The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-alpha and -beta

Abstract

Postmenopausal osteoporosis represents a failure of the response by which bone cells adapt bone mass and architecture to be sufficiently strong to withstand loading without fracture. To address why this failure should be associated with oestrogen withdrawal, we investigated the ulna's adaptive response to mechanical loading in adult female mice lacking oestrogen receptor-(ER / ), those lacking oestrogen receptor-(ER / ) and their wild-type littermates. In wild-type mice, short periods of physiologic cyclic compressive loading of the ulna in vivo over a 2-week period stimulates new bone formation. In ER -/-and ER -/-mice this osteogenic response was respectively threefold and twofold less (P<0·05). In vitro, primary cultures of osteoblast-like cells derived from these mice were subjected to a single short period of mechanical strain. Twenty-four hours after strain the number of wild-type cells was 61 25% higher than in unstrained controls (P<0·05), whereas in ER / cells there was no strain-related increase in cell number. However, the strain-related response of ER / cells could be partially rescued by transfection with functional human ER (P<0·05). ER / cells showed a 125 40% increase in cell number following strain. This was significantly greater than in wild types (P<0·05).These data support previous findings that functional ER is required for the full osteogenic response to mechanical loading and particularly the stage of this response, which involves an increase in osteoblast number. ER appears to depress the ER -mediated strain-related increase in osteoblast number in vitro, but in female transgenic mice in vivo the constitutive absence of either ER or ER appears to diminish the osteogenic response to loading.

Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice

“…Earlier studies have demonstrated that female but not male mice with ERα inactivation display reduced cortical osteogenic bone response to mechanical loading (19,(21)(22)(23)(24). To determine if the reduced osteogenic response to mechanical loading in female ERα −/− mice is caused by a lack of ERα in osteocytes, we loaded tibiae of female Dmp1-ERα −/− mice and WT mice using a standardized axial loading procedure.…”

“…As female mice with total ERα inactivation display reduced cortical osteogenic bone response to mechanical loading (19,(21)(22)(23)(24), and osteocytes are thought to function as the main mechanosensors in bone, it was biologically plausible to hypothesize that ERα in osteocytes is important for the osteogenic response to mechanical loading. However, the cortical osteogenic bone response to mechanical loading was normal in Dmp1-ERα −/− mice, demonstrating that ERα in osteocytes is not crucial for the osteogenic response to mechanical loading and, therefore, further studies are required to identify the ERα target cell type contributing to the osteogenic response to mechanical loading.…”

“…Previous studies have demonstrated that female but not male mice with ERα inactivation display reduced cortical osteogenic bone response to mechanical loading (19,(21)(22)(23)(24). In addition, we recently showed that ERα is required for the cortical osteogenic response to mechanical loading in a ligand-independent manner, involving activation function-1 but not activation function-2 in ERα in female mice (20).…”

Dose-dependent effects of genistein on bone homeostasis in rats' mandibular subchondral bone

“…ERα-/-mice produced three times less new cortical bone in response to the same mechanical stimulus as their ERα+/+ littermates [47,48] . Similarly, osteoblasts derived from ERα-/-mice failed to increase in number in response to mechanical stimulation, which can be rescued by transfection with fully functional ERα [49,50] .…”

“…In the literature, a few studies support ERα's involvement in the adaptive response of osteoblasts to mechanical strain [47][48][49][50] . ERα-/-mice produced three times less new cortical bone in response to the same mechanical stimulus as their ERα+/+ littermates [47,48] .…”