Treatment of osteoporosis with MMP inhibitors.
In the current study, we examined the effects of minocycline on the osteopenia of ovariectomized (OVX) aged rats using the marrow ablation model. This injury induces rapid bone formation followed by bone resorption in the marrow cavity. Old female rats were randomly divided into five groups: sham, OVX, OVX + minocycline (5-15 mg/day, orally), OVX + 17 beta-estradiol (25 micrograms/day, subcutaneously), and OVX + both agents. Rats were OVX, treated with minocycline and/or estrogen, followed by marrow ablation. Bone samples were collected 16 days post-marrow ablation. X-ray radiography of bones operated on showed that treatment of OVX old rats with minocycline increased bone mass in diaphyseal region. Diaphyseal bone mineral density (BMD) was measured by DEXA scan. Diaphyseal BMD of OVX rats was increased 17-25% by treatment with 5-15 mg of minocycline or 17 beta-estradiol. The effects of minocycline and estrogen treatments on the expression of osteoblast and osteoclast markers were also examined. Northern and dot blot analysis of RNA samples showed that treatment of OVX aged rats with minocycline increased the expression of type I collagen (COL I) (49%) and decreased that of interleukin-6 (IL-6) (31%). In contrast, estrogen treatment decreased the expression of interleukin-6 (IL-6) (39%), carbonic anhydrase II (CA II) (36%), and osteopontin (OP) (37%). Neither minocycline nor 17 beta-estradiol had an effect on the expression of osteocalcin (OC) and alkaline phosphatase (AP). To elucidate the mechanism by which minocycline prevented the loss of bone in OVX aged rats, we examined the colony-formation potential of bone marrow stromal cells in ex vivo cultures. Minocycline stimulated the colony-forming efficiency of marrow stromal cells derived from old animals. We have therefore concluded that the modest increase in BMD noted in OVX aged rats, in response to minocycline treatment, may be due to a change in bone remodeling that favors bone formation; and the anabolic effect of minocycline is likely due to its effect on the expression of COL I and/or the metabolism of osteoprogenitor cells.
Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
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S
Williams
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Barnes
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Wakisaka
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Ogasa
C T
CT
Liang
D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003094:Collagen / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging; D005786:Gene Expression Regulation / Q000187:drug effects; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008911:Minocycline / Q000494:pharmacology*; D053495:Osteopontin; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D010052:Ovariectomy; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar; D012795:Sialoglycoproteins / Q000235:genetics; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology
D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D004958:Estradiol; D003094:Collagen; D008666:Metalloendopeptidases; D008911:Minocycline