Tag Archives: positive

Beta Blocker Suppresses Resorption in Rats

Abstract

Low dose of propranolol down-modulates bone resorption by inhibiting inflammation and osteoclast differentiation.

Bones are widely innervated, suggesting an important role for the sympathetic regulation of bone metabolism, although there are controversial studies. We investigated the effects of propranolol in a model of experimental periodontal disease.
Rats were assigned as follows: animals without ligature; ligated animals receiving vehicle and ligated animals receiving 0.1, 5 or 20 mg·kg(-1) propranolol. After 30 days, haemodynamic parameters were measured by cardiac catheterization. Gingival tissues were removed and assessed for IL-1β, TNF-α and cross-linked carboxyterminal telopeptides of type I collagen (CTX) by elisa, or intercellular adhesion molecule 1 (ICAM-1), receptor activator of NF-κ B ligand (RANKL) and osteoprotegerin (OPG) by Western blot analysis. Sections from the mandibles were evaluated for bone resorption. Also, we analysed the ability of propranolol to inhibit osteoclastogenesis in vitro.
Propranolol at 0.1 and 5 mg·kg(-1) reduced the bone resorption as well as ICAM-1 and RANKL expression. However, only 0.1 mg·kg(-1) reduced IL-1β, TNF-α and CTX levels as well as increased the expression of OPG, but did not alter any of the haemodynamic parameters. Propranolol also suppressed in vitro osteoclast differentiation and resorptive activity by inhibiting the nuclear factor of activated T cells (NFATc)1 pathway and the expression of tartrate-resistant acid phosphatase (TRAP), cathepsin K and MMP-9.
Low doses of propranolol suppress bone resorption by inhibiting RANKL-mediated osteoclastogenesis as well as inflammatory markers without affecting haemodynamic parameters.

Rodrigues WF, Madeira MF, da Silva TA, Clemente-Napimoga JT…
Br. J. Pharmacol. Apr 2012
PMID: 21950592 | Free Full Text

Beta Blockers Improved Bone in Hypertensive Rats from Beta2 Blockade

Abstract

Effects of propranolol on bone metabolism in spontaneously hypertensive rats.

The effects of propranolol (PRO), a nonselective beta-adrenergic receptor (beta-AR) antagonist with membrane-stabilizing action on bone metabolism, were examined in spontaneously hypertensive rats (SHR) showing osteoporosis with hyperactivity of the sympathetic nervous system. Treatment of SHR with PRO at 1 and 5 mg/kg p.o. for 12 weeks increased bone mass of the lumbar vertebra and proximal tibia without affecting blood pressure, but PRO at 50 and 100 mg/kg with hypotensive action did not increase bone mass. Next, the effects of PRO at 0.1, 1, and 10 mg/kg on bone status were examined in more detail. Compared with the SHR control, not only bone mass but also biomechanical parameters of strength and toughness of the lumbar vertebrae were increased in SHR treated with PRO at 0.1 and 1 mg/kg, suggesting antiosteoporotic action. PRO at 1 mg/kg statistically increased histomorphometry indices of bone formation, whereas PRO at doses of 0.1, 1, and 10 mg/kg decreased those of bone resorption. Antiosteoporotic effect of PRO is attenuated at 10 mg/kg compared with 0.1 and 1 mg/kg. In addition, treatment with timolol, a nonselective beta-AR antagonist without membrane-stabilizing action, or butoxamine, a selective beta2-AR antagonist, at 1 mg/kg increased bone mass in SHR. These results suggested that treatment of SHR with beta-blockers at low dose improved bone loss and bone fragility. This antiosteoporotic effect of beta-blockers seems to be caused by the blocking action of beta2-AR, regardless of the membrane-stabilizing action.

Sato T, Arai M, Goto S, Togari A
J. Pharmacol. Exp. Ther. Jul 2010
PMID: 20404011 | Free Full Text

It is possible that a beta1 blocker, like Metoprolol, would not be effective.

Beta Blocker Prevents Bone Loss in Rats Receiving Labyrinthectomy

Abstract

Sympathetic B antagonist prevents bone mineral density decrease induced by labyrinthectomy.

We previously showed that bilateral vestibular lesion in rats induces a bone loss in weight bearing bones. To determine whether this effect is mediated by the sympathetic nervous system (SNS), bone mineral density (BMD) was measured in 4 groups of 10 female Wistar rats: bilateral labyrinthectomy (Bilab), Bilab with propranolol treatment, sham operated with or without propranolol. In untreated rats, 30 days after lesion Bilab animals showed a reduced BMD in distal femoral metaphysis comparatively to intact rats (p < 0.001). In treated rats, there was no difference in BMD 30 days after lesion. This protective effect of propranolol against bone loss suggests that the vestibular system influence on bone remodeling is mediated by SNS. If this hypothesis is correct, this could have important consequences in devising countermeasures to spaceflight induced bone loss.

