Heparan Sulfate in Skeletal Development and Diseases

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): 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.