FGF signaling deregulation is associated with early developmental skeletal defects in animal models for mucopolysaccharidosis type II (MPSII)

Stefania Bellesso, Marika Salvalaio, Susanna Lualdi, Elisa Tognon, Roberto Costa, Paola Braghetta, Chiara Giraudo, Roberto Stramare, Laura Rigon, Mirella Filocamo, Rosella Tomanin, Enrico Moro

Research output: Contribution to journalArticlepeer-review

Abstract

Skeletal abnormalities represent a major clinical burden in patients affected by the lysosomal storage disorder mucopolysaccharidosis type II (MPSII, OMIM #309900). While extensive research has emphasized the detrimental role of stored glycosaminoglycans (GAGs) in the bone marrow (BM), a limited understanding of primary cellular mechanisms underlying bone defects in MPSII has hampered the development of bone-targeted therapeutic strategies beyond enzyme replacement therapy (ERT). We here investigated the involvement of key signaling pathways related to the loss of iduronate-2-sulfatase activity in two different MPSII animal models, D. rerio and M. musculus. We found that FGF pathway activity is impaired during early stages of bone development in IDS knockout mice and in a newly generated Ids mutant fish. In both models the FGF signaling deregulation anticipated a slow but progressive defect in bone differentiation, regardless of any extensive GAGs storage. We also show that MPSII patient fibroblasts harboring different mutations spanning the IDS gene exhibit perturbed FGF signaling-related markers expression. Our work opens a new venue to discover possible druggable novel key targets in MPSII.

Original languageEnglish
Pages (from-to)2262-2275
Number of pages14
JournalHuman Molecular Genetics
Volume27
Issue number13
DOIs
Publication statusPublished - Jul 1 2018

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