Denise P, Besnard S, Vignaux G, Sabatier JP…
Aviakosm Ekolog Med
PMID: 20169738

Beta Blockers or Exercise Improve Bone in Rats

Abstract

Combined effects of exercise and propranolol on bone tissue in ovariectomized rats.

The bone response to physical exercise may be under control of the SNS. Using a running session in rats, we confirmed that exercise improved trabecular and cortical properties. SNS blockade by propranolol did not affect this response on cortical bone but surprisingly inhibited the trabecular response. This suggests that the SNS is involved in the trabecular response to exercise but not in the cortical response.
Animal studies have suggested that bone remodeling is under beta-adrenergic control through the sympathetic nervous system (SNS). However, the SNS contribution to bone response under mechanical loading remains unclear. The purpose of this study was to examine the preventive effect of exercise coupled with propranolol on cancellous and cortical bone compartments in ovariectomized rats.
Six-month-old female Wistar rats were ovariectomized (OVX, n = 44) or sham-operated (n = 24). OVX rats received subcutaneous injections of propranolol 0.1 mg/kg/day or vehicle and were submitted or not submitted to treadmill exercise (13 m/minute, 60 minutes/day, 5 days/week) for 10 weeks. Tibial and femoral BMD was analyzed longitudinally by DXA. At death, the left tibial metaphysis and L(4) vertebrae were removed, and microCT was performed to study trabecular and cortical bone structure. Histomorphometric analysis was performed on the right proximal tibia.
After 10 weeks, BMD and trabecular strength decreased in OVX rats, whereas bone turnover rate and cortical porosity increased compared with the Sham group (p < 0.001). Either propranolol or exercise allowed preservation of bone architecture by increasing trabecular number (+50.35% versus OVX; p < 0.001) and thickness (+16.8% versus OVX; p < 0.001). An additive effect of propranolol and exercise was observed on cortical porosity but not on trabecular microarchitecture or cortical width. Biomechanical properties indicated a higher ultimate force in the OVX-propranolol-exercise group compared with the OVX group (+9.9%; p < 0.05), whereas propranolol and exercise alone did not have any significant effect on bone strength.
Our data confirm a contribution of the SNS to the determinants of bone mass and quality and show a antagonistic effect of exercise and a beta-antagonist on trabecular bone structure.

Bonnet N, Beaupied H, Vico L, Dolleans E…
J. Bone Miner. Res. Apr 2007
PMID: 17243867

Guduchi Increases Osteoblasts and Mineralization In Vitro

Abstract

Effects of Tinospora cordifolia (Menispermaceae) on the proliferation, osteogenic differentiation and mineralization of osteoblast model systems in vitro.

Ancient Indian ayurvedic literature prescribes Tinospora cordifolia as a remedy to rheumatoid arthritis, inflammatory and allied diseases of musculo skeletal system. To investigate the effects of the alcoholic extract of Tinospora cordifolia (TC) on the proliferation, differentiation and mineralization of bone like matrix on osteoblast model systems in vitro and hence its possible use as a potential anti-osteoporotic agent.
Two in vitro osteoblast model systems were used in the study viz., human osteoblast-like cells MG-63 and primary osteoblast cells isolated from femur of rats. Cell growth and viability was assessed by standard colorimetric assays like MTT assay. The cell differentiation into osteoblastic lineage was evaluated by the activities of bone marker alkaline phosphatase. The effect of the extract on matrix mineralization was assessed by alizarin red-s staining and Von kossa staining. Cell morphology was studied by phase contrast microscopy and light microscopy (Giemsa/crystal violet staining).
Results indicate that the alcoholic extract of TC at a dosage of 25μg/ml stimulated the growth of osteoblasts, increased the differentiation of cells into osteoblastic lineage and increased the mineralization of bone like matrix on both the osteoblast model systems used in the study. Cell morphology studies clearly indicated the increase in cell numbers and absence of adverse change in the cell morphology on treatment with the extract.
TC extract has a potential influence on osteogenesis and hence its use could be explored as a potential anti-osteoporotic agent.

