Bone Protective Effects Research Articles

Potential medicinal benefits of Cosmos caudatus (Ulam Raja): A scoping review.

Cosmos caudatus is widely used as a traditional medicine in Southeast Asia. C. caudatus has been reported as a rich source of bioactive compounds such as ascorbic acid, quercetin, and chlorogenic acid. Studies have shown that C. caudatus exhibits high anti-oxidant capacity and various medicinal properties, including anti-diabetic activity, anti-hypertensive properties, anti-inflammatory responses, bone-protective effect, and anti-microbial activity. This review aims to present the potential medicinal benefits of C. caudatus from the available scientific literature. We searched PubMed and ScienceDirect database for articles published from 1995 to January 2015. Overall, 15 articles related to C. caudatus and its medicinal benefits are reviewed. All these studies demonstrated that C. caudatus is effective, having demonstrated its anti-diabetic, anti-hypertensive, anti-inflammatory, bone-protective, anti-microbial, and anti-fungal activity in both in vitro and animal studies. None of the studies showed any negative effect of C. caudatus related to medicinal use. Currently available evidence suggests that C. caudatus has beneficial effects such as reducing blood glucose, reducing blood pressure, promoting healthy bone formation, and demonstrating anti-inflammatory and anti-microbial properties. However, human clinical trial is warranted.

Treatment of osteoporosis: current state of the art.

Osteoporosis can be treated with medications and lifestyle changes, including avoiding a sedentary lifestyle, alcohol, and smoking. We will identify medications that protect against hip fractures in addition to vertebral fractures, and explore new evidence of adverse effects and risks. Bisphosphonates are used as first-line treatment. We will discuss the latest osteoporosis medications, drug interactions, potential bone protective effects of other drug classes, and the evidence of exercise and kyphoplasty.

Effects of Cabozantinib Alone and in Combination with Bortezomib in the 5TGM1 Murine Multiple Myeloma Model

Introduction: Cabozantinib (cabo) is an inhibitor of tyrosine kinases including MET, VEGFR2, RET, and the TAM family kinases TYRO3, AXL, and MER. Cabo has shown clinical activity in patients with castration-resistant prostate cancer and other solid tumors with bone metastases. Multiple myeloma (MM) is the second most common hematologic malignancy, and represents ~2% of all cancer deaths. MM is a monoclonal B-cell (plasma cell) neoplasia with clinical hallmarks of multiple osteolytic lesions causing bone pain, pathologic fractures, and hypercalcemia. Circulating levels of HGF and VEGF are upregulated in MM patients, and regulation of plasma cell-osteoblast communication by the HGF-MET signaling pathway has been implicated in the development of lytic bone disease in these patients. Thus, the primary objectives of this research were to A): determine the activity of cabo on bone lesions and tumor burden in the syngeneic 5TGM1 mouse MM model (study 1), and B): investigate the impact of cabo on overall survival of these mice when dosed alone or in combination with bortezomib (btz) (study 2).Methods: Female C57BL/KaLwRij mice were allocated to treatment groups (n=15-16 per group) with equivalent average body weights. Four experimental groups were utilized in each of 2 studies: a vehicle control group, and groups receiving single agent btz (0.5 mg/kg ip twice a week) or cabo (10 mg/kg, PO QD). Study 1 also included a higher dose cabo group (30 mg/kg, PO QD), and study 2 included a combination group: btz (0.5 mg/kg ip twice a week) plus cabo (10 mg/kg, PO QD). In study 2, each single agent group also received the vehicle from the alternate single-agent group via the appropriate route and schedule.On day 0, animals were inoculated with 5TGM1 mouse myeloma cells by IV administration. Dosing began on day 1 and continued daily until euthanasia at day 35 (study 1) or day 70 (study 2). Body weights were determined twice a week and blood samples were collected on days -1, 15, 22, and 34 for analysis of paraprotein (IgG2b) and TRACP 5b. In study 1 the development of osteolytic lesions was detected by radiography at the end of the study. Some animals were euthanized before the end of the experiment due to paraplegia. Animals euthanized within four days of the end of the experiment in study 1 were included in the analyses.Results: In study 1, btz reduced serum IgG2b levels, and decreased the frequency of soft tissue lesions, but did not show bone protective properties. Cabo exhibited bone protective effects: mean and total area of osteolytic lesions were reduced at the 30 mg/kg dose, and serum TRACP 5b values and osteoclast counts at the tumor-bone interface were reduced at both the 10 and 30 mg/kg doses. Relative bone area did not differ from control according to histomorphometry. The rise in serum IgG2b started earlier than vehicle control in both cabo-treated groups, but a significant difference was not observed in relative IgG2b at sacrifice. Cabo dose dependently increased the necrotic tumor area in bone, indicating the possibility that the rise in IgG2b may have been due to lysis of plasma cells. Both doses of cabo decreased the frequency of soft tissue lesions.In study 2, the median survival times were 36 d (vehicle), 43 d (btz), 48 d (cabo), and 55 d (cabo+btz). The prolongation of OS compared to vehicle was statistically significant for the cabo group but not for the btz group. Prolongation of OS in the combination group was significant compared to btz alone, but not when compared to cabo alone.Conclusions: Cabo showed both bone-protective and anti-tumor effects in this murine model of MM. In addition, statistically-significant prolongation of overall survival was observed with the combination of cabo+btz compared to btz alone, and with single-agent cabo compared to vehicle. Based on these results, further investigation of cabozantinib alone or in combination with other agents in multiple myeloma is warranted. DisclosuresAftab:Exelixis: Employment, Equity Ownership. Suominen:Pharmatest: Employment; Exelixis: Research Funding. Clary:Exelixis: Employment, Equity Ownership. Käkönen:Pharmatest: Employment; Exelixis: Research Funding. Fagerlund:Pharmatest: Employment; Exelixis: Research Funding. Alhoniemi:Pharmatest: Employment; Exelixis: Research Funding. Rissanen:Pharmatest: Employment; Exelixis: Research Funding. Halleen:Pharmatest: Employment; Exelixis: Research Funding.

