Deletion of a Single β-Catenin Allele in Osteocytes Abolishes the Bone Anabolic Response to Loading

Abstract

The Wnt/β-catenin signaling pathway is essential for bone cell viability, function and for skeletal integrity. To determine if β-catenin in osteocytes plays a role in the bone anabolic response to mechanical loading, 18-24 wk old osteocyte β-catenin haploinsufficient mice (Dmp1-Cre x β-catenin fl/+; HET cKO) were compared to their β-catenin fl/fl (control) littermates. Trabecular BV/TV was significantly less (58.3%) in HET cKO females versus controls, while male HET cKO and control mice were not significantly different. Trabecular number was significantly less in HET cKO mice compared to controls for both genders and trabecular separation was greater in female HET cKO mice. Osteoclast surface was significantly greater in female HET cKO mice. Cortical bone parameters in males and females showed subtle or no differences between HET cKO and controls. The right ulnae were loaded in vivo at 100 cycles, 2 Hz, 2500 με, 3 days per week for 3 weeks and the left ulnae served as non-loaded controls. Calcein and alizarin complexone dihydrate were injected 10 days and 3 days prior to sacrifice, respectively. MicroCT analysis detected an 8.7% and 7.1% increase in cortical thickness in the loaded right ulnae of male and female control mice, respectively, compared to their non-loaded left ulnae. No significant increase in new cortical bone formation was observed in the HET cKO mice. Histomorphometric analysis of control mice showed a significant increase in endocortical and periosteal mineral apposition rate (MAR), BFR/BS, BFR/BV and BFR/TV in response to loading, but no significant increases were detected in the loaded HET cKO mice. These data show that deleting a single copy of β-catenin in osteocytes abolishes the anabolic response to loading and that trabecular bone in females is more severely affected and suggest that a critical threshold of β-catenin is required for bone formation in response to mechanical loading.

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

“…However, MAR and BFR are decreased upon conditional deletion of β-catenin from osteoblast precursors in 2-mo-old mice (34). In addition, mice with β-catenin haploinsufficiency in osteocytes display a defective anabolic response to bone loading (35). These pieces of evidence have suggested a role for β-catenin signaling in osteoblastic cells controlling osteoblast activity.…”

Impaired Bone Homeostasis in Amyotrophic Lateral Sclerosis Mice with Muscle Atrophy

“…Conversely, skeletal unloading results in significant bone loss (12)(13)(14). Mechanical signals exert important influences on bone cells (12,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Osteocytes embedded in the bone matrix are thought to coordinate osteoblast and osteoclast activity in response to mechanical stimuli, translating mechanical strain into biochemical signals that ultimately regulate bone remodeling (i.e.…”

“…bone resorption and formation) (9, 17-21, 25, 26). Accumulative evidence suggests that Wnt/␤-catenin signaling plays a critical role in mediation of the mechanical regulation of bone homeostasis (17)(18)(19)(20)(21)25). Osteocyte-derived sclerostin, which is encoded by the Sost gene (27), can be induced by mechanical unloading and inhibits Wnt/␤-catenin signaling in osteoblasts (12,28,29).…”

Bone Homeostasis and Repair: Forced Into Shape

“…More recent in vivo studies have been able to delineate the osteocyte-specific factors that are important in mechanical adaptation by utilizing Cre-LoxP technology to knock out genes in an osteocyte-specific manner. These factors include IGF-I [74], Wnt/β-catenin [75], and nuclear factor erythroid 2-related factor (Nrf2) [76].…”