Bone‐cell changes in estrogen‐induced bone‐mass increase in mice: Dissociation of osteoclasts from bone surfaces

Liu, Chung‐Ching ‐C; Howard, Guy A.

doi:10.1002/ar.1092290211

Cited by 44 publications

(22 citation statements)

References 34 publications

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“…This is consistent with the results of others who have found no decrease in cortical bone area in the diaphysis of ovariectomized rats, while the metaphysis becomes osteopenic following ovariectomy (24,25), and also is consistent with the generally different responsiveness of dynamic histomorphometric parameters in metaphyseal and cortical bone to ovariectomy and hormone replacement (7,(25)(26)(27)(28). Bone also accumulates in the metaphysis after PTH therapy (29, 30), during high dose estrogen therapy (31)(32)(33)(34), and before egg production in birds (35). It is intriguing to speculate that estrogen may induce and maintain bone at this site as an estrogen-dependent quantum of bone (24) that is available as a metabolic reserve.…”

Section: Discussion One Tormationsupporting

confidence: 92%

Estrogen maintains trabecular bone volume in rats not only by suppression of bone resorption but also by stimulation of bone formation.

Chow¹,

Tobias²,

Colston³

et al. 1992

J. Clin. Invest.

244

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Estrogen is generally considered to maintain bone mass through suppression of bone resorption. We have previously demonstrated that administration of pharmacologic doses of estrogen increases bone formation in ovary-intact rats. To assess the effects of physiological concentrations of estrogen on bone formation, estrogen was administered to ovariectomized rats in which bone resorption was suppressed by the bisphosphonate 3-amino-1-hydroxypropylidene-1-bisphosphonate (AHPrBP). Animals receiving exogenous 170t-estradiol (E2) (1, 10, and 100 ,g/kg daily for 17 d) showed a dose-dependent increase in trabecular bone volume of 1.9, 25.8, and 43.6%, respectively, compared with those rats treated with AHPrBP alone. The increase in bone volume was associated with an increase in bone formation in E2-treated animals, in which bone resorption had been almost completely suppressed by AHPrBP. Neither ovariectomy, AHPrBP, nor E2 treatment had a significant effect on the volume or rate of formation of cortical bone. Thus, the increased bone resorption, which is a consequence of estrogen-deficiency, entrains increased bone formation, which masks a simultaneous reduction in estrogendependent bone formation. Therefore, in addition to the nonspecific effect of estrogen to depress formation via coupling, we have identified a specific effect of estrogen to increase formation independent of coupling. Thus it appears that estrogen maintains bone volume not only through inhibition of bone resorption, but also through stimulation of bone formation. (J.

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Section: Discussion One Tormationsupporting

confidence: 92%

Estrogen maintains trabecular bone volume in rats not only by suppression of bone resorption but also by stimulation of bone formation.

Chow¹,

Tobias²,

Colston³

et al. 1992

J. Clin. Invest.

244

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“…In vivo, 17b-estradiol increased the percentages of apoptotic osteoclasts after 1 or 3 weeks treatment of ovariectomized and sham operated mice as indicated by nuclear fragmentation and condensation, intense TRAP staining and acridine orange and TUNEL staining. The authors report the similarity of their findings to those in an earlier study in which estrogen treatment led to disintegration of osteoclasts, although the earlier study did not identify the effect as apoptosis [Liu and Howard, 1991]. In other studies, estrogen and raloxifene were shown to increase TGFb3 expression in femurs of ovariectomized mice [Yang et al, 1996].…”

Section: Estrogen and Sermsmentioning

confidence: 55%

Antiresorptive agents and osteoclast apoptosis

Stern

2007

J of Cellular Biochemistry

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Antiresorptive agents have proven to be effective therapies for the treatment of bone diseases associated with excessive osteoclast activity. Decreased osteoclast formation, inhibition of osteoclast actions, and reduced osteoclast survival represent mechanisms by which antiresorptive agents could act. The goals of this article are to present the evidence that antiresorptive agents can decrease osteoclast survival through apoptosis, to review the mechanisms by which they are thought to activate the apoptotic process, and to consider whether the actions on apoptosis fully account for the antiresorptive effects. As background, the apoptotic process will be briefly summarized together with the evidence that factors that promote osteoclast survival affect steps in the process. Following this, therapeutic agents that are both antiresorptive and can stimulate osteoclast apoptosis will be discussed. Other bone therapeutic agents that are either antiresorptive or apoptotic, but not both, will be described. Finally, newer antiresorptive compounds that elicit apoptosis and could represent potential therapeutic agents will be noted.