Cyanidin 3-O-β-D-Glucoside Improves Bone Indices.

Oxidative stress (OS) promotes bone loss after menopause, and there is evidence that dietary antioxidants may reduce the level of OS in vivo. This study examined dose-dependent effects of blackberries (BBs) containing mainly cyanidin 3-O-β-d-glucoside (C3G) in preventing bone loss in an ovariectomized (Ovx) rat model. Nine-month-old female (N=38) Sprague-Dawley rats were scanned using dual-energy X-ray absorptiometry for baseline whole body, bone mineral content (BMC), and bone mineral density (BMD). One group was sham operated (Sham) and three groups were ovariectomized (Ovx). The groups and corresponding diets were Sham+control diet (n=12), Ovx+control diet (n=12), Ovx+5% BB (n=7), and Ovx+10% BB (n=7). Control diet was AIN-93M rodent diet, and the Ovx+5% BB and Ovx+10% BB were a diet modified to contain powdered, freeze-dried BB at levels of 5% and 10% (w/w). Following 100 days of treatment, whole body BMC and BMD were reassessed and bone specimens, blood, and 24-h urine samples were collected for analyses. Findings indicate that ovariectomy (Ovx) compromised whole body BMC and trabecular microarchitecture of the proximal tibia and fourth lumbar vertebra. C3G-rich BB at the level of 5% modestly protected BMDs, loss of the tibia, lumbar vertebra, and femur by 2.4%, 2.7%, and 4.3% (P<.0013; .0437; .0004), respectively. BB 5% treatment significantly prevented loss of tibial trabecular bone volume and trabecular number by 37% and 21%, respectively (P<.05), and also significantly prevented tibial trabecular separation by 22%. We conclude that C3G-rich BB treatment at the level of 5% (w/w) but not at 10% (w/w) may modestly reduce Ovx-induced bone loss evident by improved tibial, vertebral, and femoral BMD values, and tibial bone microstructural parameters. Bone protective effects may be as a result of the synergistic effects of phenolic compounds; however, further work is required to determine BBs' specific mechanisms of action.

