Abstract
As the β-catenin pathway has been shown to be involved in mechanotransduction, we sought to determine if haploinsufficiency would affect skeletal response to unloading. It has previously been shown that deletion of both alleles of β-catenin in bone cells results in a fragile skeleton highly susceptible to fracture, but deletion of one allele using Dmp1-Cre (Ctnnb1+/loxP; Dmp1-Cre, cKO HET) has little effect on the 2 mo old skeleton. We found that under normal housing conditions, trabecular bone volume was significantly less in 5 mo old male cKO HET mice compared to controls (Ctrl/HET:Tb. BV/TV = 13.96±2.71/8.92±0.95%, Tb.N. = 4.88±0.51/3.95±0.44/mm, Tb. Sp. = 0.20±0.02/0.26±0.03mm, a 36%, 19% and 30% change respectively) but not in females suggesting an age and gender related effect. Before performing suspension experiments and to control for the environmental effects, animals with the same tail attachment and housing conditions, but not suspended (NS), were compared to normally housed (NH) animals. Attachment and housing resulted in weight loss in both genders and phenotypes. Cortical bone loss was observed in the cKO HET males (NH/NS, Ct BV/TV: 90.45±0.72/89.12±0.56%) and both diaphyseal (0.19±0.01/0.17±0.01mm) and metaphyseal (0.10±0.01/0.08±0.01mm) thickness, but not in female cKO HET mice suggesting that male cKO HET mice are susceptible to attachment and housing conditions. These results with transgenic mice emphasizes the importance of proper controls when attributing skeletal responses to unloading. With suspension, cKO HET male mice did not lose bone unlike female cKO HET mice that had greater trabecular bone loss than controls (Ctrl 9%:cKO HET 21% decrease Tb. N; Ctrl 12%:cKO HET 27% increase Tb. Sp.). Suspended and non-suspended mice lost weight compared to normally housed animals. Taken together, the data suggest a protective effect of β-catenin against the effects of stress in males and partial protection against unloading in females.
Highlights
It has been recognized for hundreds of years that the skeleton responds to loading and unloading with bone gain or bone loss [1,2,3], but the cellular and molecular mechanisms responsible have remained elusive
Osteocytes are ideally situated in bone to sense mechanical strain and translate that strain into signals for bone formation, bone resorption and regulation of mineralization [5]
Whereas greater bone loss was observed in the female cKO HETs compared to controls, the cKO HET males except for trabecular BV/TV
Summary
It has been recognized for hundreds of years that the skeleton responds to loading and unloading with bone gain or bone loss [1,2,3], but the cellular and molecular mechanisms responsible have remained elusive. Osteocytes are ideally situated in bone to sense mechanical strain and translate that strain into signals for bone formation, bone resorption and regulation of mineralization [5]. These cells are embedded in the bone matrix throughout cortical and trabecular bone and are connected to each other, the bone marrow and the bone surface via their dendrites and canalicular system [6]. Osteocytes have been shown to express greater RANKL/OPG ratios responsible for osteoclastogenesis [13]. These data show that osteocytes are mechanosensors and are required for maintaining bone mass. The role of osteocytes and their intracellular molecular mechanisms responsible for modulating strain effects on bone formation, resorption and mineralization are just beginning to be identified
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