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“…This might be explained by the effects of estrogens on osteoclastogenesis and osteoclast activity. Estrogens reduce osteoclast size (36,37) and bone resorption (37), and estrogens in female mice may thus impede the development of the bone phenotype seen in RXR-KO male mice. Supporting this idea, OvX-induced estrogen deficiency allowed female mice to develop the osteoclast RXR-dependent bone phenotype seen in male mice.…”

Section: Discussionmentioning

confidence: 99%

Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling

Menéndez-Gutierrez¹,

Röszer²,

Fuentes³

et al. 2015

J. Clin. Invest.

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R e s e a R c h a R t i c l e8under this pathological condition, we induced estrogen deficiency by bilateral ovariectomy (OvX) in 20-week-old WT and RXR-KO mice and assessed bone loss over a further 8 weeks. Consistent with the lack of a skeletal phenotype in RXR-KO females (Supplemental Figure 3), age-and sex-matched sham-operated WT and RXR-KO mice showed no differences in bone architecture or osteoclast activity ( Figure 2). However, after OvX, loss of trabecular bone mass was significantly lower in RXR-KO mice (Figure 2, A-D). In WT mice, OvX led to a marked increase in osteoclast activity, shown by a rise in urine DPD and plasma CTX concentrations (Figure 2, E and F). In contrast, the increase in DPD and CTX concentrations was significantly lower in ovariectomized RXR-KO mice (Figure 2, E and F). These findings indicate that the diminished osteoclast activity in RXR-KO female mice makes them less prone to bone loss upon OvX. Lack of RXRs leads to formation of giant and nonresorbing osteoclasts in vitro.To determine the mechanism underlying the abnormal osteoclast activation in RXR-KO mice, we cultured bone marrow cells in the presence of the cytokines macrophage colony-stimulating factor (M-CSF) and RANKL (16). Osteoclasts differentiated from RXR-KO bone marrow were significantly larger than WT-derived osteoclasts and contained more nuclei (Figure 3, A-C). In contrast, osteoclast differentiation from bone marrow cells lacking RXRα but not RXRβ was normal, supporting the functional redundancy of RXRα and RXRβ in hematopoietic cells (Supplemental Figure 5). Enlargement of osteoclasts can result in increased bone resorption (17); however, the abnormally large RXR-KO osteoclasts displayed low lytic activity when cultured in calcium-phosphate-coated plates (Figure 3D) or on bovine cortical bone slices ( Figure 3E). RXR-KO osteoclasts also showed low expression of Acp5, matrix metallopeptidase 9 (Mmp9), cathepsin-K (CtsK), and Car2, which encode molecules crucial for extracellular matrix degradation and bone resorption ( Figure 3F). In addition, real-time imaging showed that RXR-KO osteoclasts had an increased spreading over the substrate compared with WT osteoclasts ( Figure 3G and Supplemental Video 1). These in vitro results are consistent with our in vivo observations, indicating that the lack of RXRs in osteoclast progenitors leads to a cell-autonomous effect on osteoclast differentiation and activation.The M-CSF response is altered in RXR-KO osteoclast progenitors. Osteoclast size is determined by the response of osteoclast progenitors to M-CSF, which controls their proliferation and survival (18,19). This cytokine also stimulates activities of the mature resorptive osteoclast, such as spreading, motility, and cytoskeletal organization (20). We thus hypothesized that the RXR-KO osteoclast phenotype could be due to an altered M-CSF response. To test this, we first characterized the capacity of osteoclast progenitors to form myeloid colony-forming units (CFUs) and to divide in response to M-CSF. After 12 days...

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Bone‐cell changes in estrogen‐induced bone‐mass increase in mice: Dissociation of osteoclasts from bone surfaces

Cited by 44 publications

References 34 publications

Estrogen maintains trabecular bone volume in rats not only by suppression of bone resorption but also by stimulation of bone formation.

Estrogen maintains trabecular bone volume in rats not only by suppression of bone resorption but also by stimulation of bone formation.

Antiresorptive agents and osteoclast apoptosis

Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling

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