Abstract 734: Effects of Cabozantinib in the 5TGM1 murine multiple myeloma model

Abstract Cabozantinib is an inhibitor of tyrosine kinases including MET, VEGFR2, and RET, and has shown clinical activity in patients with castration-resistant prostate cancer and other solid tumors with bone metastases. Multiple myeloma (MM) is the second most common hematologic malignancy, and represents ∼2% of all cancer deaths. MM is a monoclonal B-cell (plasma cell) neoplasia with clinical hallmarks of multiple osteolytic lesions causing bone pain, pathologic fractures, and hypercalcemia. Circulating levels of HGF and VEGF are upregulated in MM patients, and regulation of plasma cell-osteoblast communication by the HGF-MET signaling pathway has been implicated in the development of lytic bone disease in these patients. Thus, our aim was to determine the activity of cabozantinib on bone lesions and tumor burden in the syngeneic 5TGM1 mouse MM model. Four experimental groups were included: negative control group receiving vehicle, positive control group receiving bortezomib (0.5 mg/kg ip twice a week), low dose cabozantinib group (10 mg/kg, PO QD) and high dose cabozantinib group (30 mg/kg, PO QD). Female C57BL/KaLwRij mice were allocated to treatment groups (n=15 per group) with equivalent average body weights. On day 0, animals were inoculated with 5TGM1 mouse myeloma cells by IV administration. Dosing began on day 1 and continued daily until euthanasia at day 35. Body weights were determined twice a week and blood samples were collected on days -1, 15, 22, and 34 for analysis of paraprotein (IgG2b) and TRACP 5b. The development of osteolytic lesions was detected by radiography at the end of the study. Some animals (4/15) were euthanized before the end of the experiment due to paraplegia in control and bortezomib groups, but none in cabozantinib groups. Animals euthanized within four days of the end of the experiment were included in the analysis. Bortezomib reduced serum IgG2b levels and decreased the frequency of soft tissue lesions, but did not show bone protective properties. Cabozantinib exhibited bone protective effects: mean and total area of osteolytic lesions were reduced at the 30 mg/kg dose, and serum TRACP 5b values and osteoclast counts at the tumor-bone interface were reduced at both the 10 and 30 mg/kg doses. Relative bone area did not differ from control according to histomorphometry. The rise in serum IgG2b started earlier than vehicle control in both cabo-treated groups, but a significant difference was not observed in relative IgG2b at sacrifice. Cabozantinib dose dependently increased the necrotic tumor area in bone, indicating the possibility that the rise in IgG2b may have been due to lysis of plasma cells. Both cabozantinib doses decreased the frequency of soft tissue lesions. In summary, cabozantinib showed both bone-protective and anti-tumor effects in this murine model of MM. Based on these promising results, further investigation of cabozantinib in multiple myeloma is warranted. Citation Format: Mari I. Suominen, Douglas O. Clary, Rami Käkönen, Katja M. Fagerlund, Esa Alhoniemi, Jukka P. Rissanen, Jussi M. Halleen, Dana T. Aftab. Effects of Cabozantinib in the 5TGM1 murine multiple myeloma model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 734. doi:10.1158/1538-7445.AM2014-734

Modulation of osteoclast formation and activity by phytoestrogens and docosahexanoic acid in RAW264.7 murine monocytes

Modulation of osteoclast formation and activity by phytoestrogens and docosahexanoic acid in RAW264.7 murine monocytes This study was conducted to determine the in vitro effects of genistein and daidzein together with docosahexanoic acid on the proliferation, osteoclastogenesis and bone resorption in RAW264.7 murine monocytes. It was seen that docosahexanoic acid, and phytoestrogens, genistein and daidzein have a bone protective effect in vitro.

Soluble guanylate cyclase as a novel treatment target for osteoporosis.

