Synergistic effects of combined therapy of curcumin and Fructus Ligustri Lucidi for treatment of osteoporosis: cellular and molecular evidence of enhanced bone formation

Abstract Purpose The purpose of this article is to review the pharmacology, efficacy, and safety of the sclerostin inhibitor romosozumab for the treatment of osteoporosis, including data from clinical trials of the drug. Summary A review of the literature was performed by searching PubMed and MEDLINE for all relevant articles published between January 2014 and February 2020 using the keywords romosozumab, romosozumab-aqqg, osteoporosis, and fracture. All relevant English-language articles evaluating the pharmacology, efficacy, or safety of romosozumab for the treatment of osteoporosis in humans were included; poster presentations were excluded. Romosozumab has been approved by the Food and Drug Administration and is considered both safe and effective for the treatment of osteoporosis in high-risk postmenopausal females. Phase 2 and phase 3 clinical trials have shown a statistically significant decrease in new vertebral fractures and an increase in bone mineral density with romosozumab use, as compared with both placebo use and use of alternative osteoporosis therapies. The primary safety concern is a potential risk of cardiovascular events; additionally, hypocalcemia must be corrected prior to initiation. Romosozumab is the first anabolic medication that both increases bone formation and decreases bone resorption. Data suggest that romosozumab is more effective than oral bisphosphonates in preventing osteoporotic fractures, though cost and safety concerns must be considered. Conclusion Romosozumab is a novel, 12-month treatment option for postmenopausal women at high risk for osteoporotic fracture that both increases bone formation and decreases bone resorption.

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Inhibition of Vaccinia Virus Replication by Two Small Interfering RNAs Targeting B1R and G7L Genes and Their Synergistic Combination with Cidofovir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01626-08 ◽

2009 ◽

Vol 53 (6) ◽

pp. 2579-2588 ◽

Cited By ~ 12

Author(s):

Solenne Vigne ◽

Sophie Duraffour ◽

Graciela Andrei ◽

Robert Snoeck ◽

Daniel Garin ◽

...

Keyword(s):

Vaccinia Virus ◽

Virus Replication ◽

Synergistic Effects ◽

Terrorist Attack ◽

Combined Therapy ◽

Interferon Response ◽

Small Interfering Rnas ◽

Antiviral Activities ◽

Inhibitory Agents

ABSTRACT In view of the threat of the potential use of variola virus in a terrorist attack, considerable efforts have been performed to develop new antiviral strategies against orthopoxviruses. Here we report on the use of RNA interference, either alone or in combination with cidofovir, as an approach to inhibit orthopoxvirus replication. Two selected small interfering RNAs (siRNAs), named siB1R-2 and siG7L-1, and a previously reported siRNA, i.e., siD5R-2 (which targets the viral D5R mRNA), were evaluated for antiviral activity against vaccinia virus (VACV) by plaque reduction and virus yield assays. siB1R-2 and siG7L-1, administered before or after viral infection, reduced VACV replication by more than 90%. Also, these two siRNAs decreased monkeypox virus replication by 95% at a concentration of 1 nM. siB1R-2 and siG7L-1 were demonstrated to specifically silence their corresponding transcripts, i.e., B1R and G7L mRNAs, without induction of a beta interferon response. Strong synergistic effects were observed when siB1R-2, siG7L-1, or siD5R-2 was combined with cidofovir. In addition, the antiviral activities of these three siRNAs were evaluated against VACV resistant to cidofovir and other acyclic nucleoside phosphonates. siG7L-1 and siD5R-2 remained active against four of five VACV mutants, while siB1R-2 showed activity against only one of the mutants. Our results showed that siRNAs are potent inhibitory agents in vitro, not only against wild-type VACV but also against several cidofovir-resistant VACV. Furthermore, we showed that a combined therapy using siRNA and cidofovir may be useful in the treatment of poxvirus infections.

