Potential Role of Lycopene in the Prevention of Postmenopausal Bone Loss: Evidence from Molecular to Clinical Studies

Osteoporosis is a metabolic bone disease characterized by reduced bone mineral density, which affects the quality of life of the aging population. Furthermore, disruption of bone microarchitecture and the alteration of non-collagenous protein in bones lead to higher fracture risk. This is most common in postmenopausal women. Certain medications are being used for the treatment of osteoporosis; however, these may be accompanied by undesirable side effects. Phytochemicals from fruits and vegetables are a source of micronutrients for the maintenance of bone health. Among them, lycopene has recently been shown to have a potential protective effect against bone loss. Lycopene is a lipid-soluble carotenoid that exists in both all-trans and cis-configurations in nature. Tomato and tomato products are rich sources of lycopene. Several human epidemiological studies, supplemented by in vivo and in vitro studies, have shown decreased bone loss following the consumption of lycopene/tomato. However, there are still limited studies that have evaluated the effect of lycopene on the prevention of bone loss in postmenopausal women. Therefore, the aim of this review is to summarize the relevant literature on the potential impact of lycopene on postmenopausal bone loss with molecular and clinical evidence, including an overview of bone biology and the pathophysiology of osteoporosis.

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Crataegus pinnatifida Bunge Inhibits RANKL-Induced Osteoclast Differentiation in RAW 264.7 Cells and Prevents Bone Loss in an Ovariectomized Rat Model

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5521562 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Minsun Kim ◽

MinBeom Kim ◽

Jae-Hyun Kim ◽

SooYeon Hong ◽

Dong Hee Kim ◽

...

Keyword(s):

Bone Loss ◽

Rat Model ◽

Osteoclast Differentiation ◽

Ovariectomized Rat ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Mineral Density ◽

Crataegus Pinnatifida

Osteoporosis is characterized by a decrease in bone microarchitecture with an increased risk of fracture. Long-term use of primary treatments, such as bisphosphonates and selective estrogen receptor modulators, results in various side effects. Therefore, it is necessary to develop alternative therapeutics derived from natural products. Crataegus pinnatifida Bunge (CPB) is a dried fruit used to treat diet-induced indigestion, loss of appetite, and diarrhea. However, research into the effects of CPB on osteoclast differentiation and osteoporosis is still limited. In vitro experiments were conducted to examine the effects of CPB on RANKL-induced osteoclast differentiation in RAW 264.7 cells. Moreover, we investigated the effects of CPB on bone loss in the femoral head in an ovariectomized rat model using microcomputed tomography. In vitro, tartrate-resistant acid phosphatase (TRAP) staining results showed the number of TRAP-positive cells, and TRAP activity significantly decreased following CPB treatment. CPB also significantly decreased pit formation. Furthermore, CPB inhibited osteoclast differentiation by suppressing NFATc1, and c-Fos expression. Moreover, CPB treatment inhibited osteoclast-related genes, such as Nfatc1, Ca2, Acp5, mmp9, CtsK, Oscar, and Atp6v0d2. In vivo, bone mineral density and structure model index were improved by administration of CPB. In conclusion, CPB prevented osteoclast differentiation in vitro and prevented bone loss in vivo. Therefore, CPB could be a potential alternative medicine for bone diseases, such as osteoporosis.

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Sclareol prevents ovariectomy-induced bone loss in vivo and inhibits osteoclastogenesis in vitro via suppressing NF-κB and MAPK/ERK signaling pathways

Food & Function ◽

10.1039/c9fo00206e ◽

2019 ◽

Vol 10 (10) ◽

pp. 6556-6567 ◽

Cited By ~ 5

Author(s):

Haiming Jin ◽

Zhenxuan Shao ◽

Qingqing Wang ◽

Jiansen Miao ◽

Xueqin Bai ◽

...

Keyword(s):

Bone Loss ◽

Bone Mass ◽

Postmenopausal Women ◽

Postmenopausal Osteoporosis ◽

Bone Quality ◽

Progressive Disease ◽

Erk Signaling ◽

Low Bone Mass

Postmenopausal osteoporosis (PMO) is a progressive disease occurring in elderly postmenopausal women that is characterized by low bone mass and impaired bone quality.

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The Non-Erythropoietic EPO Analogue (Cibinetide) Preserves Bone Mass in Mice

Blood ◽

10.1182/blood-2021-147204 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 850-850

Author(s):

Zamzam Awida ◽

Almog Bachar ◽

Hussam Saed ◽

Anton Gorodov ◽

Nathalie Ben-Califa ◽

...

