Altered bone formation response to mechanical loading in a mouse model of the progeroid disorder gerodermia osteodysplastica
Year: 2019
Type: dissertation
Abstract: Bone tissue has to constantly adapt to changing mechanical requirements. The mechanisms behind mechanosensation, mechanotransduction, signal transmission and the resulting response of bone tissue are, until this day not fully understood. A failure of these processes leads to inappropriate bone architecture, bone mass and reduced mechanical stability as seen in age-related osteoporosis or rare diseases such as osteogenesis imperfecta or gerodermia osteodysplastica (GO). GO is a progeroid disorder with wrinkled skin, osteoporosis, and spontaneous fractures caused by loss-of-function mutations in the gene GORAB (SKYL1BP1). The gene product is located in the Golgi-apparatus where it is likely involved in retrograde vesicle trafficking. Our group showed recently that loss of Gorab leads to an impairment of early osteoblast differentiation, low dermatan sulfate levels, altered TGF-b signaling and an impaired proteoglycan (decorin/biglycan) glycosylation in skin and bone resulting in an osteoporosis phenotype and spontaneous fractures in the GorabPrx1 mouse model. Unexpectedly, we observed elevated numbers of abnormally differentiated osteocytes in the mutants. Given that osteocytes are the bone cell type orchestrating the bone’s response to mechanical loading we wanted to investigate how GorabPrx1 animals react to mechanical stimulation. To this end, GorabPrx1 mutants and littermate controls (LC) were subjected to in vivo tibial loading for two weeks. Serial microCT registrations, dynamic and static histomorphometry were performed to define the different responses of the two cohorts. The results showed an astonishing complete loss of the physiological anabolic response to mechanical loading in GorabPrx1 mice. This effect was mirrored by altered strain-induced gene expression changes revealed by RNA-sequencing. In order to find the reason for this phenomenon we investigated the lacunar-canalicular osteocyte network in detail. The results show a reduced canalicular density and connectivity in spite of the higher osteocyte numbers. In a parallel approach, osteocyte-like cell lines were investigated after Gorab knock-down. The analysis of the primary cilium and mechanisms (ATP vesicle formation, calcium flux and GAP-junction function) important for mechanosensation did not reveal striking impairments. In summary, we found a loss of mechanosensitivity in GorabPrx1 mutants that is possibly due to a perturbed lacunar-canalicular osteocyte network.
Source: DepositOnce
Author: Thelen, Michael
Language: English
Topic: Bone Metabolism and Diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2964893877