Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: A key mechanism in osteoporosis

D’Amelio, Patrizia; Grimaldi, Anastasia; Bella, S. Di; Brianza, Stefano; Cristofaro, Maria Angela; Tamone, Cristina; Giribaldi, Giuliana; Ulliers, Daniela; Pescarmona, Gianpiero; Isaia, Giancarlo

doi:10.1016/j.bone.2008.02.017

Cited by 296 publications

(299 citation statements)

References 44 publications

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“…The higher BMD in ERT users in the present study might be explained by an increase in the synthesis of mature bone collagen tissue, even though ERT seems to reduce the synthesis of new collagen molecules (indicated by lower s-PINP). An alternative explanation is that ERT reduces osteoclast activity and thereby bone collagen breakdown rate (12). However, the marker for bone collagen breakdown was not significantly reduced in ERT users in the present study compared with control.…”

Section: Bone Turnover and Bmdcontrasting

confidence: 80%

Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women

Hansen

Kongsgaard²,

Holm³

et al. 2009

Journal of Applied Physiology

121

114

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Flyvbjerg A, Langberg H, Kjaer M. Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women. J Appl Physiol 106: 1385-1393, 2009. First published October 16, 2009 doi:10.1152/japplphysiol.90935.2008.-The knowledge about the effect of estradiol on tendon connective tissue is limited. Therefore, we studied the influence of estradiol on tendon synthesis, structure, and biomechanical properties in postmenopausal women. Nonusers (control, n ϭ 10) or habitual users of oral estradiol replacement therapy (ERT, n ϭ 10) were studied at rest and in response to one-legged resistance exercise. Synthesis of tendon collagen was determined by stable isotope incorporation [fractional synthesis rate (FSR)] and microdialysis technique (NH2-terminal propeptide of type I collagen synthesis). Tendon area and fibril characteristics were determined by MRI and transmission electron microscopy, whereas tendon biomechanical properties were measured during isometric maximal voluntary contraction by ultrasound recording. Tendon FSR was markedly higher in ERT users (P Ͻ 0.001), whereas no group difference was seen in tendon NH2-terminal propeptide of type I collagen synthesis (P ϭ 0.32). In ERT users, positive correlations between serum estradiol (sestradiol) and tendon synthesis were observed, whereas change in tendon synthesis from rest to exercise was negatively correlated to s-estradiol. Tendon area, fibril density, fibril volume fraction, and fibril mean area did not differ between groups. However, the percentage of medium-sized fibrils was higher in ERT users (P Ͻ 0.05), whereas the percentage of large fibrils tended to be greater in control (P ϭ 0.10). A lower Young's modulus (GPa/%) was found in ERT users (P Ͻ 0.05). In conclusion, estradiol administration was associated with higher tendon FSR and a higher relative number of smaller fibrils. Whereas this indicates stimulated collagen turnover in the resting state, collagen responses to exercise were negatively associated with s-estradiol. These results indicate a pivotal role for estradiol in maintaining homeostasis of female connective tissue. connective tissue; tendon fibrils; insulin-like growth factor-I; extracellular matrix; bone CROSS-SECTIONAL FINDINGS INDICATE that sex hormones influence tendon biomechanical properties (36), extracellular matrix adaptability in response to mechanical loading (11,21,36,41,59), and the risk of sustaining soft tissue injuries (11,24,25).Estrogen receptors have been localized in ligaments (32, 33), and tendons express transcripts for estrogen receptors (23). Nevertheless, the effect of estrogen on tendon and ligament turnover is not clarified. Thus an inhibiting effect (34, 60), no effect (51), and a stimulating effect (32) on collagen synthesis and fibroblast proliferation in vitro have been observed in anterior cruciate ligament (ACL) tissue samples. These contrasting findings are probably related to the variation between animal species and the applied methods. This ...

