Age-related changes in human oestrogen receptor α function and levels in osteoblasts

Abstract

Oestrogen receptors (ERs) are present in human osteoblasts and mediate anti-resorptive effects on bone. Human osteoblast-like cells derived from different aged healthy female donors not on hormone replacement therapy were utilized under well-defined conditions in vitro to investigate ER function and levels. Treatment with 0.1 nM oestradiol-17beta of cell strains derived from eight young women (less than 50 years of age) increased hydroxyproline levels significantly [an average (2.2+/-0.1 S.E.M.)-fold increase], whereas cells derived from nine older women (more than 50 years of age) were not significantly affected. Similarly, cell strains, derived from younger women, transfected with a consensus oestrogen-responsive element linked to chloramphenicol acetyltransferase exhibited a greater response to oestrogen than strains derived from older women. When basal ERalpha levels were measured by enzyme immunoassay and normalized on a per cell basis, osteoblast-like strains derived from younger women (n=24) had a mean value of 2.54+/-0.16 fmol of ERalpha per 10(6) cells. In contrast, strains derived from older women (n=20) had a mean value of 5.44+/-0.48 fmol of ERalpha per 10(6) cells. An age-related increase in ERalpha number was also observed in human skin-derived fibroblasts and directly in dermal biopsies from women not on hormone replacement therapy. The results demonstrate ligand concentration-dependent ERalpha induction and indicate a loss of receptor regulation and diminution of ligand-receptor signal transduction with increasing donor age.

Estrogen, exercise, and the skeleton

“…In addition, E 2 itself has been shown to upregulate ERa transcription in bone and other tissues; when more estrogen is present, more estrogen receptors are expressed. [52][53][54] Taken together, these studies support the general hypothesis that estrogen can increase or decrease the effects of strain on the skeleton by changing how many estrogen receptors are expressed in bone tissue. This overall prediction has three components.…”

“…53 In addition, human osteoblast sensitivity to E 2 declines with age, reducing both the ability of E 2 to moderate ERa transcription and the ability of ERa to transmit strain information. 52 These changes may impair the ability of bone to respond to mechanical loading, increasing the risk of osteoporosis and fracture.…”

“…35,51 Third, ERa transcription can be up-or downregulated by estrogen level. [52][53] Therefore, individuals with higher estrogen levels during skeletal growth should have greater mechanosensitivity and greater osteogenic responses to mechanical loading as compared to those with lower estrogen levels (Fig. 1).…”

Senescence‐associated intrinsic mechanisms of osteoblast dysfunctions

“…In humans, osteoblastic cells from aged donors exhibit decreased proliferative responses to growth hormone and platelet-derived growth factor compared with young donor cells (Pfeilschifter et al, 1993). Similarly, osteoblast cultures obtained from young subjects exhibited a better response to estradiol (Ankrom et al, 1998) and IGF-I (D'Avis et al, 1997) compared with cells obtained from older donors. On the other hand, there is an increasing recognition that the skeleton plays a role in energy metabolism and thus it is influenced by a number of hormones and factors that are gut-derived or involved in energy metabolism, e.g., serotonin, insulin, and leptin (Karsenty & Oury, 2010).…”

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

“…Bone biopsies from oestrogen-deficient women have fewer ER -positive osteocytes than those from oestrogen-replete women (Hoyland et al 1999) and osteoblasts cultured from postmenopausal women are less responsive to oestrogen compared with osteoblasts from younger women in terms of oestrogen-induced collagen synthesis and ERE activation (Ankrom et al 1998). In addition, reduced levels of ER mRNA have been detected in trabecular bone following ovariectomy in rats (Lim et al 1999).…”