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Bone histomorphometry: a concise review for endocrinologists and clinicians

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302010000200002 ◽

2010 ◽

Vol 54 (2) ◽

pp. 87-98 ◽

Cited By ~ 50

Author(s):

Carolina A. Moreira Kulak ◽

David W. Dempster

Keyword(s):

Bone Formation ◽

Renal Osteodystrophy ◽

Bone Histomorphometry ◽

Bone Biopsy ◽

Quantitative Information ◽

Important Research ◽

Treatment Of Osteoporosis ◽

Skeletal Fragility ◽

Concise Review ◽

Metabolic Bone

Bone histomorphometry is a quantitative histological examination of an undecalcified bone biopsy performed to obtain quantitative information on bone remodeling and structure. Labeling agents taken before the procedure deposit at sites of bone formation allowing a dynamic analysis. Biopsy is indicated to make the diagnosis of subclinical osteomalacia, to characterize the different forms of renal osteodystrophy and to elucidate cases of unexplained skeletal fragility. Bone histomorphometric parameters are divided into structural and remodeling subgroups, with the latter being subdivided into static and dynamic categories. Metabolic bone disorders such as osteomalacia, hyperparathyroidism, hypothyroidism, osteoporosis and renal osteodystrophy display different histomorphometric profiles. Antiresorptive and anabolic drugs used for the treatment of osteoporosis also induce characteristic changes in the bone biopsy. Bone histomorphometry is an important research tool in the field of bone metabolism and provides information that is not available by any other investigative approach.

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Synergistic Effects of Vascular Endothelial Growth Factor on Bone Morphogenetic Proteins Induced Bone Formation In Vivo: Influencing Factors and Future Research Directions

BioMed Research International ◽

10.1155/2016/2869572 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 25

Author(s):

Bo Li ◽

Hai Wang ◽

Guixing Qiu ◽

Xinlin Su ◽

Zhihong Wu

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Bone Formation ◽

Influencing Factors ◽

Bone Morphogenetic Proteins ◽

Synergistic Effects ◽

Future Research ◽

Vascular Endothelial ◽

Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs), as key mediators in angiogenesis and osteogenesis, are used in a combined delivery manner as a novel strategy in bone tissue engineering. VEGF has the potential to enhance BMPs induced bone formation. Both gene delivery and material-based delivery systems were incorporated in previous studies to investigate the synergistic effects of VEGF and BMPs. However, their results were controversial due to variation of methods incorporated in different studies. Factors influencing the synergistic effects of VEGF on BMPs induced bone formation were identified and analyzed in this review to reduce confusion on this issue. The potential mechanisms and directions of future studies were also proposed here. Further investigating mechanisms of the synergistic effects and optimizing these influencing factors will help to generate more effective bone regeneration.

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Low Intensity Pulsed Ultrasound for Bone Tissue Engineering

Micromachines ◽

10.3390/mi12121488 ◽

2021 ◽

Vol 12 (12) ◽

pp. 1488

Author(s):

Colleen McCarthy ◽

Gulden Camci-Unal

Keyword(s):

Bone Formation ◽

Bone Tissue ◽

Mechanical Stimulation ◽

Synergistic Effects ◽

In Vivo Studies ◽

Pulsed Ultrasound ◽

Low Intensity Pulsed Ultrasound ◽

Low Intensity

As explained by Wolff’s law and the mechanostat hypothesis, mechanical stimulation can be used to promote bone formation. Low intensity pulsed ultrasound (LIPUS) is a source of mechanical stimulation that can activate the integrin/phosphatidylinositol 3-OH kinase/Akt pathway and upregulate osteogenic proteins through the production of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). This paper analyzes the results of in vitro and in vivo studies that have evaluated the effects of LIPUS on cell behavior within three-dimensional (3D) titanium, ceramic, and hydrogel scaffolds. We focus specifically on cell morphology and attachment, cell proliferation and viability, osteogenic differentiation, mineralization, bone volume, and osseointegration. As shown by upregulated levels of alkaline phosphatase and osteocalcin, increased mineral deposition, improved cell ingrowth, greater scaffold pore occupancy by bone tissue, and superior vascularization, LIPUS generally has a positive effect and promotes bone formation within engineered scaffolds. Additionally, LIPUS can have synergistic effects by producing the piezoelectric effect and enhancing the benefits of 3D hydrogel encapsulation, growth factor delivery, and scaffold modification. Additional research should be conducted to optimize the ultrasound parameters and evaluate the effects of LIPUS with other types of scaffold materials and cell types.

