Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome

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Hereditary Multiple Exostoses (HME) is a rare autosomal dominant disorder that affects about 1 in 50,000 children worldwide. HME is characterized by cartilaginous tumors called exostoses that form in perichondrial cells along the growth plates and protrude into surrounding tissues. The exostoses can thus cause skeletal deformities, compression of nerves and blood vessels, chronic pain, and become malignant in about 5% of the patients. Current therapies are limited, and patients struggle with pain and limited mobility and undergo multiple surgeries through life. Most HME patients bear a heterozygous mutation in EXT1 or EXT2 that are responsible for heparan sulfate (HS) synthesis, thus causing a partial systemic HS deficiency. The HS chains - and the proteoglycans of which they are part- regulate and distinctly modulate many processes. Notably, they interact with and stimulate signaling by fibroblast growth factors, but interact and inhibit signaling by bone morphogenetic proteins. FGFs and BMPs generally exert anti- and pro-chondrogenic roles, respectively. However, it was unclear whether HS partial decrease is sufficient for exostosis formation, whether HS loss reverses those signaling activities –thus decreasing FGF and increasing BMP signaling-, and whether such changes induce exostosis formation. In the previous funding period, we made significant progress. We created Ext1+/-, double Ext1+/-;Ext2+/- and conditional Ext1-null mice. While single het mice were largely normal, double hets and conditional-null mice (both producing far less HS) displayed multiple exostoses and mimicked human HME. Exostosis development was preceded by local decreased levels of FGF signal transducers pMEK/pERK and increased levels of BMP signaling mediators pSmad1/5/8. In vitro studies reinforced these findings. Counter-intuitively, the HS deficiency also stimulated endogenous heparanase expression, likely enhancing chondrogenesis even further. Indeed, treatment with recombinant heparanase stimulated BMP signaling and chondrogenesis, while the heparanase inhibitor Roneparstat blocked both. Our central hypothesis is that exostosis formation is caused by: (i) a steep local deficiency in HS; (ii) decreased FGF signaling and increased BMP signaling; and (iii) a boost in chondrogenic potentials in mutant cells along the chondro-perichondrial border. We posit also that exostosis formation is preventable by drug treatment. The project will continue to provide fundamentally new insights into the cellular and molecular mechanisms of exostosis formation and by extension on the normal functioning of these mechanisms in normal perichondrial and growth plate cells. It will also test possible therapies based on those insights and thus has strong basic research value and translational medicine implications. The number of HME patients is relatively small, but the community of their families is large. This project will thus provide a renewed sense of hope to patients and families alike that this neglected disease will continue to be actively studied and a cure may one day be found.