Skip to main content
Top
Published in: Arthritis Research & Therapy 2/2012

Open Access 01-04-2012 | Research article

Estradiol ameliorates arthritis and protects against systemic bone loss in Staphylococcus aureus infection in mice

Authors: Inger Gjertsson, Marie K Lagerquist, Erik Kristiansson, Hans Carlsten, Catharina Lindholm

Published in: Arthritis Research & Therapy | Issue 2/2012

Login to get access

Abstract

Introduction

Staphylococcus aureus is a common cause of bacterial arthritis, which is associated with progressive bone loss in affected joints. We recently showed that S. aureus infection also induces a significant systemic bone loss in mice. This study was performed to assess the effect of estradiol treatment on the clinical course and outcome of S. aureus arthritis and on infection-induced bone loss in experimental S. aureus infection.

Methods

Mice were ovariectomized, treated with estradiol or placebo, and S. aureus infection was established by intravenous inoculation of bacteria.

Results

Estradiol treatment was found to decrease significantly the frequency and clinical severity of S. aureus arthritis, a finding that was accompanied with significantly higher serum levels of interleukin-10 in estradiol-treated mice. Estradiol was also highly protective against S. aureus-induced systemic trabecular, and cortical bone loss. Lack of endogenous estrogens and S. aureus infection had additive effects on trabecular bone loss. The S. aureus-infected, ovariectomized mice lost as much as 76% of their trabecular bone mass.

