Estrogen modulates the recruitment of myelopoietic cell progenitors in rat through a stromal cell-independent mechanism involving apoptosis

Abstract

Loss of ovarian function leads to a significant increase in the number of bone-resorbing osteoclasts. Estrogen replacement is known to manifest bone protective effects in the treatment of postmenopausal osteoporosis. In the present study, we used ovariectomized rats to examine the effects of estrogen loss at the osteoclast progenitor colony forming unit-granulocyte macrophage (CFU-GM) level. A significant increase in CFU-GM number was observed as early as 7 days following ovariectomy, and correlated directly with an increase in the number of osteoclast-like cells generated in marrow cultures. The increase in CFU-GM following ovariectomy was abrogated in animals that received estrogen treatment in vivo. A similar suppressive effect was observed on CFU-GM number when ovariectomized rat marrow was treated with estrogen in vitro. This effect was blocked in the presence of the estrogen antihormone ICI 164,384. Thus, the data suggest the possibility that estrogen exerts a direct effect on osteoclast progenitors, and does so through the estrogen receptor-mediated mechanism. Ovariectomy also led to an increase in the early hematopoietic stem/progenitor cell population (Thy 1.1+ cells) as determined by FLOW cytometry methods. Morphological changes as well as terminal deoxynucleotidyl transferase assays revealed that estrogen treatment negated growth factor-induced proliferation of these early progenitors by promoting apoptosis. The cellular effects of estrogen in vitro together with the immunocytochemical detection of the estrogen receptor in these cells, strongly support the contention that in addition to osteoclast progenitors such as CFU-GM, earlier hematopoietic progenitors are also unique cellular targets for estrogen action.

Down-Regulation of Osteoclast Differentiation by Daidzein via Caspase 3

“…Estrogens modulate osteoclastogenesis by a double mechanism: an effect on stromal cells/osteoblasts, which produce the indispensable growth factors and cytokines, and a direct effect on osteoclast progenitors. (36,38,43,44) In mouse bone marrow cultures and in the murine monocytic cell line RAW 264.7, the hormone inhibits osteoclast precursor differentiation by a mechanism involving c-Jun repression (40) and by decreasing their responsiveness to RANKL. (41) In this study, we showed that daidzein and estradiol also influence the life span of osteoclast progenitors, because both induce apoptosis of bone marrow cells, as assessed by selective caspase-8 and caspase-3 activation, followed by nuclear fragmentation and formation of apoptotic bodies.…”

“…(41) In this study, we showed that daidzein and estradiol also influence the life span of osteoclast progenitors, because both induce apoptosis of bone marrow cells, as assessed by selective caspase-8 and caspase-3 activation, followed by nuclear fragmentation and formation of apoptotic bodies. (45) Other studies have shown that estrogen may modulate the recruitment of rat myelopoietic cell progenitors through a mechanism involving apoptosis (36) and induce apoptosis in a human preosteoclastic cell line. (46) The similar effects of daidzein and 17␤-estradiol suggest that they have a common ER-mediated action.…”

Identification of inflammatory and proresolving lipid mediators in bone marrow and their lipidomic profiles with ovariectomy and omega‐3 intake

“…Estrogens and glucocorticoids regulate the activities of cyclooxygenase (COX) and LOX [25][26][27][28][29][30]. Changes in progenitor cell number and fate also occur following surgical menopause [31][32][33] and altered lipid mediator synthesis may contribute to these changes. We hypothesized that ovariectomy would give raise to an altered profile of LOX-derived lipid mediators in bone marrow such that a relative abundance of proinflammatory as opposed to anti-inflammatory/proresolving lipid mediators would occur.…”

A TA Repeat Polymorphism in the Estrogen Receptor Gene Is Associated with Osteoporotic Fractures but Polymorphisms in the First Exon and Intron Are Not

“…(15,16) Lack of estrogen results in increased osteoclast number and bone resorbing activity. (17,18) Two different ER genes have been shown. The ER-␣ gene is located on chromosome 6q25-27, comprises eight exons, and spans more than 140 kilobases (kb).…”