Osteoporosis is a major health problem leading to fractures that cause substantial morbidity and mortality. Current osteoporosis therapies have significant drawbacks, creating a need for novel bone-anabolic agents. We previously showed that the nitric oxide/cyclic GMP (cGMP)/protein kinase G pathway mediates some of the anabolic effects of estrogens and mechanical stimulation in osteoblasts and osteocytes, leading us to hypothesize that cGMP-elevating agents may have bone-protective effects. We tested cinaciguat, a prototype of a novel class of soluble guanylate cyclase activators, in a mouse model of estrogen deficiency-induced osteoporosis. Compared with sham-operated mice, ovariectomized mice had lower serum cGMP concentrations, which were largely restored to normal by treatment with cinaciguat or low-dose 17β-estradiol. Microcomputed tomography of tibiae showed that cinaciguat significantly improved trabecular bone microarchitecture in ovariectomized animals, with effect sizes similar to those obtained with estrogen replacement therapy. Cinaciguat reversed ovariectomy-induced osteocyte apoptosis as efficiently as estradiol and enhanced bone formation parameters in vivo, consistent with in vitro effects on osteoblast proliferation, differentiation, and survival. Compared with 17β-estradiol, which completely reversed the ovariectomy-induced increase in osteoclast number, cinaciguat had little effect on osteoclasts. Direct guanylate cyclase stimulators have been extremely well tolerated in clinical trials of cardiovascular diseases, and our findings provide proof-of-concept for this new class of drugs as a novel, anabolic treatment strategy for postmenopausal osteoporosis, confirming an important role of nitric oxide/cGMP/protein kinase G signaling in bone.

Time and dose-dependent effects of Labisia pumila on bone oxidative status of postmenopausal osteoporosis rat model.

Postmenopausal osteoporosis can be associated with oxidative stress and deterioration of antioxidant enzymes. It is mainly treated with estrogen replacement therapy (ERT). Although effective, ERT may cause adverse effects such as breast cancer and pulmonary embolism. Labisia pumila var. alata (LP), a herb used traditionally for women’s health was found to protect against estrogen-deficient osteoporosis. An extensive study was conducted in a postmenopausal osteoporosis rat model using several LP doses and duration of treatments to determine if anti-oxidative mechanisms were involved in its bone protective effects. Ninety-six female Sprague-Dawley rats were randomly divided into six groups; baseline group (BL), sham-operated (Sham), ovariectomised control (OVXC), ovariectomised (OVX) and given 64.5 μg/kg of Premarin (ERT), ovariectomised and given 20 mg/kg of LP (LP20) and ovariectomised and given 100 mg/kg of LP (LP100). The groups were further subdivided to receive their respective treatments via daily oral gavages for three, six or nine weeks of treatment periods. Following euthanization, the femora were dissected out for bone oxidative measurements which include superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA) levels. Results: The SOD levels of the sham-operated and all the treatment groups were significantly higher than the OVX groups at all treatment periods. The GPx level of ERT and LP100 groups at the 9th week of treatment were significantly higher than the baseline and OVX groups. MDA level of the OVX group was significantly higher than all the other groups at weeks 6 and 9. The LP20 and LP100 groups at the 9th week of treatment had significantly lower MDA levels than the ERT group. There were no significant differences between LP20 and LP100 for all parameters. Thus, LP supplementations at both doses, which showed the best results at 9 weeks, may reduce oxidative stress which in turn may prevent bone loss via its anti-oxidative property.

Vanillic acid exerts oestrogen-like activities in osteoblast-like UMR 106 cells through MAP kinase (MEK/ERK)-mediated ER signaling pathway