Keyword(s):

Bone Loss ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Conflicts Of Interest ◽

Erythroid Progenitors ◽

Mineral Density ◽

Female Mice ◽

Tissue Protection

Abstract Background and aims: Erythropoietin (EPO) is a pleiotropic cytokine, which besides its classical role in driving erythropoiesis, displays tissue protective and immunomodulatory activities. EPO also induces bone loss. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. Cibinetide (CIB), a non-erythropoietic analogue of EPO, specifically binds to the heteromeric receptor and confers tissue protection. Our published findings that EPO stimulates osteoclast precursors and entrains a decrease in bone density, raise questions regarding the underlying molecular mechanisms. Here, we evaluated the role of the heteromeric complex in bone metabolism using CIB alone and in combination with EPO in vivo and in vitro. Results: CIB injections to 12-week-old female mice (120 µg/kg thrice weekly for 4 weeks) resulted in a significant increase in tissue mineral density in cortical bone by 5.8% (1416.4±39.27 vs 1338.74±16.56 mgHA/cm 3) and in trabecular bone by 5.2% (1056.52±30.94 vs 1004.13±16.91 mg HA/cm 3) (n=10 in each group, p< 0.05 versus saline-injected controls), as measured by microCT (Figure 1A). To evaluate the capacity of CIB to attenuate EPO mediated bone loss, we administered CIB (300 µg/kg) for 5 consecutive days, to 13-week-old female mice that also received 2 injections of 120U EPO on days 1 and 4. Flow cytometry analysis revealed a 1.8-fold reduction in the number of osteoclast progenitors, defined as Lin -CD11b −CD115 +Ly6C hi, in the EPO + CIB injected mice, compared to the mice injected with EPO alone (n=7 in each group, p< 0.05). Hemoglobin levels and TER119 + bone marrow (BM) erythroid progenitors were similar in both groups. In vitro, EPO administration to BM-derived macrophages (BMDM) enhanced osteoclastogenesis, whereas CIB had an opposite, dose-dependent effect. Combining CIB with EPO inhibited osteoclastogenesis in BMDM, suggesting that CIB overrides the pro-osteoclastogenic effect of EPO (Figure 1B). Conclusions: Our findings highlight the increasing complexity of EPOR signaling in bone and pave the way for clinical translation through potential combination therapy of EPO and CIB in anemic and in cancer patients. Adjunctive administration of CIB may prevent or attenuate bone loss while preserving the erythropoietic actions of EPO. This study was supported by a grant from the Dotan Hemato-oncology Fund, the Cancer Biology Research Center, Tel Aviv University to DN and YG. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms23010055 ◽

2021 ◽

Vol 23 (1) ◽

pp. 55

Author(s):

Zamzam Awida ◽

Almog Bachar ◽

Hussam Saed ◽

Anton Gorodov ◽

Nathalie Ben-Califa ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Loss ◽

Bone Mineral ◽

Molecular Mechanisms ◽

Mineral Density ◽

Female Mice ◽

Epo Receptor

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin−CD11b−Ly6Chi CD115+, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.

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Identification and Functional Characterization of Metabolites for Bone Mass in Peri-/Post-menopausal Chinese Women

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab146 ◽

2021 ◽

Author(s):

Rui Gong ◽

Hong-Mei Xiao ◽

Yin-Hua Zhang ◽

Qi Zhao ◽

Kuan-Jui Su ◽

...

Keyword(s):

Fatty Acids ◽

Bone Loss ◽

Osteoclast Differentiation ◽

Dodecanoic Acid ◽

Mineral Density ◽

Ovariectomized Mice ◽

Post Menopausal ◽

Functional Mechanisms

Abstract Context Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. Objective We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri-/post-menopausal women. Design and Methods We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares (PLS) regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. Results Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module, causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. DA treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (e.g.,10, 100μM). Conclusions This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.

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Osteoporosis Recovery byAntrodia camphorataAlcohol Extracts through Bone Regeneration in SAMP8 Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/2617868 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Hen-Yu Liu ◽

Chiung-Fang Huang ◽

Chun-Hao Li ◽

Ching-Yu Tsai ◽

Wei-Hong Chen ◽

...