Conclusions

Treatment with estradiol ameliorates S. aureus arthritis and is protective against infection-induced systemic bone loss in experimental S. aureus infection.
Appendix
Available only for authorised users
Literature
1.
go back to reference Lipsky BA, Weigelt JA, Gupta V, Killian A, Peng MM: Skin, soft tissue, bone, and joint infections in hospitalized patients: epidemiology and microbiological, clinical, and economic outcomes. Infect Control Hosp Epidemiol. 2007, 28: 1290-1298. 10.1086/520743.CrossRefPubMed Lipsky BA, Weigelt JA, Gupta V, Killian A, Peng MM: Skin, soft tissue, bone, and joint infections in hospitalized patients: epidemiology and microbiological, clinical, and economic outcomes. Infect Control Hosp Epidemiol. 2007, 28: 1290-1298. 10.1086/520743.CrossRefPubMed
2.
go back to reference Tarkowski A: Infection and musculoskeletal conditions: infectious arthritis. Best Pract Res. 2006, 20: 1029-1044. 10.1016/j.berh.2006.08.001.CrossRef Tarkowski A: Infection and musculoskeletal conditions: infectious arthritis. Best Pract Res. 2006, 20: 1029-1044. 10.1016/j.berh.2006.08.001.CrossRef
3.
go back to reference Verdrengh M, Carlsten H, Ohlsson C, Tarkowski A: Rapid systemic bone resorption during the course of Staphylococcus aureus-induced arthritis. J Infect Dis. 2006, 194: 1597-1600. 10.1086/508751.CrossRefPubMed Verdrengh M, Carlsten H, Ohlsson C, Tarkowski A: Rapid systemic bone resorption during the course of Staphylococcus aureus-induced arthritis. J Infect Dis. 2006, 194: 1597-1600. 10.1086/508751.CrossRefPubMed
4.
go back to reference Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, Yamaguchi A, Yoshiki S, Matsuda T, Hirano T, Kishimoto T, Suda T: IL-6 is produced by osteoblasts and induces bone resorption. J Immunol. 1990, 145: 3297-3303.PubMed Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, Yamaguchi A, Yoshiki S, Matsuda T, Hirano T, Kishimoto T, Suda T: IL-6 is produced by osteoblasts and induces bone resorption. J Immunol. 1990, 145: 3297-3303.PubMed
5.
go back to reference Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR: Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986, 319: 516-518. 10.1038/319516a0.CrossRefPubMed Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR: Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986, 319: 516-518. 10.1038/319516a0.CrossRefPubMed
6.
go back to reference Zhao YX, Tarkowski A: Impact of interferon-gamma receptor deficiency on experimental Staphylococcus aureus septicemia and arthritis. J Immunol. 1995, 155: 5736-5742.PubMed Zhao YX, Tarkowski A: Impact of interferon-gamma receptor deficiency on experimental Staphylococcus aureus septicemia and arthritis. J Immunol. 1995, 155: 5736-5742.PubMed
7.
go back to reference Bremell T, Tarkowski A: Preferential induction of septic arthritis and mortality by superantigen-producing staphylococci. Infect Immun. 1995, 63: 4185-4187.PubMed Bremell T, Tarkowski A: Preferential induction of septic arthritis and mortality by superantigen-producing staphylococci. Infect Immun. 1995, 63: 4185-4187.PubMed
8.
go back to reference Zhao YX, Ljungdahl A, Olsson T, Tarkowski A: In situ hybridization analysis of synovial and systemic cytokine messenger RNA expression in superantigen-mediated Staphylococcus aureus arthritis. Arthritis Rheum. 1996, 39: 959-967. 10.1002/art.1780390613.CrossRefPubMed Zhao YX, Ljungdahl A, Olsson T, Tarkowski A: In situ hybridization analysis of synovial and systemic cytokine messenger RNA expression in superantigen-mediated Staphylococcus aureus arthritis. Arthritis Rheum. 1996, 39: 959-967. 10.1002/art.1780390613.CrossRefPubMed
9.
go back to reference Hultgren O, Eugster HP, Sedgwick JD, Korner H, Tarkowski A: TNF/lymphotoxin-alpha double-mutant mice resist septic arthritis but display increased mortality in response to Staphylococcus aureus. J Immunol. 1998, 161: 5937-5942.PubMed Hultgren O, Eugster HP, Sedgwick JD, Korner H, Tarkowski A: TNF/lymphotoxin-alpha double-mutant mice resist septic arthritis but display increased mortality in response to Staphylococcus aureus. J Immunol. 1998, 161: 5937-5942.PubMed
10.
