Pathogenesis of MHE: Recent advances and prospects for therapies

Abstract

Multiple hereditary exostoses (MHE) is a congenital autosomal-dominant disorder caused by mutations in the Golgi-associated heparan sulfate (HS)-synthesizing enzymes, EXT1 or EXT2, leading to HS deficiency throughout the body. The disease is characterized by the presence of exostoses (known also as osteochondromas) that are cartilage-capped outgrowths forming next to, but never within, the growth plates of limb and trunk skeletal elements. The exostoses interfere with growth plate function and the MHE children could display growth retardation and skeletal deformities, as well as chronic pain, impingement of nerves and tendons, urinary obstruction, or other symptoms. To elucidate the mechanisms of exostosis formation and growth, we have created mouse models in which Ext1 or Ext2 were ablated broadly or conditionally. We will describe published and unpublished data from our recent studies that provide insights into the genesis and preferential anatomical location of the exostoses in the growing skeleton. In particular, the data suggest that the exostoses are triggered by a redistribution and aberrant activation of prochondrogenic signaling proteins within the growth plate and/or adjacent perichondrium, with the possible involvement and recruitment of local progenitor cells including those in the groove of Ranvier. We will also present data from in vitro cellular studies that provide insights into underlying biochemical and molecular mechanisms. Our studies are leading to a better understanding of MHE pathogenesis and point to prospects for possible future therapies.