Title: Expression of a Degradation-Resistant β-Catenin Mutant in Osteocytes Protects the Skeleton From Mechanodeprivation-Induced Bone Wasting

Abstract

ABSTRACT Mechanical stimulation is a key regulator of bone mass, maintenance, and turnover. Wnt signaling is a key regulator of mechanotransduction in bone, but the role of β-catenin—an intracellular signaling node in the canonical Wnt pathway—in disuse mechanotransduction is not defined. Using the β-catenin exon 3 flox (constitutively active [CA]) mouse model, in conjunction with a tamoxifen-inducible, osteocyte-selective Cre driver, we evaluated the effects of degradation-resistant β-catenin on bone properties during disuse. We hypothesized that if β-catenin plays an important role in Wnt-mediated osteoprotection, then artificial stabilization of β-catenin in osteocytes would protect the limbs from disuse-induced bone wasting. Two disuse models were tested: tail suspension, which models fluid shift, and botulinum-toxin (botox)-induced muscle paralysis, which models loss of muscle force. Tail suspension was associated with a significant loss of tibial bone mass and density, reduced architectural properties, and decreased bone formation indices in uninduced (control) mice, as assessed by dual-energy X-ray absorptiometry (DXA), micro-computed tomography (µCT), and histomorphometry. Activation of the βcatCA allele in tail-suspended mice resulted in little to no change in those properties; ie, these mice were protected from bone loss. Similar protective effects were observed among botox-treated mice when the βcatCA was activated. RNAseq analysis ofmore » altered gene regulation in tail-suspended mice yielded 35 genes, including Wnt11, Gli1, Nell1, Gdf5, and Pgf, which were significantly differentially regulated between tail-suspended β-catenin stabilized mice and tail-suspended nonstabilized mice. Our findings indicate that selectively targeting/blocking of β-catenin degradation in bone cells could have therapeutic implications in mechanically induced bone disease. © 2019 American Society for Bone and Mineral Research.« less

Authors:

Bullock, Whitney A. ;

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Hoggatt, April M.; Horan, Daniel J.; Lewis, Karl J.; Yokota, Hiroki; Hann, Steven; Warman, Matthew L.; Sebastian, Aimy; Loots, Gabriela G.; Pavalko, Fredrick M.; Robling, Alexander G.

Publication Date:

Fri Jun 07 00:00:00 EDT 2019

Research Org.:

Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Org.:

USDOE National Nuclear Security Administration (NNSA); National Inst. of Health; Dept. of Veteran Affairs

OSTI Identifier:

2301774

Alternate Identifier(s):

OSTI ID: 1546873; OSTI ID: 1604287

Report Number(s):

LLNL-JRNL-778757
Journal ID: ISSN 0884-0431

Grant/Contract Number:  

AC52‐07NA27344; AC52-07NA27344; AR065971; AR070624; AR053237; DK075730; AR069029; BX001478

Resource Type:

Published Article

Journal Name:

Journal of Bone and Mineral Research

Additional Journal Information:

Journal Name: Journal of Bone and Mineral Research Journal Volume: 34 Journal Issue: 10; Journal ID: ISSN 0884-0431

Publisher:

Oxford University Press

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; β–catenin; CTNNB1; WNT; disuse; osteoporosis