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 ... More
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. ? 2019 American Society for Bone and Mineral Research.
