Estrogen and raloxifene in experimental arthritis and osteoporosis

Abstract

In postmenopausal rheumatoid arthritis (RA), both the estrogen deficiency and the inflammatory diseasecontribute to the development of generalized osteoporosis. This leads to an increased risk of fracture,with high morbidity and mortality. More than 50% of women with postmenopausal RA suffer fromosteoporosis. Hormone replacement therap1 (HRT) is used to treat postmenopausal osteoporosis. HRThas also been shown to ameliorate RA, with decreased joint destruction, reduced inflammation,increased bone density and better patient health assessment. Unfortunately, longterm hormonaltreatment is associated with severe side effects, and is no longer recommended.The aims of this thesis were to establish a murine model for studies of osteoporosis in postmenopausalRA. To investigate the relative contributions of estrogen deficiency and inflammation to osteoporosisdevelopment in arthritic disease. To examine whether treatment with raloxifene, a selective estrogenreceptor modulator, would have the same beneficial anti-arthritic and anti-osteoporotic effects asestrogen. Furthermore, we wanted to compare the mechanisms for these effects between estrogen andraloxifene.We found that lack of endogenous estrogen and arthritic disease contributed equally and additivel1 toosteoporosis development in collagen-induced arthritis, a murine model of human RA. ArthriticovariectomiJed mice lost 55% of their trabecular bone mineral density (BMD) compared with cyclinghealthy mice.Raloxifene potentl1 decreased the frequency and severity of arthritis, protected the joints from erosions,and preserved the BMD. These effects were sustained when treatment was given both as prophylaxisand in established disease, and during longterm treatment.Raloxifene down-regulated the expression of TNFalpha and RANKL mRNA in the spleen. These moleculesare important mediators of bone loss after menopause and in RAK In contrast to estrogen, raloxifene didnot affect the effector phase of the disease, as demonstrated in collagen-antibod1 induced arthritisKMan1 estrogenic effects are mediated via the classical estrogen receptors and binding to the estrogenresponse elements, which regulate gene transcription. We found that raloQifene activated this pathwa1 at1/4 of the intensity of estrogen.In conclusion, our results show that estrogen deficienc1 and inflammation contribute equally to boneloss in arthritis. Furthermore, raloxifene has potent anti-arthritic and anti-osteoporotic effects, and ispossibly a valuable addition to conventional treatment of postmenopausal RA.