Interaction with Estrogen Receptors as Treatment of Arthritis and Osteoporosis
Estrogen is a steroid hormone having, in addition to its effects on sexual differentiation and reproduction, important impact on the immune system and on bone. Estrogen exerts its effects via activation of its two receptors ERα and ERβ. Our knowledge of how estrogen manages to mediate its various properties in different organs has increased tremendously by studies of ER targeted mice (Matthews and Gustafsson 2003; Hewitt, Harrell and Korach 2005). It has been evident that the effects of estrogen on bone to a large extent are mediated via its action on immune cells. Estrogen has a dichotomous impact on the immune system by down regulation of inflammatory immune responses but simultaneous upregulation of immunoglobulin production. Consequently, immune mediated diseases in humans and in animal models are modulated by estrogen. Estrogen deficiency after ovarectomy in mice and menopause in women are associated with significant bone loss. In rheumatic diseases such as rheumatoid arthritis (RA) osteoporosis is frequent and in postmenopausal RA the degree of bone loss is dramatically increased. Hormone replacement therapy (HRT) in murine and human arthritis has, as expected beneficial effects on bone loss but it also ameliorates inflammation and inflammation triggered joint destruction (Holmdahl, Jansson, and Andersson 1986; Forsblad d’Elia, Larsen, Mattsson, et al. 2003b). RA is a chronic autoimmune disease with complex pathogenesis (Holmdahl, Bockermann, Backlund, et al. 2002) displaying a variety of inflammatory mechanisms resulting in joint destruction (Gravallese 2002) and generalized osteoporosis (Haugeberg, Orstavik and Kvien 2003). Hence, in order to understand the mechanisms for estrogen mediated effects on bone loss in inflammatory diseases it is necessary to dissect the different stages at which the estrogen has potential modulating properties. Long-term use of HRT has been associated with increased risk of breast cancer, thrombosis and possibly also stroke (Prelevic, Kocjan, and Markou 2005). Accordingly, there is great need for new activators of estrogen receptors (ERs) selectively reproducing only the beneficial effects of estrogen.
KeywordsBone Mineral Density Estrogen Receptor Bone Loss Hormone Replacement Therapy Joint Destruction
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