Abiramasundari G, Sumalatha KR, Sreepriya M
J Ethnopharmacol May 2012
PMID: 22449439

Berberine is Antiosteoporotic in Rats

Abstract

Anti-osteoporotic activity of aqueous-methanol extract of Berberis aristata in ovariectomized rats.

Traditionally Berberis aristata is employed for its supposed properties in treatment of joint pain and also used in alleviating symptoms of menopause. The aim of the present study is to evaluate the antiosteoporotic effect of Berberis aristata in ovariectomized (OVX) rats.

Sprague-Dawley rats were divided into sham and OVX groups. The OVX rats were further divided into four groups, which received standard estrogen (0.0563 mg/kg) and 100, 300, and 500 mg/kg aqueous-methanol extract of Berberis aristata, daily for 42 days. The uterine weight, bone loss, ash content, biomechanical, biochemical and histopathological observation were carried out for antiosteoporotic activity.
The experimental animals treated with Berberis aristata aqueous-methanol extract showed dose dependent activity. The significant increase in uterine weight, femur BMD, ash content and lumbar hardness were observed. In addition, increased levels of calcium and phosphorus in serum and significant decreased in urine were observed as compared to control OVX group. The histopathological results also confirm the protective effect of extract.
The present findings strongly suggest that Berberis aristata possess the potent antiosteoporosis activity in ovariectomized rats and substantiates the ethnic use in treatment of postmenopausal osteoporosis.

Yogesh HS, Chandrashekhar VM, Katti HR, Ganapaty S…
J Ethnopharmacol Mar 2011
PMID: 21182919

Coptisine Inhibits Osteoclasts In Mouse Cells

Abstract

Coptisine inhibits RANKL-induced NF-κB phosphorylation in osteoclast precursors and suppresses function through the regulation of RANKL and OPG gene expression in osteoblastic cells.

Excessive receptor activator of NF-κB ligand (RANKL) signaling causes enhanced osteoclast formation and bone resorption. The downregulation of RANKL expression and its downstream signals may be an effective therapeutic approach to the treatment of bone loss diseases such as osteoporosis. Here, we found that coptisine, one of the isoquinoline alkaloids from Coptidis Rhizoma, exhibited inhibitory effects on osteoclastogenesis in vitro. Although coptisine has been studied for its antipyretic, antiphotooxidative, dampness dispelling, antidote, antinociceptive, and anti-inflammatory activities in vitro and in vivo, its effects on osteoclastogenesis have not been investigated. Therefore, we evaluated the effects of coptisine on osteoblastic cells as well as osteoclast precursors for osteoclastogenesis in vitro. The addition of coptisine to cocultures of mouse bone marrow cells and primary osteoblastic cells with 10(-8) M 1α,25(OH)(2)D(3) caused significant inhibition of osteoclast formation in a dose-dependent manner. Reverse transcriptase polymerase chain reaction (RT-PCR) analyses revealed that coptisine inhibited RANKL gene expression and stimulated the osteoprotegerin gene expression induced by 1α,25(OH)(2)D(3) in osteoblastic cells. Coptisine strongly inhibited RANKL-induced osteoclast formation when added during the early stage of bone marrow macrophage (BMM) cultures, suggesting that it acts on osteoclast precursors to inhibit RANKL/RANK signaling. Among the RANK signaling pathways, coptisine inhibited NF-κB p65 phosphorylations, which are regulated in response to RANKL in BMMs. Coptisine also inhibited the RANKL-induced expression of NFATc1, which is a key transcription factor. In addition, 10 μM coptisine significantly inhibited both the survival of mature osteoclasts and their pit-forming activity in cocultures. Thus, coptisine has potential for the treatment or prevention of several bone diseases characterized by excessive bone destruction.

Lee JW, Iwahashi A, Hasegawa S, Yonezawa T…
J Nat Med Jan 2012
PMID: 21656335

Berberine Decreases Bone Loss in Rat Cells

Abstract

Effects of berberine on differentiation and bone resorption of osteoclasts derived from rat bone marrow cells.

To observe the effects of berberine on osteoclastic differentiation and bone resorption action in vitro, and to investigate the cellular mechanism of its inhibitory effects on bone resorption.
The multinucleated osteoclasts (MNCs) were derived by 1,25-dihydroxyvitamin D3 and dexamethasone from bone marrow cells in the coculture system with primary osteoblastic cells. The tartrate-resistant acid phosphatase (TRAP) staining and image analysis of bone resorption pit on dental slices were used to identify osteoclast. The activity of TRAP was measured by p-nitrophenyl sodium phosphate assay. The bone resorption pit area on the bone slices formed by osteoclasts was measured by computer image processing.
At the concentrations of 0.1, 1 and 10 micromol/L, berberine dose-dependently suppressed the formation of TRAP-positive multinucleated cells, the TRAP activity and the osteoclastic bone resorption. The strongest inhibitory effect was exhibited at the concentration of 10 micromol/L, with the inhibiting rate of 60.45%, 42.12% and 72.69% respectively.
Berberine can decrease bone loss through inhibition of osteoclast formation, differentiation and bone resorption.

