Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis
Article first published online: 28 SEP 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 10, pages 3261–3270, October 2007
How to Cite
Jochems, C., Islander, U., Kallkopf, A., Lagerquist, M., Ohlsson, C. and Carlsten, H. (2007), Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis. Arthritis & Rheumatism, 56: 3261–3270. doi: 10.1002/art.22873
- Issue published online: 28 SEP 2007
- Article first published online: 28 SEP 2007
- Manuscript Accepted: 12 JUN 2007
- Manuscript Received: 15 OCT 2006
- Medical Faculty of Göteborg University
- Göteborg Medical Society
- King Gustav V's 80-Year Foundation
- Sahlgrenska Foundation
- NovoNordic Foundation
- Börje Dahlin Foundation
- Swedish Association Against Rheumatism
- Reumaforskningsfond Margareta
- Swedish Research Council
In postmenopausal rheumatoid arthritis (RA), both estrogen deficiency and the inflammatory disease contribute to the development of generalized osteoporosis. Hormone replacement therapy (HRT) with estradiol preserves bone mineral density (BMD) and ameliorates arthritis, but long-term therapy is no longer an option due to significant side effects. We therefore used a mouse model of human RA to test the hypothesis that a selective estrogen receptor modulator (SERM), the raloxifene analog LY117018, could be beneficial in the treatment of both arthritis and osteoporosis.
Female DBA/1 mice were ovariectomized and arthritis was induced with collagen immunization. Mice received an injection of raloxifene, estradiol, or vehicle control, administered prophylactically or therapeutically, and thereafter the clinical arthritis score was evaluated continuously. At termination, BMD was analyzed with peripheral quantitative computed tomography. Paws were collected for histology, and sera were analyzed for cytokines and markers of bone and cartilage turnover. Levels of cytokine messenger RNA (mRNA) were investigated with real-time polymerase chain reaction.
Treatment with raloxifene dramatically decreased the frequency and severity of arthritis. Effective preservation of bone and cartilage was seen in raloxifene-exposed mice, as demonstrated by increased BMD and decreased serum levels of cartilage oligomeric matrix protein in the raloxifene-treated mice compared with controls. Decreased levels of mRNA for both tumor necrosis factor α and RANKL in spleen cells from raloxifene-treated arthritic mice indicated an immunosuppressive action of this SERM.
In a well-established model of postmenopausal RA, the raloxifene analog LY117018 potently inhibits the progression of arthritis and the associated development of osteoporosis, both in a prophylactic and in a therapeutic regimen. Since long-term HRT has been associated with significant side effects, raloxifene may be a useful adjuvant treatment for postmenopausal RA.