scholarly journals Targeting actin-bundling protein L-plastin as an anabolic therapy for bone loss

2020 ◽  
Vol 6 (47) ◽  
pp. eabb7135
Author(s):  
Xiaoqun Li ◽  
Lipeng Wang ◽  
Biaotong Huang ◽  
Yanqiu Gu ◽  
Ying Luo ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Therapeutic Potential ◽  
Nuclear Factor Κb ◽  
Specific Protein ◽  
Tartrate Resistant Acid Phosphatase ◽  
Phosphatidylinositol 3 Kinase ◽  
Protein L ◽  
Vessel Growth ◽  
Anabolic Therapy

The actin-bundling protein L-plastin (LPL) mediates the resorption activity of osteoclasts, but its therapeutic potential in pathological bone loss remains unexplored. Here, we report that LPL knockout mice show increased bone mass and cortical thickness with more mononuclear tartrate-resistant acid phosphatase–positive cells, osteoblasts, CD31hiEmcnhi endothelial vessels, and fewer multinuclear osteoclasts in the bone marrow and periosteum. LPL deletion impeded preosteoclasts fusion by inhibiting filopodia formation and increased the number of preosteoclasts, which release platelet-derived growth factor-BB to promote CD31hiEmcnhi vessel growth and bone formation. LPL expression is regulated by the phosphatidylinositol 3-kinase/AKT/specific protein 1 axis in response to receptor activator of nuclear factor–κB ligand. Furthermore, we identified an LPL inhibitor, oroxylin A, that could maintain bone mass in ovariectomy-induced osteoporosis and accelerate bone fracture healing in mice. In conclusion, we showed that LPL regulates osteoclasts fusion, and targeting LPL serves as a novel anabolic therapy for pathological bone loss.

scholarly journals Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

2018 ◽  
Vol 48 (5) ◽  
pp. 2091-2102 ◽  
Author(s):  
Xin Sui ◽  
Shijian Deng ◽  
Mengmeng Liu ◽  
Linlin Fan ◽  
Yunfei Wang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Bone Growth ◽  
Osteoclast Differentiation ◽  
Marker Genes ◽  
Tartrate Resistant Acid Phosphatase ◽  
Bone Homeostasis ◽  
Micro Computed Tomography ◽  
Constitutive Activation

Background/Aims: Activation of the Wnt/β-catenin signalling pathway has been widely investigated in bone biology and shown to promote bone formation. However, its specific effects on osteoclast differentiation have not been fully elucidated. Our study aimed to identify the role of β-catenin in osteoclastogenesis and bone homeostasis. Methods: In the present study, exon 3 in the β-catenin gene (Ctnnb1) allele encoding phosphorylation target serine/threonine residues was flanked by floxP sequences. We generated mice exhibiting conditional β-catenin activation (Ctsk-Cre;Ctnnb1flox(exon3)/+, designated CA-β-catenin) by crossing Ctnnb1flox(exon3)/flox(exon3) mice with osteoclast-specific Ctsk-Cre mice. Bone growth and bone mass were analysed by micro-computed tomography (micro-CT) and histomorphometry. To further examine osteoclast activity, osteoclasts were induced from bone marrow monocytes (BMMs) isolated from CA-β-catenin and Control mice in vitro. Osteoclast differentiation was detected by tartrate-resistant acid phosphatase (TRAP) staining, immunofluorescence staining and reverse transcription-quantitative PCR (RT–qPCR) analysis. Results: Growth retardation and low bone mass were observed in CA-β-catenin mice. Compared to controls, CA-β-catenin mice had significantly reduced trabecular bone numbers under growth plates as well as thinner cortical bones. Moreover, increased TRAP-positive osteoclasts were observed on the surfaces of trabecular bones and cortical bones in the CA-β-catenin mice; consistent results were observed in vitro. In the CA-β-catenin group, excessive numbers of osteoclasts were induced from BMMs, accompanied by the increased expression of osteoclast-associated marker genes. Conclusion: These results indicated that the constitutive activation of β-catenin in osteoclasts promotes osteoclast formation, resulting in bone loss.

scholarly journals The Fungal Metabolite (+)-Terrein Abrogates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-κB Ligand–Induced Osteoclastogenesis by Suppressing Protein Kinase-C α/βII Phosphorylation

2021 ◽  
Vol 12 ◽  
Author(s):  
Kyosuke Sakaida ◽  
Kazuhiro Omori ◽  
Masaaki Nakayama ◽  
Hiroki Mandai ◽  
Saki Nakagawa ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Bone Metabolism ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Common Disease ◽  
Mouse Bone Marrow ◽  
Nuclear Factor ◽  
Receptor Activator

Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-κB ligand (RANKL)–induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKCα/βII, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.

