Bone Homeostasis as a Multifaceted Puzzle: from WNT Ligands to Metal-ion Transporters
26 April 2017
UAntwerp, Campus Drie Eiken, Building Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken
4:00 PM - 6:00 PM
Wim Van Hul
PhD defence Gretl Hendrickx - Department of Biomedical Sciences
Bone homeostasis is a process characterized by the constant and lifelong remodeling of bone tissue to sustain bone mineral density (BMD) and quality. Here, mainly genetic factors contribute to the determination of BMD, which is why genetic variation also contributes to the development of skeletal pathologies characterized by a too low or high BMD. Osteoporosis is the most prevalent skeletal disorder, characterized by a low BMD and an increased fracture risk and with a complex genetic background. Just as well, there are rare monogenic bone disorders with deviating BMD values caused by only one mutation with a large impact on the skeleton. Studying BMD and bone homeostasis by means of different genetic skeletal disorders was already proven to be an efficient strategy. The aim of this thesis was therefore to further elucidate the regulation of BMD by performing genetic and functional research on two different bone disorders; osteoporosis and Hyperostosis Cranialis Interna.
Osteoporosis was investigated through the study of WNT4, WNT5B and WNT16, three genes previously associated with BMD and all part of the WNT signaling pathway. First, a candidate gene association study of WNT16 identified additional associations with BMD at distinct skeletal sites. Further genetic screening of WNT16 in two populations with deviating BMD values detected a functional variant in the Kozak consensus sequence of WNT16, resulting in a higher translation efficiency and associated with a higher BMD. A follow-up functional study investigating the mechanism of action of WNT16 on the WNT signaling pathway demonstrated differential actions of WNT16 in different cell types and a possible orchestrating role for Gα subunits herein. In contrast to WNT16, genetic screening of WNT4 and WNT5B did not reveal interesting variants for further analysis.
In the second part of this thesis, we investigated Hyperostosis Cranialis Interna (HCI), a rare and monogenic bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified a mutation (p.L441R) in SLC39A14 (ZIP14), encoding a zinc transporter. We show that p.L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc. Conditional knock-in mice overexpressing p.L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, p.L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of p.L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.
In conclusion, by investigating two different bone disorders, we contributed to the genetic knowledge on BMD. Functional studies towards the mechanisms of action of WNT16 and ZIP14 additionally led to novel insights in the multifaceted process of bone homeostasis.