THE ROLE OF PROTEOGLYCAN SULFATION IN SKELETAL DEVELOPMENT AND MAINTENANCE: AN IN VIVO APPROACH WITH A MOUSE MODEL OF DIASTROPHIC DYSPLASIA

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene cause a family of recessive diseases including in order of increasing severity a form of multiple ephiphyseal dysplasia, diastrophic dysplasia (DTD), atelosteogenesis type 2 and achondrogenesis 1B. The main biochemical consequence of sulfate transport impairment is cartilage proteoglycan (PG) undersulfation that affect skeletal development and growth. We have recently generated the first mouse strain (dtd mouse) with a mutation in the Dtdst gene previously identified in a DTD patient with marked short stature, bilateral clubfoot, characteristic hand deformities, progressive kyphoscoliosis and joint stiffness and we have demonstrated that this mouse model reproduces at the clinical, morphological and biochemical level the skeletal phenotype of human DTD. Biochemical studies performed so far have suggested that any terapy aimed at normal sulfate level restoration might be useful to ameliorate patient conditions. The dtd mouse strain we have generated is a useful tool to explore pathogenetic and therapeutic aspects of DTDST disorders which can not be obtained for ethical reasons in humans. The objective of the proposal are: a) how PG undersulfation affects chondrocyte proliferation and differentiation in the growth plate, b) how PG undersulfation causes an osteopenic phenotype, c) the role of heparan sulfate PGs in FGF signaling, d) other pathways of sulfate recruitment to increase PG sulfation. These studies will allow a better understanding of the molecular basis of DTDST chondrodysplasias and the development of new strategies of pharmacological treatment considering the starting age of tissue alteration and the specific area of the tissue (different zones of the growth plate) to be targeted by the drug.