Abstract
BackgroundCollagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA). Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM) raloxifene in CIA in DBA/1-mice. B10.Q-ncf1*/*mice are B10.Q mice with a mutated Ncf1 gene. In B10.Q-ncf1*/*mice, CIA develops as a chronic relapsing disease, which more accurately mimics human RA. We investigated the role of endogenous and exogenous sex steroids and raloxifene in the course of this model of chronic arthritis. We also examined whether treatment would prevent the development of inflammation-triggered generalized osteoporosis.MethodsFemale B10.Q-ncf1*/*mice were sham-operated or ovariectomized, and CIA was induced. 22 days later, when 30% of the mice had developed arthritis, treatment with raloxifene, estradiol or vehicle was started, and the clinical disease was evaluated continuously. Treatment was continued until day 56 after immunization. At termination of the experiment (day 73), bone mineral density (BMD) was analyzed, paws were collected for histological examination, and sera were analyzed for markers of cartilage turnover and pro-inflammatory cytokines.ResultsRaloxifene and estradiol treatment, as well as endogenous estrogen, decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis. These effects were associated with lower serum levels of the pro-inflammatory cytokine IL-6.ConclusionsThis is the first study to show that raloxifene and estradiol can ameliorate established erosive arthritis and inflammation-triggered osteoporosis in this chronic arthritis model. We propose that treatment with raloxifene could be a beneficial addition to the treatment of postmenopausal RA.
Highlights
Collagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA)
Endogenous and exogenous estrogen as well as raloxifene treatment hampered arthritis in B10.Q-ncf1*/* mice and protected joints from destruction To examine the anti-arthritic properties of sex steroids, ovariectomized female B10.Q-ncf1*/* mice were treated therapeutically from day 22 until day 56 post immunization, with either raloxifene (60 μg/day), estradiol (1.0 μg/day) or vehicle (Miglyol 812)
The raloxifene treatment group had a frequency of arthritis of 40% at the start of treatment, whereas the other groups only displayed 20% of mice with arthritis. In spite of this difference, our results clearly show that raloxifene treatment resulted in a slower onset of arthritis and a lower frequency of disease, compared to vehicle treated mice (P < 0.05 for the entire experiment)
Summary
Collagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA). Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM) raloxifene in CIA in DBA/1-mice. 22 days later, when 30% of the mice had developed arthritis, treatment with raloxifene, estradiol or vehicle was started, and the clinical disease was evaluated continuously. CIA is a model of human RA, and has been widely used to investigate disease mechanisms and treatments [13]. We have previously shown potent anti-arthritic effects of the selective estrogen receptor modulator (SERM) raloxifene in CIA in mice, when raloxifene was given as prophylaxis, therapy or in severe established disease [14,15]. Raloxifene hampered arthritis development, joint destruction and the development of generalized osteoporosis to the same degree as estradiol treatment. The rationale for using raloxifene instead of HRT is that estrogen treatment has been shown to increase the risk for cancer of the breast and uterus, as well as stroke, whereas raloxifene treatment does not have these side effects [16,17,18]
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