Keyword(s):

Bone Loss ◽

Bone Matrix ◽

Mineral Density ◽

Antrodia Camphorata ◽

Osteoporosis Therapy ◽

Alizarin Red ◽

Alcohol Extract ◽

Samp8 Mice

Antrodia camphoratahas previously demonstrated the efficacy in treating cancer and anti-inflammation. In this study, we are the first to evaluateAntrodia camphorataalcohol extract (ACAE) for osteoporosis recoveryin vitrowith preosteoblast cells (MC3T3-E1) andin vivowith an osteoporosis mouse model established in our previous studies, ovariectomized senescence accelerated mice (OVX-SAMP8). Our results demonstrated that ACAE treatment was slightly cytotoxic to preosteoblast at 25 μg/mL, by which the osteogenic gene expression (RUNX2, OPN, and OCN) was significantly upregulated with an increased ratio of OPG to RANKL, indicating maintenance of the bone matrix through inhibition of osteoclastic pathway. Additionally, evaluation by Alizarin Red S staining showed increased mineralization in ACAE-treated preosteoblasts. Forin vivostudy, our results indicated that ACAE inhibits bone loss and significantly increases percentage bone volume, trabecular bone number, and bone mineral density in OVX-SAMP8 mice treated with ACAE. Collectively,in vitroandin vivoresults showed that ACAE could promote osteogenesis and prevent bone loss and should be considered an evidence-based complementary and alternative medicine for osteoporosis therapy through the maintenance of bone health.

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Anti–IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss

Journal of Experimental Medicine ◽

10.1084/jem.20102234 ◽

2011 ◽

Vol 208 (9) ◽

pp. 1849-1861 ◽

Cited By ~ 47

Author(s):

Yu-Hsiang Hsu ◽

Wei-Yu Chen ◽

Chien-Hui Chan ◽

Chih-Hsing Wu ◽

Zih-Jie Sun ◽

...

Keyword(s):

Monoclonal Antibody ◽

Bone Loss ◽

Therapeutic Potential ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Osteoporotic Bone ◽

Mineral Density

IL-20 is a proinflammatory cytokine of the IL-10 family that is involved in psoriasis, rheumatoid arthritis, atherosclerosis, and stroke. However, little is known about the role of IL-20 in bone destruction. We explored the function of IL-20 in osteoclastogenesis and the therapeutic potential of anti–IL-20 monoclonal antibody 7E for treating osteoporosis. Higher serum IL-20 levels were detected in patients with osteopenia and osteoporosis and in ovariectomized (OVX) mice. IL-20 mediates osteoclastogenesis by up-regulating the receptor activator of NF-κB (RANK) expression in osteoclast precursor cells and RANK ligand (RANKL) in osteoblasts. 7E treatment completely inhibited osteoclast differentiation induced by macrophage colony-stimulating factor (M-CSF) and RANKL in vitro and protected mice from OVX-induced bone loss in vivo. Furthermore, IL-20R1–deficient mice had significantly higher bone mineral density (BMD) than did wild-type controls. IL-20R1 deficiency also abolished IL-20–induced osteoclastogenesis and increased BMD in OVX mice. We have identified a pivotal role of IL-20 in osteoclast differentiation, and we conclude that anti–IL-20 monoclonal antibody is a potential therapeutic for protecting against osteoporotic bone loss.

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The Ovariectomized Rat as a Model for Studying Alveolar Bone Loss in Postmenopausal Women

BioMed Research International ◽

10.1155/2015/635023 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 44

Author(s):

Bryan D. Johnston ◽

Wendy E. Ward

Keyword(s):

Chronic Disease ◽

Bone Loss ◽

Postmenopausal Women ◽

Alveolar Bone ◽

Measurement Techniques ◽

Postmenopausal Bone Loss ◽

Ovariectomized Rat ◽

Mineral Density ◽

Increased Risk ◽

Tooth Retention

In postmenopausal women, reduced bone mineral density at the hip and spine is associated with an increased risk of tooth loss, possibly due to a loss of alveolar bone. In turn, having fewer natural teeth may lead to compromised food choices resulting in a poor diet that can contribute to chronic disease risk. The tight link between alveolar bone preservation, tooth retention, better nutritional status, and reduced risk of developing a chronic disease begins with the mitigation of postmenopausal bone loss. The ovariectomized rat, a widely used preclinical model for studying postmenopausal bone loss that mimics deterioration of bone tissue in the hip and spine, can also be used to study mineral and structural changes in alveolar bone to develop drug and/or dietary strategies aimed at tooth retention. This review discusses key findings from studies investigating mandible health and alveolar bone in the ovariectomized rat model. Considerations to maximize the benefits of this model are also included. These include the measurement techniques used, the age at ovariectomy, the duration that a rat is studied after ovariectomy and habitual diet consumed.