Mild stimulatory effect of a probiotic mix on bone mass when treatment is initiated 1.5 weeks after ovariectomy in mice.

2021 ◽  
Author(s):  
Claes Ohlsson ◽  
Lina Lawenius ◽  
Annica Andersson ◽  
Karin L. Gustafsson ◽  
Jianyao Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Bone Loss ◽  
Regulatory T Cells ◽  
Bone Mass ◽  
Therapeutic Potential ◽  
Probiotic Bacteria ◽  
Trabecular Thickness ◽  
Early Postmenopausal Women ◽  
Bone Width ◽  
Probiotic Treatment

Studies in humans and rodents show that probiotic bacteria can protect from bone loss caused by sex-steroid deficiency. We showed earlier that a mixture of three probiotic bacteria, Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312 and DSM 15313 (L. Mix) protects mice from ovariectomy (ovx)-induced bone loss when treatment was started two weeks before sham and ovx surgery. In addition, the same probiotic treatment protected against lumbar spine bone loss in early postmenopausal women. In the present study we wanted to evaluate the therapeutic potential of L. Mix by starting treatment 1.5 weeks after ovx when most of the rapid bone loss as a result of estrogen deficiency, has already occurred. Treatment with L. Mix for 5.5 weeks increased the trabecular thickness but not the trabecular number in the proximal metaphyseal region of tibia compared to vehicle treatment. Cortical thickness and cortical area of the mid-diaphyseal part of tibia were decreased in the vehicle-treated ovx mice but not in L. Mix-treated ovx mice compared to sham mice. The bone protective effects of L. Mix in ovx mice were associated with a protection against ovx-induced reduction of the frequency of regulatory T-cells and of the expression of Tgfβ in the bone marrow. In conclusion, the probiotic L. Mix exerted a moderate stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 weeks after ovariectomy in mice. This effect was associated with effects on bone protecting regulatory T-cells. The results suggest that L. Mix may exert beneficial effects on bone mass when treatment is started after ovariectomy.

scholarly journals Dauricine Protects from LPS-Induced Bone Loss via the ROS/PP2A/NF-κB Axis in Osteoclasts

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 588 ◽  
Author(s):  
Hyun-Jung Park ◽  
Malihatosadat Gholam Zadeh ◽  
Jae-Hee Suh ◽  
Hye-Seon Choi
Keyword(s):  
Reactive Oxygen Species ◽  
Bone Loss ◽  
Nuclear Localization ◽  
Therapeutic Potential ◽  
Isoquinoline Alkaloid ◽  
Tartrate Resistant Acid Phosphatase ◽  
Oxygen Species ◽  
Trap Staining

Dauricine (DAC), an isoquinoline alkaloid, exhibits anti-inflammatory activity. We hypothesized that DAC may prevent the inflammatory bone loss induced by lipopolysaccharide (LPS). LPS-induced bone loss was decreased by DAC in female C57BL/6J mice as evaluated by micro-computerized tomography (μCT) analysis. In vivo tartrate-resistant acid phosphatase (TRAP) staining showed that the increased number of osteoclasts (OCs) in LPS-treated mice was attenuated by DAC, indicating that DAC exhibited bone sparing effects through acting on OCs. DAC also decreased the differentiation and activity of OCs after LPS stimulation in vitro. LPS-induced cytosolic reactive oxygen species (cROS) oxidized PP2A, a serine/threonine phosphatase, leading to the activation of IKKα/β, followed by the nuclear localization of p65. DAC decreased LPS-induced ROS, resulting in the recovery of the activity of PP2A by reducing its oxidized form. Consequently, DAC reduced the phosphorylation of IKKα/β to block the nuclear localization of p65, which decreased NF-κB activation. Taken together, DAC reduced the differentiation and activity of OCs by decreasing ROS via the ROS/PP2A/NF-κB axis, resulting in protection from LPS-induced bone loss. We have demonstrated that LPS-induced bone loss was inhibited by DAC via its action on OCs, implying the therapeutic potential of DAC against inflammatory bone loss.