Sambucus williamsii Hance (SWH) has been used for treatment of bone and joint disease in China for thousands of years. Our previous study showed that SWH extract and its bioactive fraction could effectively prevent oestrogen-deficiency induced bone loss in ovariectomized mice. The present study aimed to study the bone protective effects of vanillic acid (VA), a phenolic acid isolated from the bioactive fraction of SWH, and to characterize the signaling pathways that mediated its actions in rat osteoblast-like UMR 106 cells. VA significantly stimulated proliferation, alkaline phosphatase (ALP) activities as well as significantly altered the mRNA expression of genes involved in osteoblast functions and osteoclastogenesis in UMR 106 cells. Co-treatment of UMR 106 cells with 10−6M ICI182,780 (a specific oestrogen receptor (ER) antagonist) abolished the stimulatory effects of VA on osteoblast proliferation and ALP activities, suggesting the role of ER in mediating its actions. However, VA (10−12 to 10−6M) failed to bind to ERα or ERβ and did not activate oestrogen response element (ERE)-luciferase activities via ERα or ERβ in UMR 106 cells. In contrast, 10−10 and 10−8M of VA induced the phosphorylation of MEK 1/2, ERK1/2 and ERα at Ser118 residue in UMR 106 cells, suggesting that MAP kinase-mediated pathway is involved in mediating its actions. Taken together, our results indicated that VA is a bioactive compound in SWH that exerts stimulatory effects in osteoblast-like cells via non-genomic, but not classical, ER signaling pathway.

Development of a UPLC-MS/MS bioanalytical method for the pharmacokinetic study of (-)-epiafzelechin, a flavan-3-ol with osteoprotective activity, in C57BL/6J mice.

(-)-Epiafzelechin is a flavan-3-ol commonly found in plant source. Biological studies suggested that (-)-epiafzelechin may have anti-inflammatory, anti-oxidant and bone-protective effect. However, it's in vivo efficacy remains to be demonstrated. A specific detection method for (-)-epiafzelechin was successfully developed by using UPLC-MS/MS to quantify the amount of (-)-epiafzelechin present in mice plasma after a liquid-liquid extraction by ethyl acetate. The separation was achieved by using a reversed-phase C18 column with a 16 min gradient elution protocol consisting of water (0.1%, v/v, formic acid) and 0-70% ACN (0.1%, v/v, formic acid). The lower limit of quantitation for (-)-epiafzelechin was found to be 12.5 ng/mL. This method exhibited a good linearity (r(2)=0.992). The intra-day and inter-day precision were within 12%, while the accuracy was between 97.6 and 113. 4%. A quantity of 10mg/kg synthetic (-)-epiafzelechin was administered to C57BL/6J mice by intravenous (i.v.) and intraperitoneal (i.p.) injections and the blood was collected at different time points. The plasma was then analyzed by the UPLC-MS/MS method, and the plasma drug concentration-time curves for i.v. and i.p. (-)-epiafzelechin injection were constructed. The maximum concentrations (Cmax) of (-)-epiafzelechin in blood by i.v. and i.p. injection were found to be 10.6 and 6.0 μg/mL, respectively, while the time for reaching Cmax in i.p. injection was found to be 15 min. The distribution half-lives of (-)-epiafzelechin after i.v. and i.p. injection were found to be 7.0 and 12.6 min, respectively. Some of the PK parameters were found to be similar in both i.v. and i.p. injections of (-)-epiafzelechin owing to its high solubility in water.

AB0390 Serum RANKL Activity is Suppressed by TNF Alpha Inhibition but not with MTX Alone

BackgroundBone is, together with cartilage a central target of rheumatoid arthritis (RA). Chronic synovitis attacks the juxtaarticular bone, where it causes bone erosions. Formation of bone erosions is a consequence...

Antioxidant-rich berries exert modest bone protective effects in postmenopausal smokers without improving biomarkers of bone metabolism

Phenolic compounds from berries have shown bone protective effects in animal studies. We hypothesized that consumption of 45 g of blackberries or blueberries for 9 months will prevent smoking-induced bone loss in postmenopausal women. Postmenopausal smokers (n = 45) and nonsmokers (n = 20) were recruited. Smokers were randomly assigned to treatment groups: smoker control (n = 21); smoker + 45 g freeze-dried blackberries (n = 8); or smoker + 45 g freeze-dried blueberries (n = 16). We measured bone mineral density (BMD) at 0 and 9 months, urinary deoxypyridinoline, bone alkaline phosphate, osteocalcin, thiobarbituric acid reactive substances (TBARS) and highly sensitive C-reactive protein at 0, 3, 6, 9 months. Bone loss of total body BMD was statistically significant in S-C and S-BL groups, but not in S-BB and NS groups (p = 0.0284). Findings indicated that blackberries but not blueberries modestly protected against smoking-induced bone loss in postmenopausal smokers.

