Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis.
OBJECTIVE
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.


METHODS
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.


RESULTS
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 alpha and RANKL in spleen cells from raloxifene-treated arthritic mice indicated an immunosuppressive action of this SERM.


CONCLUSIONS
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.
Jochems
Caroline
C
Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. caroline.jochems@rheuma.gu.se
Islander
Ulrika
U
Kallkopf
Anna
A
Lagerquist
Marie
M
Ohlsson
Claes
C
Carlsten
Hans
H
D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy*; D015519:Bone Density / Q000187:drug effects*; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D051379:Mice; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy; D017698:Postmenopause; D011759:Pyrrolidines / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020849:Raloxifene Hydrochloride / Q000031:analogs & derivatives; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D011759:Pyrrolidines; D053245:RANK Ligand; D012333:RNA, Messenger; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D020849:Raloxifene Hydrochloride; C025430:LY 117018