Heparin acts synergistically with interleukin-11 to induce STAT3 activation and in vitro osteoclast formation

Blood ◽  
2002 ◽  
Vol 100 (7) ◽  
pp. 2530-2536 ◽  
Author(s):  
Kimberly J. Walton ◽  
Joanne M. Duncan ◽  
Paula Deschamps ◽  
Stephen G. Shaughnessy
Keyword(s):  
Bone Loss ◽  
Bone Marrow Cells ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Serine Phosphorylation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Multinucleated Cells ◽  
Interleukin 11

We have previously demonstrated that long-term heparin treatment causes cancellous bone loss in rats due in part to an increase in the number of osteoclasts lining the trabecular bone surface. In the present study, we investigated this phenomenon by examining the ability of heparin to synergistically enhance interleukin-11 (IL-11)–induced osteoclast formation. Treatment of murine calvaria and bone marrow cells with IL-11 was found to induce the formation of tartrate-resistant acid phosphatase-positive (TRAP+) multinucleated cells (MNCs) in a dose-dependent fashion. No effect was seen when cocultures were treated with heparin alone. However, when cocultures were treated with both IL-11 and heparin, IL-11's ability to induce TRAP+ MNC formation was enhanced 6-fold. In an attempt to resolve the mechanism responsible for this effect, we examined the ability of heparin to influence IL-11 signaling using murine calvaria cells. Heparin was found to enhance both IL-11–induced STAT3-DNA complex formation and transactivation without altering either STAT3 (signal transducer and activator of transcription-3) tyrosine or serine phosphorylation. Heparin was also found to enhance IL-11's ability to induce the expression of both receptor activator of nuclear factor–κB ligand (RANKL) and glycoprotein (gp) 130. When taken together, these findings suggest a plausible mechanism by which heparin may cause increased osteoclastogenesis and therefore bone loss when administered long-term.

scholarly journals Lycorine Attenuates Autophagy in Osteoclasts via an Axis of mROS/TRPML1/TFEB to Reduce LPS-Induced Bone Loss

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Hyun-Jung Park ◽  
Malihatosadat Gholam-Zadeh ◽  
Jae-Hee Suh ◽  
Hye-Seon Choi
Keyword(s):  
Bone Loss ◽  
Transient Receptor Potential ◽  
Nuclear Translocation ◽  
Therapeutic Potential ◽  
Receptor Potential ◽  
Tartrate Resistant Acid Phosphatase ◽  
Main Role ◽  
Sequestosome 1

Lycorine, a plant alkaloid, exhibits anti-inflammatory activity by acting in macrophages that share precursor cells with osteoclasts (OCs). We hypothesized that lycorine might decrease bone loss by acting in OCs after lipopolysaccharide (LPS) stimulation, since OCs play a main role in LPS-induced bone loss. Microcomputerized tomography (μCT) analysis revealed that lycorine attenuated LPS-induced bone loss in mice. In vivo tartrate-resistant acid phosphatase (TRAP) staining showed that increased surface area and number of OCs in LPS-treated mice were also decreased by lycorine treatment, suggesting that OCs are responsible for the bone-sparing effect of lycorine. In vitro, the increased number and activity of OCs induced by LPS were reduced by lycorine. Lycorine also decreased LPS-induced autophagy in OCs by evaluation of decreased lipidated form of microtubule-associated proteins 1A/1B light chain 3B (LC3) (LC3II) and increased sequestosome 1 (p62). Lycorine attenuated oxidized transient receptor potential cation channel, mucolipin subfamily (TRPML1) by reducing mitochondrial reactive oxygen species (mROS) and decreased transcription factor EB (TFEB) nuclear translocation. Lycorine reduced the number and activity of OCs by decreasing autophagy in OCs via an axis of mROS/TRPML1/TFEB. Collectively, lycorine protected against LPS-induced bone loss by acting in OCs. Our data highlight the therapeutic potential of lycorine for protection against inflammatory bone loss.

scholarly journals The Effects of Berry Anthocyanin-Rich Diets for the Protection Against Ovariectomy-Induced Bone Loss