go back to reference Couper KN, Blount DG, Riley EM: IL-10: the master regulator of immunity to infection. J Immunol. 2008, 180: 5771-5777.CrossRefPubMed Couper KN, Blount DG, Riley EM: IL-10: the master regulator of immunity to infection. J Immunol. 2008, 180: 5771-5777.CrossRefPubMed
11.
go back to reference Gjertsson I, Hultgren OH, Tarkowski A: Interleukin-10 ameliorates the outcome of Staphylococcus aureus arthritis by promoting bacterial clearance. Clin Exp Immunol. 2002, 130: 409-414. 10.1046/j.1365-2249.2002.01999.x.CrossRefPubMed Gjertsson I, Hultgren OH, Tarkowski A: Interleukin-10 ameliorates the outcome of Staphylococcus aureus arthritis by promoting bacterial clearance. Clin Exp Immunol. 2002, 130: 409-414. 10.1046/j.1365-2249.2002.01999.x.CrossRefPubMed
12.
go back to reference Owens JM, Gallagher AC, Chambers TJ: IL-10 modulates formation of osteoclasts in murine hemopoietic cultures. J Immunol. 1996, 157: 936-940.PubMed Owens JM, Gallagher AC, Chambers TJ: IL-10 modulates formation of osteoclasts in murine hemopoietic cultures. J Immunol. 1996, 157: 936-940.PubMed
13.
go back to reference Sasaki H, Hou L, Belani A, Wang CY, Uchiyama T, Muller R, Stashenko P: IL-10, but not IL-4, suppresses infection-stimulated bone resorption in vivo. J Immunol. 2000, 165: 3626-3630.CrossRefPubMed Sasaki H, Hou L, Belani A, Wang CY, Uchiyama T, Muller R, Stashenko P: IL-10, but not IL-4, suppresses infection-stimulated bone resorption in vivo. J Immunol. 2000, 165: 3626-3630.CrossRefPubMed
14.
go back to reference Verdrengh M, Carlsten H, Ohlsson C, Tarkowski A: Addition of bisphosphonate to antibiotic and anti-inflammatory treatment reduces bone resorption in experimental Staphylococcus aureus-induced arthritis. J Orthop Res. 2007, 25: 304-310. 10.1002/jor.20317.CrossRefPubMed Verdrengh M, Carlsten H, Ohlsson C, Tarkowski A: Addition of bisphosphonate to antibiotic and anti-inflammatory treatment reduces bone resorption in experimental Staphylococcus aureus-induced arthritis. J Orthop Res. 2007, 25: 304-310. 10.1002/jor.20317.CrossRefPubMed
15.
go back to reference Verdrengh M, Bokarewa M, Ohlsson C, Stolina M, Tarkowski A: RANKL-targeted therapy inhibits bone resorption in experimental Staphylococcus aureus-induced arthritis. Bone. 2010, 46: 752-758. 10.1016/j.bone.2009.10.028.CrossRefPubMed Verdrengh M, Bokarewa M, Ohlsson C, Stolina M, Tarkowski A: RANKL-targeted therapy inhibits bone resorption in experimental Staphylococcus aureus-induced arthritis. Bone. 2010, 46: 752-758. 10.1016/j.bone.2009.10.028.CrossRefPubMed
16.
go back to reference D'Elia HF, Larsen A, Mattsson LA, Waltbrand E, Kvist G, Mellstrom D, Saxne T, Ohlsson C, Nordborg E, Carlsten H: Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis. J Rheumatol. 2003, 30: 1456-1463.PubMed D'Elia HF, Larsen A, Mattsson LA, Waltbrand E, Kvist G, Mellstrom D, Saxne T, Ohlsson C, Nordborg E, Carlsten H: Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis. J Rheumatol. 2003, 30: 1456-1463.PubMed
17.
go back to reference Holmdahl R, Jansson L, Andersson M: Female sex hormones suppress development of collagen-induced arthritis in mice. Arthritis Rheum. 1986, 29: 1501-1509. 10.1002/art.1780291212.CrossRefPubMed Holmdahl R, Jansson L, Andersson M: Female sex hormones suppress development of collagen-induced arthritis in mice. Arthritis Rheum. 1986, 29: 1501-1509. 10.1002/art.1780291212.CrossRefPubMed
18.
go back to reference Jansson L, Holmdahl R: Enhancement of collagen-induced arthritis in female mice by estrogen receptor blockage. Arthritis Rheum. 2001, 44: 2168-2175. 10.1002/1529-0131(200109)44:9<2168::AID-ART370>3.0.CO;2-2.CrossRefPubMed Jansson L, Holmdahl R: Enhancement of collagen-induced arthritis in female mice by estrogen receptor blockage. Arthritis Rheum. 2001, 44: 2168-2175. 10.1002/1529-0131(200109)44:9<2168::AID-ART370>3.0.CO;2-2.CrossRefPubMed
19.
go back to reference Jochems C, Islander U, Kallkopf A, Lagerquist M, Ohlsson C, Carlsten H: Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis. Arthritis Rheum. 2007, 56: 3261-3270. 10.1002/art.22873.CrossRefPubMed Jochems C, Islander U, Kallkopf A, Lagerquist M, Ohlsson C, Carlsten H: Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis. Arthritis Rheum. 2007, 56: 3261-3270. 10.1002/art.22873.CrossRefPubMed
20.
