate is also thought to play a role in their pathogenesis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Tyree, Bernadette
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Inubushi, Toshihiro; Nozawa, Satoshi; Matsumoto, Kazu et al. (2017) Aberrant perichondrial BMP signaling mediates multiple osteochondromagenesis in mice. JCI Insight 2:
Saez, Borja; Ferraro, Francesca; Yusuf, Rushdia Z et al. (2014) Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood 124:2937-47
Huegel, Julianne; Mundy, Christina; Sgariglia, Federica et al. (2013) Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in Hereditary Multiple Exostoses. Dev Biol 377:100-12
Mundy, Christina; Yasuda, Tadashi; Kinumatsu, Takashi et al. (2011) Synovial joint formation requires local Ext1 expression and heparan sulfate production in developing mouse embryo limbs and spine. Dev Biol 351:70-81
Ogata-Iwao, Minako; Inatani, Masaru; Iwao, Keiichiro et al. (2011) Heparan sulfate regulates intraretinal axon pathfinding by retinal ganglion cells. Invest Ophthalmol Vis Sci 52:6671-9
Zak, Beverly M; Schuksz, Manuela; Koyama, Eiki et al. (2011) Compound heterozygous loss of Ext1 and Ext2 is sufficient for formation of multiple exostoses in mouse ribs and long bones. Bone 48:979-87
Matsumoto, Kazu; Irie, Fumitoshi; Mackem, Susan et al. (2010) A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses. Proc Natl Acad Sci U S A 107:10932-7
Matsumoto, Yoshihiro; Matsumoto, Kazu; Irie, Fumitoshi et al. (2010) Conditional ablation of the heparan sulfate-synthesizing enzyme Ext1 leads to dysregulation of bone morphogenic protein signaling and severe skeletal defects. J Biol Chem 285:19227-34
Matsumoto, Kazu; Li, Yingcui; Jakuba, Caroline et al. (2009) Conditional inactivation of Has2 reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb. Development 136:2825-35