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 391-391
Author(s):  
Marcus Elam ◽  
Jacquenlyn Valenzuela ◽  
Olivia Bouffard ◽  
Dalia Vasquez ◽  
Karenna Alexandra Martin ◽  
...  
Keyword(s):  
Body Weight ◽  
Bone Loss ◽  
Bone Mass ◽  
Agricultural Research ◽  
Lumbar Vertebrae ◽  
The United States ◽  
Normal Diet ◽  
Female Rats ◽  
Tartrate Resistant Acid Phosphatase ◽  
Low Bone Mass

Abstract Objectives Osteoporosis is a condition of low bone mass that may affect women due to an abrupt cessation of ovarian hormones and increased level inflammation and oxidation. As the United States population increases and longevity rises, low bone mass that could lead to fractures poses an even greater health issue and cause for unnecessary health expenses. More and more, individuals are seeking alternatives such as functional foods as oppose to drug medications to attenuate the bone loss. Fruits like dried plums and certain berries are purported to have beneficial effects as strong antioxidants in retarding bone loss resulting from aging. To provide further in vivo evidence of blueberry effects and determine whether strawberry is supportive of bone health for the benefit of human consumption. The hypothesis of this study is that blueberry- and strawberry-rich diets will prevent or slow the progression of ovariectomy-induced bone loss in a rat model (Sprague Dawley) of osteoporosis. Methods We fed 15 estrogen-deficient female rats (3-month old) with either a blueberry-rich (10% w/w), strawberry-rich (10% w/w), or normal diet (Ovx), and 3 intact (Sham) rats a normal diet for 13 weeks. Upon sacrifice, we collected major organs, blood, vertebrae, femora, and tibiae for analysis. Three-point bending tests were performed using a compressive hydraulic system on the femora and tibiae to asses bone fracture point, stiffness, and elasticity. Tissue mineralization of the 6th lumbar vertebrae were measured as ratio of ash to dry weight burning at 800°C in a muffled furnace. Serum bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b are being measured currently for presentation of results at the conference. Results There were no differences in body weight between groups at the start or termination of the study, nor were changes in body weight different (P > 0.05). Tissue mineralization trended to significance (P < 0.08) between Sham and Ovx groups, but not when comparing blueberry and strawberry groups to Ovx. The remaining data will be reported at the conference. Conclusions Thus far, we cannot conclude that berry-rich diets are sufficient to protect against ovariectomy-induced bone loss in female rats. Funding Sources The Agricultural Research Institute (ARI) of California State University.

scholarly journals Ethanol Extracts of FreshDavallia formosana(WL1101) Inhibit Osteoclast Differentiation by Suppressing RANKL-Induced Nuclear Factor-κB Activation

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Tzu-Hung Lin ◽  
Rong-Sen Yang ◽  
Kuan-Chin Wang ◽  
Dai-Hua Lu ◽  
Houng-Chi Liou ◽  
...  
Keyword(s):  
Bone Loss ◽  
Nuclear Translocation ◽  
Therapeutic Potential ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Ovariectomized Rats ◽  
Nuclear Factor ◽  
Receptor Activator ◽  
Trabecular Bone Loss ◽  
Ethanol Extracts

The rhizome ofDavallia formosanais commonly used to treat bone disease including bone fracture, arthritis, and osteoporosis in Chinese herbal medicine. Here, we report the effects of WL1101, the ethanol extracts of fresh rhizomes ofDavallia formosanaon ovariectomy-induced osteoporosis. In addition, excess activated bone-resorbing osteoclasts play crucial roles in inflammation-induced bone loss diseases, including rheumatoid arthritis and osteoporosis. In this study, we examined the effects of WL1101 on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Treatment with WL1101 significantly inhibited RANKL-stimulated osteoclastogenesis. Two isolated active compounds, ((−)-epicatechin) or WL14 (4-hydroxy-3-aminobenzoic acid) could also inhibit RANKL-induced osteoclastogenesis. WL1101 suppressed the RANKL-induced nuclear factor-κB (NF-κB) activation and nuclear translocation, which is the key process during osteoclastogenesis, by inhibiting the activation of IκB kinase (IKK) and IκBα. In animal model, oral administration of WL1101 (50 or 200 mg/kg/day) effectively decreased the excess bone resorption and significantly antagonized the trabecular bone loss in ovariectomized rats. Our results demonstrate that the ethanol extracts of fresh rhizomes ofDavallia formosanainhibit osteoclast differentiation via the inhibition of NF-κB activation and effectively ameliorate ovariectomy-induced osteoporosis. WL1101 may thus have therapeutic potential for the treatment of diseases associated with excessive osteoclastic activity.