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Section: Bone Turnover and Bmdcontrasting

confidence: 80%

Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women

Hansen

Kongsgaard²,

Holm³

et al. 2009

Journal of Applied Physiology

121

114

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“…4 TNFa and RANKL are well known pro-osteoclastogenic cytokines. 5 TNF-a induces OC formation in the presence of adequate levels of RANKL, 5 upregulates stromal cell production of RANKL and increases the responsiveness of OC precursors to RANKL. RANKL has an essential role in bone physiology by upregulating OC activity and formation.…”

Section: Inflammatory Diseases Immune System and Bonementioning

confidence: 99%

Osteoimmunology: from mice to humans

Sassi¹

2016

Bonekey Reports

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The immune system has been recognized as one of the most important regulators of bone turnover and its deregulation is implicated in several bone diseases such as postmenopausal osteoporosis and inflammatory bone loss; recently it has been suggested that the gut microbiota may influence bone turnover by modulation of the immune system. The study of the relationship between the immune system and bone metabolism is generally indicated under the term 'osteoimmunology'. The vast majority of these studies have been performed in animal models; however, several data have been confirmed in humans as well: this review summarizes recent data on the relationship between the immune system and bone with particular regard to the data confirmed in humans.

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“…Women with postmenopausal osteoporosis exhibit higher T-cell activities than healthy postmenopausal subjects; thus, T cells contribute to the bone loss caused by estrogen deficiency in humans and mice. 3 Estrogen plays a pivotal role as an inhibitor of bone resorption by acting directly on OCs to decrease their resorption activity and increase their rate of apoptosis. 27 In our study, both OC differentiation and bone resorption were efficiently suppressed by E2 at concentrations that fall within the ranging from 10 27 to 10 29 M; importantly, these concentrations fall within those that occur under physiological conditions.…”

Section: Modulation Of Treg Cells On Osteoclast Functionsmentioning

confidence: 99%

“…In addition, T lymphocytes play a fundamental role in postmenopausal bone loss and in the induction of osteoclastogenesis in humans. 3 OCs are multinucleated cells that are derived from hematopoietic precursors of the monocyte/macrophage lineage in the presence of macrophage colony-stimulating factor (M-CSF) and RANKL. [4][5][6][7] Many other cytokines have been shown to affect bone metabolism and OC activity, including interleukin (IL)-1, IL-4, IL-7, IL-10, IL-13 and TNF.…”

Section: Introductionmentioning

confidence: 99%

Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro

et al. 2010

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Cross-talk has been shown to occur between the immune system and bone metabolism pathways. In the present study, we investigated the impact of CD4 1 CD25 1 Foxp3 1 regulatory T (Treg) cells on osteoclastogenesis and bone resorption. Treg cells that were isolated and purified from peripheral blood mononuclear cells (PBMCs) of healthy adults inhibited both the differentiation of osteoclasts (OCs) from human embryo bone marrow cells (BMCs) and the pit formation in a dose-dependent manner. In cell cocultures, the production levels of both interleukin-10 (IL-10) and transforming growth factor-beta 1 (TGF-b1) were proportionally upregulated as the ratio of Treg cells to BMCs was increased, and the inhibition of OC differentiation and bone resorption by Treg cells was completely reversed by anti-IL-10 and anti-TGF-b1 antibodies. Treatment of BMC and Treg cell cocultures with 17b-estradiol (E2) at concentrations between 10 27 and 10 29 mol/l suppressed OC differentiation and bone resorption more efficiently than it did in cultures of BMCs alone; this enhanced suppression occurred via the stimulation of Treg cell IL-10 and TGF-b1 expression. These data suggest that Treg cells suppress OC differentiation and bone resorption by secreting IL-10 and TGF-b1. E2 enhances the suppressive effects of Treg cells on OC differentiation and bone resorption by stimulating IL-10 and TGF-b1 secretion from these cells. Therefore, Treg cell-derived IL-10 and TGF-b1 are likely involved in the regulation of E2 on bone metabolism and represent potential therapeutic targets for the treatment of postmenopausal osteoporosis (PMO).

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Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: A key mechanism in osteoporosis

Cited by 296 publications

References 44 publications

Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women

Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women

Osteoimmunology: from mice to humans

Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro

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