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Female-Specific Role of Progranulin to Suppress Bone Formation

Endocrinology ◽

10.1210/en.2018-00842 ◽

2019 ◽

Vol 160 (9) ◽

pp. 2024-2037 ◽

Cited By ~ 1

Author(s):

Liping Wang ◽

Theresa Roth ◽

Mary C Nakamura ◽

Robert A Nissenson

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Microglial Cells ◽

Treatment Of Osteoporosis ◽

Female Mice ◽

Diet Induced Obesity ◽

Skeletal Effects ◽

Female Specific ◽

Osteogenic Factors

Abstract Progranulin (PGRN) is best known as a glial protein for which deficiency leads to the most common inherited form of frontotemporal dementia. Recently, PGRN has been found to be an adipokine associated with diet-induced obesity and insulin resistance. Therefore, PGRN may have homeostatic effects on bone because PGRN is reported to promote the differentiation of bone-resorbing osteoclasts. We investigated the actions of PGRN on bone using PGRN gene (Grn) knockout (KO) mice and transgenic mice with PGRN mutation and surprisingly found that loss of PGRN prevented the bone loss in female mice induced by aging and estrogen deficiency, whereas it had no effect on male bones during aging. Strikingly, bone formation was increased in female (but not male) PGRN KO mice. We also found that loss of PGRN inhibited bone resorption and osteoclastogenesis in both male and female mice and promoted the production of osteogenic factors in osteoclast lineage cells. These results indicate that PGRN serves to uncouple bone turnover in female mice by promoting bone resorption and suppressing bone formation. Furthermore, we demonstrated that microglial cells/macrophages, but not adipocytes, are an important source of PGRN in producing negative skeletal effects in females. Targeting PGRN production by microglial cells/macrophage-lineage cells may provide a therapeutic approach for the treatment of osteoporosis in females.

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Promotion of Bone Formation by Red Yeast Rice in Experimental Animals: A Systematic Review and Meta-Analysis

BioMed Research International ◽

10.1155/2020/7231827 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Bin Wu ◽

Jie-Feng Huang ◽

Bang-Jian He ◽

Chen-Wei Huang ◽

Jian-Hua Lu

Keyword(s):

Bone Mineral Density ◽

Bone Formation ◽

Bone Mineral ◽

Meta Analysis ◽

Red Yeast Rice ◽

Osteoblast Proliferation ◽

Mineral Density ◽

Treatment Of Osteoporosis ◽

Experimental Animals ◽

Red Yeast

Objective. To systematically evaluate the effects of red yeast rice (RYR) and its extract on bone formation in experimental animals and to provide reference data for clinical research on the treatment of osteoporosis. Methods. Chinese and English language databases, including Web of Science, PubMed, the Cochrane Library, Elsevier, Google Scholar, SpringerLink, Embase, China National Knowledge Infrastructure (CNKI), Weipu Chinese Sci-tech periodical full-text database (VIP), and Wanfang Data Knowledge Service Platform (Wanfang), were searched from their establishment to February 2020 using the following terms: “hongqu,” “red yeast rice,” “Monascus purpureus-fermented rice,” “bone mineral density,” “osteoblast,” “osteoporosis,” and “animal models.” After excluding nonrelevant articles, Review Manager 5.2 was used to evaluate article quality and to analyze the data. Outcome indicators included bone mineral density (BMD), osteoblast proliferation, and the expression of alkaline phosphatase (ALP). Results. A total of 11 randomized controlled trials were included in the meta-analysis, all of which were animal studies. Six studies included data on BMD, five on osteoblast proliferation, and six on the expression of ALP. The results of the meta-analysis showed that RYR can significantly improve BMD (standardized mean difference SMD=3.12, 95% confidence interval (CI) 1.41 to 4.83, P=0.0003), promote osteoblast proliferation (SMD=1.64, 95% CI 1.04 to 2.23, P<0.00001), and increase ALP expression in rats (SMD=1.25, 95% CI 0.69 to 1.80, P<0.00001). Conclusions. RYR can promote bone formation in experimental animals and may be useful for the treatment of osteoporosis.

