Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual

Abstract

The detection of estrogen receptor-α (ERα) in osteoblasts and osteoclasts over 20 years ago suggested that direct effects of estrogens on both of these cell types are responsible for their beneficial effects on the skeleton, but the role of ERα in osteoblast lineage cells has remained elusive. In addition, estrogen activation of ERα in osteoclasts can only account for the protective effect of estrogens on the cancellous, but not the cortical, bone compartment that represents 80% of the entire skeleton. Here, we deleted ERα at different stages of differentiation in murine osteoblast lineage cells. We found that ERα in osteoblast progenitors expressing Osterix1 (Osx1) potentiates Wnt/β-catenin signaling, thereby increasing proliferation and differentiation of periosteal cells. Further, this signaling pathway was required for optimal cortical bone accrual at the periosteum in mice. Notably, this function did not require estrogens. The osteoblast progenitor ERα mediated a protective effect of estrogens against endocortical, but not cancellous, bone resorption. ERα in mature osteoblasts or osteocytes did not influence cancellous or cortical bone mass. Hence, the ERα in both osteoblast progenitors and osteoclasts functions to optimize bone mass but at distinct bone compartments and in response to different cues. IntroductionThe volume of bone mass is determined by the balance between two opposing processes, bone removal (resorption) by osteoclasts and bone formation by osteoblasts. Under physiologic circumstances, formation compensates for the effect of resorption by adding bone either in the same anatomical site from which it was previously resorbed, in a process called remodeling, or in a different site, as in the case of the sculpting of bones during growth, in a process called modeling (1).After birth, long bones in both sexes increase in length. In parallel with linear growth, females and males experience an enlargement and thickening of the bone cortex, because bone apposition at the periosteal (outer) envelope exceeds the widening of the medullar cavity by endocortical resorption. Importantly, with the onset of puberty, estrogens inhibit, while androgens stimulate, periosteal bone formation, thereby contributing to sexual dimorphism and the greater bone mass in the male (2). At the same time, endocortical resorption is attenuated by either estrogens or androgens, producing increased cortical thickness at the end of puberty in both sexes. In line with the inhibitory effect of estrogens on periosteal bone formation, estrogen deficiency in female rodents and postmenopausal women increases periosteal apposition in an attempt to compensate for the endocortical loss of bone. At the end of puberty, estrogens are essential for the closure of the epiphyses and the cessation of linear growth (3).Estrogens also slow the rate of bone remodeling and help to maintain a balance between bone formation and resorption by attenuating the birth rate of osteoclast and osteoblast progenitors in the bone marrow and exerting a proapop...

Sirtuin1 (Sirt1) Promotes Cortical Bone Formation by Preventing β-Catenin Sequestration by FoxO Transcription Factors in Osteoblast Progenitors

“…All mice carrying the Osx1-Cre transgene had lower body weight when compared with the wild-type and Sirt1 f/f littermate controls (Fig. 1A) in agreement with previous reports that the Osx1-Cre transgene decreases body size (18,23). Sirt1 deletion, however, did not affect body weight as Sirt1 ⌬Osx1 mice were indistinguishable from the Osx1-Cre littermates.…”

“…A potential explanation for these findings could be cross-talk between Sirt1 and estrogen receptor ␣ (ER␣), documented in other cell types (33). Nonetheless, in earlier work of ours, deletion of ER␣ in osteoprogenitor cells did not affect endocortical bone formation (18), suggesting that the effects of Sirt1 in osteoprogenitors are independent of ER␣.…”

“…Bone Imaging and Histology-Microcomputed tomography analysis of vertebrae and femora was done after the bones were dissected, cleaned, fixed in 10% Millonig's formalin, and transferred to 100% ethanol, loaded into 10-mm diameter scanning tubes, imaged (CT40, Scanco Medical), and analyzed as described previously (18). For histology, femora were fixed in 10% Millonig's formalin, transferred to 100% ethanol, and embedded undecalcified in methyl methacrylate.…”

“…For histology, femora were fixed in 10% Millonig's formalin, transferred to 100% ethanol, and embedded undecalcified in methyl methacrylate. Endocortical and periosteal bone formations were assessed in longitudinal 5-m-thick femoral sections using the OsteoMeasure analysis system (OsteoMetrics, Inc.) as described before (18). Cancellous bone formation measurements were restricted to the secondary spongiosa.…”

Multifarious effects of 17-β-estradiol on apolipoprotein E receptors gene expression during osteoblast differentiation <i>in vitro </i>

“…Mice with deletion of ERα in MSC showed decreased periosteal bone formation due to decreased canonical Wnt signaling pathway (76). In our study, LRP5, LRP6, LRP4, and Apoer2, which are involved in the Wnt signaling pathway, presented different effects with E2.…”