Genetic and functional study of LRP4 and the R-spondins in bone formation

Date: 4 May 2016

Venue: UAntwerp, Campus Drie Eiken, Building Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerp)

Time: 4:00 PM - 6:00 PM

PhD candidate: Igor Fijalkowski

Principal investigator: Wim Van Hul

Co-principal investigator: Eveline Boudin

Short description: PhD defence Igor Fijalkowski - Department of Biomedical Sciences



Abstract

Osteoporosis is the most common disease affecting human bone and represents a major socioeconomic burden to our society. Fractures are the most prominent outcome of osteoporosis as illustrated by the occurrence of nearly 1000 osteoporotic fractures per hour worldwide.

A great majority of currently available osteoporosis treatments focus on lowering bone resorption rates, thus preventing further bone loss. However as bone resorption remains tightly linked to bone formation, all these drugs ultimately lead to a decrease in production of new bone, among other side-effects. In light of these facts, major scientific effort was devoted to the search of novel anabolic treatment targets, stimulating bone formation and reversing the bone loss that already occurred. Over the years, the studies of rare bone disorders have contributed greatly to our understanding of skeletal biology and indicated numerous promising targets for the treatment of osteoporosis.

The aim of this thesis was to further investigate the genes involved in the pathogenesis of different osteochondrodysplasias in order to provide novel insights into the biology of human bone and to identify potential targets for the development of novel treatments of common bone diseases.

In this thesis, the involvement of several Wnt signaling modulators, namely LRP4 and the R-spondins in the bone biology is studied. We identified a novel mutation in LRP4 as causative for sclerosteosis in a Portuguese patient and functionally evaluated the proteins involvement in the regulation of canonical Wnt signaling. We investigated the mechanistic grounds of sclerosteosis and Cenani-Lenz syndrome providing genotype-phenotype correlation for different types of LRP4 mutations. Moreover, we performed a mutation analysis of the R-spondin genes in a population of patients suffering from different forms of craniotubular hyperostosis. We evaluated the expression profile of all R-spondin genes during osteoblastogenesis and performed an association study between common variations in these genes and bone mineral density in the healthy population. Lastly, we investigated a novel family suffering from facioaudiosymphalangism syndrome where we identified a novel mutation in the gene encoding noggin as causative for the observed phenotype.

Taken together, we believe that our studies provided novel insights into the pathogenesis of several osteochondrodysplasias and indicated LRP4 as a potent drug target to be used in future treatments of osteoporosis. Moreover, this project led to the generation of a novel murine in vivo model that will likely contribute to the elucidation of the LRP4 function in bone biology.