go back to reference Engdahl C, Jochems C, Windahl SH, Borjesson AE, Ohlsson C, Carlsten H, Lagerquist MK: Amelioration of collagen-induced arthritis and immune-associated bone loss through signaling via estrogen receptor alpha, and not estrogen receptor beta or G protein-coupled receptor 30. Arthritis Rheum. 2010, 62: 524-533.PubMed Engdahl C, Jochems C, Windahl SH, Borjesson AE, Ohlsson C, Carlsten H, Lagerquist MK: Amelioration of collagen-induced arthritis and immune-associated bone loss through signaling via estrogen receptor alpha, and not estrogen receptor beta or G protein-coupled receptor 30. Arthritis Rheum. 2010, 62: 524-533.PubMed
21.
go back to reference Bremell T, Lange S, Svensson L, Jennische E, Grondahl K, Carlsten H, Tarkowski A: Outbreak of spontaneous staphylococcal arthritis and osteitis in mice. Arthritis Rheum. 1990, 33: 1739-1744. 10.1002/art.1780331120.CrossRefPubMed Bremell T, Lange S, Svensson L, Jennische E, Grondahl K, Carlsten H, Tarkowski A: Outbreak of spontaneous staphylococcal arthritis and osteitis in mice. Arthritis Rheum. 1990, 33: 1739-1744. 10.1002/art.1780331120.CrossRefPubMed
22.
go back to reference Windahl SH, Vidal O, Andersson G, Gustafsson JA, Ohlsson C: Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice. J Clin Invest. 1999, 104: 895-901. 10.1172/JCI6730.CrossRefPubMed Windahl SH, Vidal O, Andersson G, Gustafsson JA, Ohlsson C: Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice. J Clin Invest. 1999, 104: 895-901. 10.1172/JCI6730.CrossRefPubMed
24.
go back to reference Ostensen M, Aune B, Husby G: Effect of pregnancy and hormonal changes on the activity of rheumatoid arthritis. Scand J Rheumatol. 1983, 12: 69-72. 10.3109/03009748309102886.CrossRefPubMed Ostensen M, Aune B, Husby G: Effect of pregnancy and hormonal changes on the activity of rheumatoid arthritis. Scand J Rheumatol. 1983, 12: 69-72. 10.3109/03009748309102886.CrossRefPubMed
25.
go back to reference Sakiniene E, Bremell T, Tarkowski A: Addition of corticosteroids to antibiotic treatment ameliorates the course of experimental Staphylococcus aureus arthritis. Arthritis Rheum. 1996, 39: 1596-1605. 10.1002/art.1780390921.CrossRefPubMed Sakiniene E, Bremell T, Tarkowski A: Addition of corticosteroids to antibiotic treatment ameliorates the course of experimental Staphylococcus aureus arthritis. Arthritis Rheum. 1996, 39: 1596-1605. 10.1002/art.1780390921.CrossRefPubMed
26.
go back to reference Yang L, Liang J, Yao G, Chen P, Hou Y: 17beta-estradiol regulates the numbers, endocytosis, stimulative capacity and IL-10 secretion of mouse spleen dendritic cells. Toxicol Lett. 2005, 155: 239-246. 10.1016/j.toxlet.2004.09.016.CrossRefPubMed Yang L, Liang J, Yao G, Chen P, Hou Y: 17beta-estradiol regulates the numbers, endocytosis, stimulative capacity and IL-10 secretion of mouse spleen dendritic cells. Toxicol Lett. 2005, 155: 239-246. 10.1016/j.toxlet.2004.09.016.CrossRefPubMed
27.
go back to reference Kanda N, Tamaki K: Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol. 1999, 103: 282-288. 10.1016/S0091-6749(99)70503-8.CrossRefPubMed Kanda N, Tamaki K: Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol. 1999, 103: 282-288. 10.1016/S0091-6749(99)70503-8.CrossRefPubMed
28.
go back to reference Polanczyk MJ, Hopke C, Vandenbark AA, Offner H: Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res. 2006, 84: 370-378. 10.1002/jnr.20881.CrossRefPubMed Polanczyk MJ, Hopke C, Vandenbark AA, Offner H: Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res. 2006, 84: 370-378. 10.1002/jnr.20881.CrossRefPubMed
29.
go back to reference Hong MH, Williams H, Jin CH, Pike JW: The inhibitory effect of interleukin-10 on mouse osteoclast formation involves novel tyrosine-phosphorylated proteins. J Bone Miner Res. 2000, 15: 911-918.CrossRefPubMed Hong MH, Williams H, Jin CH, Pike JW: The inhibitory effect of interleukin-10 on mouse osteoclast formation involves novel tyrosine-phosphorylated proteins. J Bone Miner Res. 2000, 15: 911-918.CrossRefPubMed
30.