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Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Acta Endocrinologica ◽

10.1530/eje-13-0136 ◽

2013 ◽

Vol 169 (2) ◽

pp. R39-R57 ◽

Cited By ~ 44

Author(s):

Jens Bollerslev ◽

Kim Henriksen ◽

Morten Frost Nielsen ◽

Kim Brixen ◽

Wim Van Hul

Keyword(s):

Bone Formation ◽

Bone Metabolism ◽

Energy Homeostasis ◽

Autosomal Dominant ◽

Chloride Transport ◽

Ex Vivo ◽

Whole Body ◽

High Bone Mass ◽

Treatment Of Osteoporosis ◽

Autosomal Dominant Osteopetrosis

Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller ofLRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis).Ex vivostudies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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Effects of Estrogen Receptor and Wnt Signaling Activation on Mechanically Induced Bone Formation in a Mouse Model of Postmenopausal Bone Loss

International Journal of Molecular Sciences ◽

10.3390/ijms21218301 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8301

Author(s):

Astrid Liedert ◽

Claudia Nemitz ◽

Melanie Haffner-Luntzer ◽

Fabian Schick ◽

Franz Jakob ◽

...

Keyword(s):

Estrogen Receptor ◽

Bone Loss ◽

Bone Formation ◽

Bone Mass ◽

Postmenopausal Bone Loss ◽

Paracrine Factors ◽

Treatment Of Osteoporosis ◽

Ovariectomized Mice ◽

Underlying Mechanisms ◽

Signaling Activation

In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated manner. Because the response of bone to mechanical signals is dependent on functional estrogen receptor (ER) and Wnt/β-catenin signaling and is impaired in postmenopausal osteoporosis by estrogen deficiency, it is of paramount importance to elucidate the underlying mechanisms as a basis for the development of new strategies in the treatment of osteoporosis. The present study aimed to investigate the effectiveness of the activation of the ligand-dependent ER and the Wnt/β-catenin signal transduction pathways on mechanically induced bone formation using ovariectomized mice as a model of postmenopausal bone loss. We demonstrated that both pathways interact in the regulation of bone mass adaption in response to mechanical loading and that the activation of Wnt/β-catenin signaling considerably increased mechanically induced bone formation, whereas the effects of estrogen treatment strictly depended on the estrogen status in the mice.

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Platycodin D enhances LDLR expression and LDL uptake via down-regulation of IDOL mRNA in hepatic cells

Scientific Reports ◽

10.1038/s41598-020-76224-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yu-Jeong Choi ◽

Sol Ji Lee ◽

Hyo In Kim ◽

Hee Jung Lee ◽

So Jung Kang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Synergistic Effects ◽

Biological Activities ◽

Therapeutic Option ◽

Molecular Evidence ◽

Triterpenoid Saponin ◽

Atherosclerotic Cardiovascular Disease ◽

Down Regulation ◽

Hepatic Cells

AbstractThe root of Platycodon grandiflorum (PG) has long been used as a traditional herbal medicine in Asian country. Platycondin D (PD), triterpenoid saponin that is a main constituent of PG, exhibits various biological activities such as anti-inflammatory, anti-oxidant, anti-diabetic, and anti-cancer effects. A previous study showed that PD had cholesterol-lowering effects in mice that develop hypercholesterolemia, but the underlying molecular mechanisms have not been elucidated during the last decade. Here, we demonstrated that both PG and PD markedly increased levels of cell surface low-density lipoprotein receptor (LDLR) by down-regulation of the E3 ubiquitin ligase named inducible degrader of the LDLR (IDOL) mRNA, leading to the enhanced uptake of LDL-derived cholesterol (LDL-C) in hepatic cells. Furthermore, cycloheximide chase analysis and in vivo ubiquitination assay revealed that PD increased the half-life of LDLR protein by reducing IDOL-mediated LDLR ubiquitination. Finally, we demonstrated that treatment of HepG2 cells with simvastatin in combination with PG and PD had synergistic effects on the improvement of LDLR expression and LDL-C uptake. Together, these results provide the first molecular evidence for anti-hypercholesterolemic activity of PD and suggest that PD alone or together with statin could be a potential therapeutic option in the treatment of atherosclerotic cardiovascular disease.

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