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bioRxiv · 10.1101/2023.08.24.554623

Osterix-driven LINC complex disruption in vivo diminishes bone microarchitecture in 8-week male mice but not after 6-week voluntary wheel running

Birks, S.·Howard, S.·O'Rourke, C.·Thompson, W. R.·Lau, A.·Uzer, G.
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Abstract

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is a crucial connective component between the nuclear envelope and the cytoskeleton involving various cellular processes including nuclear positioning, nuclear architecture, and mechanotransduction. How LINC complexes regulate bone formation in vivo, however, is not well understood. To start bridging this gap, here we created a LINC disruption murine model using transgenic mice expressing Cre recombinase enzyme under the control of the Osterix (Osx-Cre) which is primarily active in pre-osteoblasts and floxed Tg(CAG-LacZ/EGFP-KASH2) mice. Tg(CAG-LacZ/EGFP-KASH2) mice contain a lox-STOP-lox flanked LacZ gene which is deleted upon cre recombination allowing for the overexpression of an EGFP-KASH2 fusion protein. This overexpressed protein disrupts endogenous Nesprin-Sun binding leading to disruption of LINC complexes. Thus, crossing these two lines results in a Osx-driven LINC disruption (ODLD) specific to pre-osteoblasts. In this study, we investigated how this LINC disruption affects exercise induced bone accrual. ODLD cells had decreased osteogenic and adipogenic potential in vitro compared to non-disrupted controls and sedentary ODLD mice showed decreased bone quality at 8-weeks. Upon access to a voluntary running wheel ODLD animals showed increased running time and distance; however, our 6-week exercise intervention did not significantly affect bone microarchitecture and bone mechanical properties.

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Birks, S., Howard, S., O'Rourke, C., Thompson, W. R., Lau, A., Uzer, G.. 2023-08-26. Osterix-driven LINC complex disruption in vivo diminishes bone microarchitecture in 8-week male mice but not after 6-week voluntary wheel running. https://doi.org/10.1101/2023.08.24.554623

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