go back to reference Park-Min KH, Ji JD, Antoniv T, Reid AC, Silver RB, Humphrey MB, Nakamura M, Ivashkiv LB: IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression. J Immunol. 2009, 183: 2444-2455. 10.4049/jimmunol.0804165.CrossRefPubMed Park-Min KH, Ji JD, Antoniv T, Reid AC, Silver RB, Humphrey MB, Nakamura M, Ivashkiv LB: IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression. J Immunol. 2009, 183: 2444-2455. 10.4049/jimmunol.0804165.CrossRefPubMed
31.
go back to reference Luo CY, Wang L, Sun C, Li DJ: Estrogen enhances the functions of CD4(+)CD25(+)Foxp3(+) regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell Mol Immunol. 2011, 8: 50-58.CrossRefPubMed Luo CY, Wang L, Sun C, Li DJ: Estrogen enhances the functions of CD4(+)CD25(+)Foxp3(+) regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell Mol Immunol. 2011, 8: 50-58.CrossRefPubMed
32.
go back to reference Santora K, Rasa C, Visco D, Steinetz BG, Bagnell CA: Antiarthritic effects of relaxin, in combination with estrogen, in rat adjuvant-induced arthritis. J Pharmacol Exp Ther. 2007, 322: 887-893. 10.1124/jpet.107.122903.CrossRefPubMed Santora K, Rasa C, Visco D, Steinetz BG, Bagnell CA: Antiarthritic effects of relaxin, in combination with estrogen, in rat adjuvant-induced arthritis. J Pharmacol Exp Ther. 2007, 322: 887-893. 10.1124/jpet.107.122903.CrossRefPubMed
33.
go back to reference Marriott I, Huet-Hudson YM: Sexual dimorphism in innate immune responses to infectious organisms. Immunol Res. 2006, 34: 177-192. 10.1385/IR:34:3:177.CrossRefPubMed Marriott I, Huet-Hudson YM: Sexual dimorphism in innate immune responses to infectious organisms. Immunol Res. 2006, 34: 177-192. 10.1385/IR:34:3:177.CrossRefPubMed
34.
go back to reference Meghji S, Crean SJ, Hill PA, Sheikh M, Nair SP, Heron K, Henderson B, Mawer EB, Harris M: Surface-associated protein from Staphylococcus aureus stimulates osteoclastogenesis: possible role in S. aureus-induced bone pathology. Br J Rheumatol. 1998, 37: 1095-1101. 10.1093/rheumatology/37.10.1095.CrossRefPubMed Meghji S, Crean SJ, Hill PA, Sheikh M, Nair SP, Heron K, Henderson B, Mawer EB, Harris M: Surface-associated protein from Staphylococcus aureus stimulates osteoclastogenesis: possible role in S. aureus-induced bone pathology. Br J Rheumatol. 1998, 37: 1095-1101. 10.1093/rheumatology/37.10.1095.CrossRefPubMed
35.
go back to reference Somayaji SN, Ritchie S, Sahraei M, Marriott I, Hudson MC: Staphylococcus aureus induces expression of receptor activator of NF-kappaB ligand and prostaglandin E2 in infected murine osteoblasts. Infect Immun. 2008, 76: 5120-5126. 10.1128/IAI.00228-08.CrossRefPubMed Somayaji SN, Ritchie S, Sahraei M, Marriott I, Hudson MC: Staphylococcus aureus induces expression of receptor activator of NF-kappaB ligand and prostaglandin E2 in infected murine osteoblasts. Infect Immun. 2008, 76: 5120-5126. 10.1128/IAI.00228-08.CrossRefPubMed
36.
go back to reference Sinigaglia L, Varenna M, Girasole G, Bianchi G: Epidemiology of osteoporosis in rheumatic diseases. Rheum Dis Clin North Am. 2006, 32: 631-658. 10.1016/j.rdc.2006.07.002.CrossRefPubMed Sinigaglia L, Varenna M, Girasole G, Bianchi G: Epidemiology of osteoporosis in rheumatic diseases. Rheum Dis Clin North Am. 2006, 32: 631-658. 10.1016/j.rdc.2006.07.002.CrossRefPubMed
37.
go back to reference Forsblad D'Elia H, Larsen A, Waltbrand E, Kvist G, Mellstrom D, Saxne T, Ohlsson C, Nordborg E, Carlsten H: Radiographic joint destruction in postmenopausal rheumatoid arthritis is strongly associated with generalised osteoporosis. Ann Rheum Dis. 2003, 62: 617-623. 10.1136/ard.62.7.617.CrossRefPubMed Forsblad D'Elia H, Larsen A, Waltbrand E, Kvist G, Mellstrom D, Saxne T, Ohlsson C, Nordborg E, Carlsten H: Radiographic joint destruction in postmenopausal rheumatoid arthritis is strongly associated with generalised osteoporosis. Ann Rheum Dis. 2003, 62: 617-623. 10.1136/ard.62.7.617.CrossRefPubMed
Metadata
Title
Estradiol ameliorates arthritis and protects against systemic bone loss in Staphylococcus aureus infection in mice
Authors
Inger Gjertsson
Marie K Lagerquist
Erik Kristiansson
Hans Carlsten
Catharina Lindholm
Publication date
01-04-2012
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 2/2012
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar3799

Other articles of this Issue 2/2012

Arthritis Research & Therapy 2/2012 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.