Taxifolin Inhibits Receptor Activator of NF-κB Ligand-Induced Osteoclastogenesis of Human Bone Marrow-Derived Macrophages in vitro and Prevents Lipopolysaccharide-Induced Bone Loss in vivo

Pharmacology ◽  
2018 ◽  
Vol 103 (1-2) ◽  
pp. 101-109 ◽  
Author(s):  
Hong-Qi Zhang ◽  
Yun-Jia Wang ◽  
Guan-Teng Yang ◽  
Qi-Le Gao ◽  
Ming-Xing Tang
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Therapeutic Potential ◽  
Osteoclast Differentiation ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Tartrate Resistant Acid Phosphatase ◽  
Receptor Activator

It has been reported that taxifolin inhibit osteoclastogenesis in RAW264.7 cells. In our research, the inhibition effects of taxifolin on the osteoclastogenesis of human bone marrow-derived macrophages (BMMs) induced by receptor activator of NF-κB ligand (RANKL) as well as the protection effects in lipopolysaccharide-induced bone lysis mouse model have been demonstrated. In vitro, taxifolin inhibited RANKL-induced osteoclast differentiation of human BMMs without cytotoxicity. Moreover, taxifolin significantly suppressed RANKL-induced gene expression, including tartrate-resistant acid phosphatase, matrix metalloproteinase-9 nuclear factor of activated T cells 1 and cathepsin K, and F-actin ring formation. Further studies showed that taxifolin inhibit osteoclastogenesis via the suppression of the NF-κB signaling pathway. In vivo, taxifolin prevented bone loss in mouse calvarial osteolysis model. In conclusion, the results suggested that taxifolin has a therapeutic potential for osteoclastogenesis-related diseases such as osteoporosis, osteolysis, and rheumatoid arthritis.

scholarly journals Different Molecular Mechanisms Underlie Ethanol-Induced Bone Loss in Cycling and Pregnant Rats

Endocrinology ◽  
2006 ◽  
Vol 147 (1) ◽  
pp. 166-178 ◽  
Author(s):  
Kartik Shankar ◽  
Mats Hidestrand ◽  
Rani Haley ◽  
Robert A. Skinner ◽  
William Hogue ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Mineral ◽  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Tartrate Resistant Acid Phosphatase ◽  
Mineral Density ◽  
Pregnant Rats ◽  
Estradiol Levels

Chronic ethanol (EtOH) consumption can result in osteopenia. In the current study, we examined the modulation of EtOH-induced bone loss during pregnancy. Nonpregnant and pregnant dams were intragastrically infused either control or EtOH-containing diets throughout gestation (gestation d 5 through 20 or an equivalent period of 15 d) by total enteral nutrition. The effects of EtOH (8.5 to 14 g/kg/d) on tibial bone mineral density (BMD), mineral content (BMC), and bone mineral area were assessed at gestation d 20 via peripheral quantitative computerized tomography. EtOH caused a dose-dependent decrease in BMD and BMC without affecting bone mineral area. Trabecular BMD and BMC were significantly lower in EtOH-treated, nonpregnant dams, compared with pregnant cohorts at the same infused dose of EtOH and urinary ethanol concentrations. Static histomorphometric analysis of tibiae from pregnant rats after EtOH treatment showed decreased osteoblast and osteoid surface, indicating inhibited bone formation, whereas EtOH-treated cycling rats showed higher osteoclast and eroded surface, indicative of increased bone resorption. Circulating osteocalcin and 1,25-dihydroxyvitamin D3 were lower in both EtOH-fed nonpregnant and pregnant rats. Gene expression of osteoclast markers, 70 kDa v-ATPase, and tartrate-resistant acid phosphatase were increased selectively in nonpregnant EtOH-treated rats but not pregnant rats. Moreover, only nonpregnant EtOH-fed rats showed induction in bone marrow receptor activator of nuclear factor-κB ligand mRNA and decreased circulating 17β-estradiol levels. Our data suggest that EtOH-induced bone loss in pregnant rats is mainly due to inhibited bone formation, whereas in nonpregnant rats, the data are consistent with increased osteoclast activation and bone resorption concomitant with decreased estradiol levels.

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