Influence of Aromatase Inhibition on the Bone Protective Effects of Testosterone

Influence of Aromatase Inhibition on the Bone Protective Effects of Testosterone

Influence of aromatase inhibition on the bone-protective effects of testosterone.

The influence of the aromatase enzyme in androgen-induced bone maintenance after skeletal maturity remains somewhat unclear. Our purpose was to determine whether aromatase activity is essential to androgen-induced bone maintenance. Ten-month-old male Fisher 344 rats (n = 73) were randomly assigned to receive Sham surgery, orchiectomy (ORX), ORX + anastrozole (AN; aromatase inhibitor), ORX + testosterone-enanthate (TE, 7.0 mg/wk), ORX + TE + AN, ORX + trenbolone-enanthate (TREN; nonaromatizable, nonestrogenic testosterone analogue; 1.0 mg/wk), or ORX + TREN + AN. ORX animals exhibited histomorphometric indices of high-turnover osteopenia and reduced cancellous bone volume compared with Shams. Both TE and TREN administration suppressed cancellous bone turnover similarly and fully prevented ORX-induced cancellous bone loss. TE- and TREN-treated animals also exhibited greater femoral neck shear strength than ORX animals. AN co-administration slightly inhibited the suppression of bone resorption in TE-treated animals but did not alter TE-induced suppression of bone formation or the osteogenic effects of this androgen. In TREN-treated animals, AN co-administration produced no discernible effects on cancellous bone turnover or bone volume. ORX animals also exhibited reduced levator ani/bulbocavernosus (LABC) muscle mass and elevated visceral adiposity. In contrast, TE and TREN produced potent myotrophic effects in the LABC muscle and maintained fat mass at the level of Shams. AN co-administration did not alter androgen-induced effects on muscle or fat. In conclusion, androgens are able to induce direct effects on musculoskeletal and adipose tissue, independent of aromatase activity.

Water Extract of Acer tegmentosum Reduces Bone Destruction by Inhibiting Osteoclast Differentiation and Function

The stem of Acer tegmentosum has been widely used in Korea for the treatment of hepatic disorders. In this study, we investigated the bone protective effect of water extract of the stem of Acer tegmentosum (WEAT). We found that WEAT inhibits osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclast differentiation. In osteoclast precursor cells, WEAT inhibited RANKL-induced activation of JNK, NF-κB, and cAMP response element-binding protein, leading to suppression of the induction of c-Fos and nuclear factor of activated T cells cytoplasmic 1, key transcription factors for osteoclast differentiation. In addition, WEAT inhibited bone resorbing activity of mature osteoclasts. Furthermore, the oral administration of WEAT reduced RANKL-induced bone resorption and trabecular bone loss in mice. Taken together, our study demonstrates that WEAT possesses a protective effect on bone destruction by inhibiting osteoclast differentiation and function.

Dietary L-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary l-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+l-lysine·HCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. l-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary l-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of l-lysine. Dietary l-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/phosphate solution. In conclusion, dietary supplementation of l-lysine ameliorated VC by modifying key pathways that exacerbate VC.

Infliximab attenuates inflammatory osteolysis in a model of periodontitis in Wistar rats

