Osteocyte Wnt/β-catenin pathway activation upon mechanical loading is altered in ovariectomized mice

Abstract

Estrogen levels decline in both sexes with age, but more dramatically in females. Activation of the Wnt/β-catenin signaling pathway is central to the regulation of bone mass accrual and maintenance and in response to mechanical loading. Using the ovariectomized mouse model we examined the effect of estrogen loss on the osteocyte's ability to activate the Wnt/β-catenin pathway following mechanical loading. Female TOPGAL mice underwent ovariectomy (OVX) ( n = 10) or sham surgery ( n = 10) at 16 weeks of age. Four weeks post-surgery, a single loading session (global strain of 2200 με for 100 cycles at 2 Hz) was performed on the right forearm with the left as a non-loaded control. Mice ( n = 5) were sacrificed at 1 or 24 hr post-load. Ulnae were stained for β-catenin activation, femurs were used for μCT and 3-pt bending/biomechanical testing, and tibiae were used for histology analysis and to determine osteocyte lacunar size using SEM and high resolution micro-XCT. A 2.2-fold increase in β-catenin signaling activation was observed 24 hr post-load in the Sham group but did not occur in the OVX group. The OVX group versus control had significant losses ( p < 0.05) in trabecular BMD (−8%), BV/TV (−35%) and thickness (−23%), along with cortical thickness (−6%) and periosteal perimeter (−4%). The OVX group had significantly higher trabecular bone osteoclast numbers (63%), OCS/BS (77%) and N.OC/BPm (94%) and a significant decrease in osteoblast number (53%), OBS/BS (37%) and N.OB/BPm (40%) compared to the sham group ( p < 0.05). Cortical bone lacunar number/lacunar volume and bone biomechanical properties did not change between groups. Given that the ulna is a cortical bone loading model and the lack of changes in osteocyte lacunar number/volume in cortical bone, which would alter strains experienced by osteocytes, these data suggest the absence of estrogen resulted in intrinsic changes in the ability of the osteocyte to respond to mechanical load, rather than changes in the biomechanical and architectural properties of bone.

Bone remodeling: an operational process ensuring survival and bone mechanical competence

“…Autocrine loop impairment caused by estrogen deficiency induces an osteoporosis phenotype. 94 In addition to its effects on bone remodeling, estrogen regulates mechanotransduction in osteocytes by affecting FFSS, 95 Wnt/β-catenin expression, 96 and Cx43 expression. 97 Its removal triggers osteocyte apoptosis and alters the oxidative microenvironment, leading to the loss of osteocyte resistance to oxidative stress.…”

Recent research advances in pain mechanisms in McCune–Albright syndrome thinking about the pain mechanism of FD/MAS

“…Estrogen (ES) plays an important role in the regulation of skeletal maturation and bone remodeling. At the cellular level, ES inhibits osteoclast differentiation, and deficiency in ES leads to increased osteoclast formation, which reduces osteoclast number and decreases the number of active remodeling units [ 31 ]. Testosterone activates osteoblasts by activating steroid receptors (either directly or via aromatization to estradiol) to regulate FD/MAS abnormal bone remodeling [ 32 ].…”

Inactivation of AR or ERα in Extrahypothalamic Neurons Does not Affect Osteogenic Response to Loading in Male Mice

“…In females also, the osteocyte has been excluded as the main mediator of sex steroid effects on skeletal adaptation (39). Recent studies nevertheless suggest that estrogen withdrawal results in intrinsic changes in the ability of the osteocyte to sense and respond to mechanical loading (40,41). Of note, Cre recombinase activity in abovementioned conditional knockouts was driven by the Dmp1 or osteocalcin promoter, resulting in sex steroid receptor ablation in mature osteoblasts and/or terminally differentiated osteocytes.…”