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MILK-DERIVED BIOACTIVE PEPTIDES WITH ANTIOSTEOPOROTIC EFFECT: A MINI REVIEW

FUDMA Journal of Sciences ◽

10.33003/fjs-2020-0403-277 ◽

2020 ◽

Vol 4 (3) ◽

pp. 351-357

Author(s):

Sanusi Bello Mada ◽

Philip Cefas Abaya ◽

Dorcas Bolanle James ◽

Muawiya Musa Abarshi ◽

Muhammad Said Tanko

Keyword(s):

Bone Loss ◽

Postmenopausal Osteoporosis ◽

Bioactive Peptides ◽

Bone Fragility ◽

Mineral Density ◽

Promoting Effect ◽

Subsequent Increase ◽

Potential Health

Postmenopausal osteoporosis is a global health problem characterized by decreased in bone mineral density (BMD) and progressive deterioration of microarchitecture and subsequent increase in bone fragility and susceptibility to fracture. More than 200 million people suffer from osteoporosis worldwide with about 8.9 million fractures and the prevalence rate of osteoporosis is expected to increase significantly in the future because of increased in life expectancy and aging population. Milk-derived bioactive peptides from cow, goat, sheep, buffalo, and camel exhibit several potential health promoting effect including antiosteoporosis, antihypertensive, antioxidative, antithrombotic, immunomodulatory and anti-inflammatory effects. Epidemiological and intervention studies have shown that milk and milk-derived peptides prevented bone loss in pre- and postmenopausal women. Moreover, quite a lot of studies have reported that milk-derived bioactive peptides can induce osteoblast cell proliferation, differentiation and also prevented bone loss in osteoporotic rats model. Thus, milk-derived peptides exhibits beneficial effect against bone-related diseases and can be of particular interest towards prevention and management of postmenopausal osteoporosis. Hence, the present review summarizes various studies using ISI, SCOPUS and PubMed indexed journals to elucidate the potential role of milk-derived bioactive peptides with in vitro and in vivo antiosteoporotic property

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Integrated Strategy of Network Pharmacological Prediction and Experimental Validation Elucidate Possible Mechanism of Bu-Yang Herbs in Treating Postmenopausal Osteoporosis via ESR1

Frontiers in Pharmacology ◽

10.3389/fphar.2021.654714 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hanting Xia ◽

Jiangyuan Liu ◽

Wenlong Yang ◽

Min Liu ◽

Yunfeng Luo ◽

...

Keyword(s):

Postmenopausal Osteoporosis ◽

Experimental Validation ◽

Bone Microarchitecture ◽

Estrogen Signaling ◽

Network Pharmacology ◽

Dependent Manner ◽

Mineral Density ◽

Integrated Strategy

Postmenopausal osteoporosis (PMOP) is a type of bone metabolism disease-related to estrogen deficiency with an increasing incidence. Traditional Chinese (TCM) has always been used and showed effectiveness in treating PMOP. In the current study, Bu-Yang herbs were considered to be the most frequently used and efficient TCM herbs in PMOP treatment. However, chemical and pharmacological profiles were not elucidated. Network pharmacology was conducted on representative Bu-Yang herbs (Yin-Yang-Huo. Du-Zhong, Bu-Gu-Zhi, Tu-Si-Zi) to investigate the mechanism of Bu-Yang herbs on PMOP. Chemical compounds, potential targets, and disease related genes were available from the corresponding database. Results showed that Bu-Yang herbs could interact with ESR1 and estrogen signaling pathways. For further validation, the Bu-Yang decoction (BYD), formula consisted of the above-mentioned 4 Bu-Yang herbs was presented for experimental validation. In vivo, BYD significantly reversed ovariectomy (OVX)-induced osteoporosis progress in a dose-dependent manner by up-regulation of bone mineral density and amelioration of bone microarchitecture. In vitro, BYD dramatically improved the proliferation and mineral nodules formation of osteoblasts. Both in vitro and in vivo results illustrated that the phenotype change induced by BYD is correlated with up-regulated of ESR1 and activation of the β-catenin pathway. Meanwhile, inhibition of ESR1 by ICI182, 780 blocked the osteogenic phenotype and β-catenin pathway activation induced by BYD. In conclusion, the current study suggested that Bu-Yang herbs are the most useful TCM herbs in treating PMOP. Furthermore, the integrated strategy of network pharmacology prediction with experimental validation suggested that BYD exerted its anti-PMOP via ESR1 and the downstream mechanism might be activation of the β-catenin signaling pathway.

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