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

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

Research output: Contribution to journalArticle

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 of 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.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - Jan 1 2019

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Osteocytes
Catenins
Skeleton
Bone and Bones
Tail
Hindlimb Suspension
Botulinum Toxins
Fluid Shifts
X-Ray Microtomography
Muscles
Bone Diseases
Photon Absorptiometry
Tamoxifen
Osteogenesis
Paralysis
Bone Density
Genes
Exons
Extremities
Alleles

Keywords

  • CTNNB1
  • DISUSE
  • OSTEOPOROSIS
  • WNT
  • β-CATENIN

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Expression of a Degradation-Resistant β-Catenin Mutant in Osteocytes Protects the Skeleton From Mechanodeprivation-Induced Bone Wasting. / Bullock, Whitney A.; Hoggatt, April M.; Horan, Daniel J.; Lewis, Karl J.; Yokota, Hiroki; Hann, Steven; Warman, Matthew L.; Sebastian, Aimy; Loots, Gabriela G.; Pavalko, Fredrick; Robling, Alexander.

In: Journal of Bone and Mineral Research, 01.01.2019.

Research output: Contribution to journalArticle

Bullock, Whitney A. ; Hoggatt, April M. ; Horan, Daniel J. ; Lewis, Karl J. ; Yokota, Hiroki ; Hann, Steven ; Warman, Matthew L. ; Sebastian, Aimy ; Loots, Gabriela G. ; Pavalko, Fredrick ; Robling, Alexander. / Expression of a Degradation-Resistant β-Catenin Mutant in Osteocytes Protects the Skeleton From Mechanodeprivation-Induced Bone Wasting. In: Journal of Bone and Mineral Research. 2019.
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AU - Horan, Daniel J.

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AU - Yokota, Hiroki

AU - Hann, Steven

AU - Warman, Matthew L.

AU - Sebastian, Aimy

AU - Loots, Gabriela G.

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AU - Robling, Alexander

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