Minocycline prevents the decrease in bone mineral density and trabecular bone in ovariectomized aged rats.
In the current study, we examined the effects of minocycline, on the osteopenia of ovariectomized aged rats. Old female rats were randomly divided into five groups: sham, ovariectomized control and ovariectomized treated with minocycline, 17beta-estradiol, or both agents. Bone samples were collected 8 wk after the treatment. Ovariectomy reduced bone mineral density of the whole femur and at the condylar, distal metaphyseal and head-neck-trochanter regions 10%-19% and the loss of bone density was prevented by treatment with minocycline or 17beta-estradiol. Histomorphometric analysis of distal femur showed ovariectomy reduced the trabecular bone area, the trabecular bone number, trabecular bone thickness and increased the trabecular bone separation. The microanatomic structure of trabecular bone also showed that the number of nodes, node to node, cortical to node, node to free end was reduced by ovariectomy. Treatment with minocycline attenuated the effect of ovariectomy on trabecular bone in aged animals. In contrast, cortical bone was not affected by ovariectomy or minocycline treatment. The effect of minocycline on bone turnover was also examined. Minocycline increased osteoid surface, mineralizing surface, mineral apposition rate, bone formation rate and reduced eroded surface. We have therefore concluded that the modest increase in bone mineral density and the improvement in the trabecular bone status noted in minocycline treated ovariectomized aged rats is likely due to an increase in bone formation coupled with a decrease in bone resorption.
Williams S, Wakisaka A, Zeng QQ, Barnes J…
Bone Dec 1996
Tetracyclines convert the osteoclastic-differentiation pathway of progenitor cells to produce dendritic cell-like cells.
Tetracyclines, such as doxycycline and minocycline, are used to suppress the growth of bacteria in patients with inflammatory diseases. Tetracyclines have been shown to prevent bone loss, but the mechanism involved is unknown. Osteoclasts and dendritic cells (DCs) are derived from common progenitors, such as bone marrow-derived macrophages (BMMs). In this article, we show that tetracyclines convert the differentiation pathway, resulting in DC-like cells not osteoclasts. Doxycycline and minocycline inhibited the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis of BMMs, but they had no effects on cell growth and phagocytic activity. They influenced neither the proliferation nor the differentiation of bone-forming osteoblasts. Surprisingly, doxycycline and minocycline induced the expression of DC markers, CD11c and CD86, in BMMs in the presence of RANKL. STAT5 is involved in DC differentiation induced by GM-CSF. Midostaurin, a STAT5-signaling inhibitor, and an anti-GM-CSF-neutralizing Ab suppressed the differentiation induced by GM-CSF but not by tetracyclines. In vivo, the injection of tetracyclines into RANKL-injected mice and RANKL-transgenic mice suppressed RANKL-induced osteoclastogenesis and promoted the concomitant appearance of CD11c(+) cells. These results suggested that tetracyclines prevent bone loss induced by local inflammation, including rheumatoid arthritis and periodontitis, through osteoclast-DC-like cell conversion.
Kinugawa S, Koide M, Kobayashi Y, Mizoguchi T…
J. Immunol. Feb 2012
PMID: 22250082 | Free Full Text
Inhibitory effect of minocycline on osteoclastogenesis in mouse bone marrow cells.
To study the effects of minocycline hydrochloride (MINO) on the formation of tartrate-resistant acid phosphatase (TRAP) staining-positive multinucleated osteoclast-like cells in mouse bone marrow cells (BMCs) treated with 1α,25(OH)(2)D(3) or soluble receptor activator of nuclear factor-κB ligand (s-RANKL).
Mouse BMCs were cultured in alpha-modified minimum essential medium containing foetal calf serum (10%) and tetracyclines (2.5, 5 and 10μM), such as MINO, tetracycline hydrochloride (TC), oxytetracycline hydrochloride (OXT) or doxycycline (DOXY) in the presence of 1α,25(OH)(2)D(3) (10nM) or s-RANKL (20ng/ml) for 7 days, and the number of TRAP staining-positive osteoclast-like cells was counted. In RNA isolated from BMCs treated with 1α,25(OH)(2)D(3) or s-RANKL in the presence or absence of MINO, the expressions of osteoclast differentiation relating to mRNA were analysed by reverse transcription-polymerase chain reaction. Cell viability was examined in mouse BMCs and rabbit osteoclasts treated with MINO (0.25-20μM and 2-50μM, respectively) for 24h.
MINO, TC, OXT or DOXY inhibited 1α,25(OH)(2)D(3)-induced osteoclast-like cell formation in mouse BMCs dose dependently. MINO suppressed 1α,25(OH)(2)D(3)-induced up-regulation of mRNA expressions of TRAP, cathepsin K, carbonic anhydrase II, and calcitonin receptor, but not RANKL. MINO inhibited s-RANKL-induced osteoclast-like cell formation and up-regulation of mRNA expressions for nuclear factor of activated T-cells c1 (NFATc1), a key regulator of osteoclast differentiation; however, MINO had no effects on the viability of mouse BMCs and rabbit osteoclasts.
MINO inhibits RANKL-induced osteoclastogenesis via down-regulation of NFATc1 mRNA expression in osteoclast precursor cells.
Nagasawa T, Arai M, Togari A
Arch. Oral Biol. Sep 2011
Effect of minocycline on osteoporosis.
The effect of oral minocycline on osteopenia in ovariectomized (OVX) old rats was examined in this study. Rats were divided into 4 groups: sham-operated, OVX followed by treatment with vehicle, minocycline, or 17 beta-estradiol. The treatment was initiated one day after OVX and proceeded for 8 wks. OVX reduced bone mineral density (BMD) in the whole femur and in the femoral regions that are enriched in trabecular bone. Treatment with minocycline or estrogen prevented a decrease in BMD. Femoral trabecular bone area, trabecular number, and trabecular thickness were reduced, and trabecular separation was increased by OVX. Treatment with minocycline or estrogen abolished the detrimental effects induced by OVX. OVX also reduced indices that reflect the interconnectivity of trabecular bone, and the loss of trabecular connectivity was prevented by treatment with minocycline or estrogen. Based on the levels of urinary pyridinoline, we showed that the effect of estrogen, but not minocycline, was primarily through its inhibitory effect on bone resorption. Analysis of bone turnover activity suggests that OVX increased parameters associated with bone resorption (eroded surface) and formation (osteoid surface, mineralizing surface, mineral apposition rate, and bone formation rate). Treatment with minocycline reduced bone resorption modestly and stimulated bone formation substantially. In contrast, treatment with estrogen drastically reduced parameters associated with both bone resorption and formation. We have concluded that oral minocycline can effectively prevent the decrease in BMD and trabecular bone through its dual effects on bone resorption and formation.
Williams S, Wakisaka A, Zeng QQ, Barnes J…
Adv. Dent. Res. Nov 1998
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.
Williams S, Barnes J, Wakisaka A, Ogasa H…
Ann. N. Y. Acad. Sci. Jun 1999