Periodontitis is a chronic inflammatory disease related to tooth loss in adults. Infliximab is a chimeric monoclonal antibody against TNF-α and is prescribed for the treatment of systemic inflammatory diseases. This study aimed to investigate the role of infliximab on experimental periodontal disease (EPD). EPD was induced by passing a 3.0 nylon thread around the upper left second molar in Wistar rats. Animals were either treated with intravenous infliximab (1, 5, 7, and 10 mg/kg) or saline solution 30 min before the periodontitis induction and were followed until they were sacrificed on the 11th day. A subset of rats was euthanized on the third day for analysis of gingival myeloperoxidase (MPO) and the blood MPO granulocyte index. In addition, we analyzed the bone loss index (BLI), the periodontal histopathological score, and the periodontal collagen network using confocal microscopy. We also analyzed metalloproteinase-1/-8, RANK, RANK-L, and osteoprotegerin in maxillary tissue by immunohistochemistry Gingival MPO, IL-1β, TNF-α were measured by ELISA. EPD caused leukocytosis, significant increases in BLI and gingival pro-inflammatory cytokines and cell infiltrates, with worse histopathological scores and periodontal collagen derangement. Infliximab (5 mg/kg) reduced granulocyte blood counts, gingival IL-1β, TNF-α, and MPO levels, diminished MMP-1/-8, RANK, and RANK-L bone immunolabeling with better periodontal histopathological scores and collagen network in comparison with the challenged saline group. We concluded that infliximab had significant anti-inflammatory and bone-protective effects in Wistar rats challenged by periodontitis.

Incretin Based Therapies: Bone Protective Effects

Type 2 Diabetes Mellitus (T2D) and osteoporosis have been found recently to be tightly correlated. In fact, T2D can result in bone loss through different mechanisms resulting in alteration of bone matrix and inhibition of bone formation. Fracture risk also increases significantly. New antidiabetic agents, dipeptidyl peptidase-4 inhibitors and glucagon like peptide -1 agonists have shown promise in many fields beyond glycemic control. Benefits on the skeletal system are multiple through direct stimulation of osteoblasts, inhibition of advanced glycation end products and inhibition of bone resorption. However, clinical evidence in humans is still not enough to allow definitive conclusions.

New lignans from the bioactive fraction of Sambucus williamsii Hance and proliferation activities on osteoblastic-like UMR106 cells

Four new lignans (1, 7–9), together with nine known ones, were isolated from the anti-osteoporosis fraction of the extract of Sambucus williamsii Hance which was eluted by 50% and 95% aqueous ethanol over D101 macroporous resin column. Their structures were elucidated by NMR spectroscopic analyses, and the absolute configurations of all compounds were determined by application of circular dichroism method. All the compounds were reported for the first time from the Sambucus genus and firstly studied for their proliferation effects on osteoblastic-like UMR 106 cell. The data showed that compounds 2–9 significantly promoted cell proliferation in some dose, especially compounds 2, 3, 4, 5, and 7 increased osteoblastic cell numbers by 31.3%, 28.3%, 25.6%, 25.1% and 26.0% at 10−10M, 10−10M, 10−7M, 10−10M and 10−10M, respectively, which suggested that lignans were the components accounting for the bone protective effects of SWH.

Iguratimod Synergizes with Methotrexate to Exert Anti-Inflammatory and Bone-Protective Effect and Block the Progression of Collagen-Induced Arthritis in Mices

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation and disability. The most widely used Disease-Modifying Antirheumatic Drug (DMARD) is methotrexate and it continues to be the gold standard. However, the use of high-dose methotrexate is associated with severe adverse effects. Iguratimod, which is currently used in clinics in China and Japan, is a novel oral DMARD for the treatment of RA. In this study, the effect of combination of methotrexate and iguratimod on murine Collagen-Induced Arthritis (CIA) and its mechanism was determined. Oral administration of iguratimod (3 mg/kg, 10 mg/kg) combined with methotrexate (1 mg/kg) potently blocked CIA development and delayed its progression, which was stronger than iguratimod or methotrexate used alone. Furthermore, infiltration of inflammatory cells into the synovium was remarkably inhibited by combination therapy and importantly, no bone erosion and joint destructions were observed in combination therapy group. In addition, combined administration of these two DMARDs suppressed production of cytokines (IL-17, IFN-γ, IL-6 and TNF-α) and antibodies (IgG and IgG2b) in serum, as well as humoral and cellular responses in CIA mice. Consistent with its effects in vivo, iguratimod combined with methotrexate significantly suppressed T and B cells responses in vitro. Taken together, our findings suggest that combination treatment with iguratimod and methotrexate should be an intriguing and preferable therapeutic strategy for treating RA.