Wei P, Jiao L, Qin LP, Yan F…
Zhong Xi Yi Jie He Xue Bao Apr 2009
PMID: 19361364 | Free Full Text

Palmatine Inhibits Resorption in Mouse Cells

Abstract

Palmatine attenuates osteoclast differentiation and function through inhibition of receptor activator of nuclear factor-κb ligand expression in osteoblast cells.

Osteoclasts are the only cell type capable of resorbing mineralized bone, and they act under the control of numerous cytokines produced by supporting cells such as osteoblasts and stromal cells. Among cytokines, receptor activator of nuclear factor-κB ligand (RANKL) was found to be a key osteoclastogenetic molecule that directly binds to its cognate receptor, RANK, on osteoclast precursor cells. In turn, RANKL, which is an essential factor for differentiation and activation of osteoclasts, is one of the major targets of anti-resorptive agents. In this study, we found that palmatine, an isoquinoline alkaloid originally isolated from Coptis chinensis, had an inhibitory effect on osteoclast differentiation and function in vitro. Palmatine inhibited osteoclast formation in the co-culture system with mouse bone marrow cells (BMC) and osteoblasts in the presence of 10 nM 1α,25-(OH)(2)D(3). Palmatine did not affect osteoclast formation induced by RANKL in the BMC cultures. Reverse-transcription polymerase chain reaction (RT-PCR) analysis showed that palmatine significantly inhibited the expression of 1α,25-(OH)(2)D(3)-induced expression of RANKL mRNAs in stromal cells without loss of cell viability. Moreover, palmatine suppressed resorption pit formation by mature osteoclasts on dentin slices and induced disruption of actin ring formation in mature osteoclasts with an impact on cell viability. Taken together, these results suggest that palmatine attenuates osteoclast differentiation through inhibition of RANKL expression in osteoblast cells, and its inhibitory effect on bone resorption is due to its disruptive effect on actin rings in mature osteoclasts. Therefore, palmatine might be an ideal candidate as an anti-resorptive agent for the prevention and treatment of bone disorders such as osteoporosis.

Lee JW, Mase N, Yonezawa T, Seo HJ…
Biol. Pharm. Bull. 2010
PMID: 20930384 | Free Full Text

Berberine Prevents Osteoporosis from Steroids in Rats

Abstract

Preventive effects of berberine on glucocorticoid-induced osteoporosis in rats.

Glucocorticoids are widely used to treat chronic diseases such as rheumatoid arthritis and asthma. However, long-term glucocorticoid therapy can result in serious side effects, such as osteoporosis. The present study investigated the preventive effects of berberine on glucocorticoid-induced osteoporosis in rats. Male Sprague Dawley rats were treated with vehicle, glucocorticoid, glucocorticoid and berberine, or glucocorticoid and calcium carbonate with vitamin D (3) for 12 weeks. The proximal tibiae of all rats were processed without decalcification for quantitative bone histomorphometry, and femur mechanical testing as well as bone mineral density (BMD) were analyzed. A significant decrease was found in the glucocorticoid-treated group compared with the control group in such indices as biomechanical quality, BMD, trabecular bone volume/total tissue area (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), mineral apposition rate (MAR), bone formation rate/total tissue area (BFR/TV), and bone formation rate/trabecular bone surface (BFR/BS). In addition, significantly increased trabecular separation (Tb.Sp), osteoclast number/trabecular bone volume (Oc.N/BV), and osteoclast surface/trabecular bone surface (Oc.S/BS) were observed in the glucocorticoid-treated group, compared with the control group. Berberine and calcium carbonate with vitamin D (3) prevented the decrease in biomechanical quality, BMD, BV/TV, Tb.N, Tb.Th, MAR, BFR/TV, and BFR/BS, as well as increased Tb.Sp, Oc.N/BV, and Oc.S/BS in glucocorticoid-induced osteoporotic rats. The present results suggest that berberine prevents glucocorticoid-induced osteoporosis by inhibiting bone resorption and improving bone formation.

Xu D, Yang W, Zhou C, Liu Y…
Planta Med. Nov 2010
PMID: 20577944