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Osteoporosis: From Molecular Mechanisms to Therapies 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 63075

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Prof. Dr. Chih-Hsin Tang

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Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan
Interests: arthritis; bone cancer; osteoporosis; metastasis; drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue "Osteoporosis: From Molecular Mechanisms to Therapies" (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/osteoporosis_ijms).

Osteoporosis is a common skeletal disorder, occuring as a result of an imbalance between bone resorption and bone formation, with bone breakdown exceeding bone building. Bone resorption inhibitors, e.g., bisphosphonates, have been designed to treat osteoporosis. Teriparatide, an anabolic agent, stimulates bone formation and corrects the characteristic changes in the trabecular microarchitecture. However, these drugs are associated with significant side effects. It is therefore crucial that we continue to research the pathogenesis of osteoporosis and seek novel modes of therapy. We invite researchers to submit original research and review articles covering significant developments in the pathogenesis of osteoporosis, as well as novel medicines or strategies that hold promise in the prevention and/or treatment of this disease. In particular, we welcome research covering novel signaling pathways, signaling molecules, or osteoporosis medications under development.

Prof. Dr. Chih-Hsin Tang
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

Osteoporosis
Treatment
Prevention
Molecular mechanisms
Signaling pathways

Published Papers (11 papers)

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Editorial

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3 pages, 160 KiB

Open AccessEditorial

Osteoporosis: From Molecular Mechanisms to Therapies 2.0

by Chih-Hsin Tang

Int. J. Mol. Sci. 2020, 21(21), 8005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218005 - 28 Oct 2020

Cited by 5 | Viewed by 2021

Abstract

Osteoporosis is a common skeletal disorder, occurring as a result of an imbalance between bone resorption and bone formation, with bone breakdown exceeding bone building. Bone resorption inhibitors, e.g., bisphosphonates, have been designed to treat osteoporosis. Teriparatide, an anabolic agent, stimulates bone formation and corrects the characteristic changes in the trabecular microarchitecture. However, these drugs are associated with significant side effects. It is therefore crucial that we continue to research the pathogenesis of osteoporosis and seek novel modes of therapy. This editorial summarizes and discusses the themes of the ten articles published in our Special Issue “Osteoporosis: From Molecular Mechanisms to Therapies 2.0”, a continuation of our 2019 Special Issue "Osteoporosis: From Molecular Mechanisms to Therapies" (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/osteoporosis_ijms). These Special Issues detail important global scientific findings that contribute to our current understanding of osteoporosis. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

Research

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16 pages, 2976 KiB

Open AccessArticle

The Role of Piper sarmentosum Aqueous Extract as a Bone Protective Agent, a Histomorphometric Study

by Siti Fadziyah Mohamad Asri, Ima Nirwana Soelaiman, Mohamad Aris Mohd Moklas, Nurul Huda Mohd Nor, Nurul Hayati Mohamad Zainal and Elvy Suhana Mohd Ramli

Int. J. Mol. Sci. 2020, 21(20), 7715; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207715 - 19 Oct 2020

Cited by 11 | Viewed by 3065

Abstract

Glucocorticoids are one of the causes of secondary osteoporosis. The aqueous extract of Piper sarmentosum contains flavonoids that possess antioxidant effects. In this study, we determined the effects of aqueous Piper sarmentosum leaf extract on structural, dynamic and static histomorphometric changes from osteoporotic bones of rats induced with glucocorticoids. Thirty-two Sprague-Dawley rats were divided equally into four groups—Sham control group given vehicles (intramuscular (IM) olive oil and oral normal saline); AC: Adrenalectomised (Adrx) control group given IM dexamethasone (DEX) (120 μg/kg/day) and vehicle (oral normal saline); AP: Adrx group administered IM DEX (120 μg/kg/day) and aqueous Piper sarmentosum leaf extract (125 mg/kg/day) orally; and AG: Adrx group administered IM DEX (120 μg/kg/day) and oral glycyrrhizic acid (GCA) (120 mg/kg/day). Histomorphometric measurements showed that the bone volume, trabecular thickness, trabecular number, osteoid and osteoblast surfaces, double-labelled trabecular surface, mineralizing surface and bone formation rate of rats given aqueous Piper sarmentosum leaf extract were significantly increased (p < 0.05), whereas the trabecular separation and osteoclast surface were significantly reduced (p < 0.05). This study suggests that aqueous Piper sarmentosum leaf extract was able to prevent bone loss in prolonged glucocorticoid therapy. Thus, Piper sarmentosum has the potential to be used as an alternative medicine against osteoporosis and osteoporotic fractures in patients undergoing long-term glucocorticoid therapy. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

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19 pages, 3007 KiB

Open AccessArticle

Aberrant BMP2 Signaling in Patients Diagnosed with Osteoporosis

by Hilary W. Durbano, Daniel Halloran, John Nguyen, Victoria Stone, Sean McTague, Mark Eskander and Anja Nohe

Int. J. Mol. Sci. 2020, 21(18), 6909; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186909 - 21 Sep 2020

Cited by 17 | Viewed by 3132

Abstract

The most common bone disease in humans is osteoporosis (OP). Current therapeutics targeting OP have several negative side effects. Bone morphogenetic protein 2 (BMP2) is a potent growth factor that is known to activate both osteoblasts and osteoclasts. It completes these actions through both SMAD-dependent and SMAD-independent signaling. A novel interaction between the BMP type Ia receptor (BMPRIa) and casein kinase II (CK2) was discovered, and several CK2 phosphorylation sites were identified. A corresponding blocking peptide (named CK2.3) was designed to further elucidate the phosphorylation site’s function. Previously, CK2.3 demonstrated an increased osteoblast activity and decreased osteoclast activity in a variety of animal models, cell lines, and isolated human osteoblasts. It is hypothesized that CK2.3 completes these actions through the BMP signaling pathway. Furthermore, it was recently discovered that BMP2 did not elicit an osteogenic response in osteoblasts from patients diagnosed with OP, while CK2.3 did. In this study, we explore where in the BMP pathway the signaling disparity or defect lies in those diagnosed with OP. We found that osteoblasts isolated from patients diagnosed with OP did not activate SMAD or ERK signaling after BMP2 stimulation. When OP osteoblasts were stimulated with BMP2, both BMPRIa and CK2 expression significantly decreased. This indicates a major disparity within the BMP signaling pathway in patients diagnosed with osteoporosis. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

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13 pages, 5040 KiB

Open AccessArticle

CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma

by Ju-Fang Liu, Chiang-Wen Lee, Chih-Yang Lin, Chia-Chia Chao, Tsung-Ming Chang, Chien-Kuo Han, Yuan-Li Huang, Yi-Chin Fong and Chih-Hsin Tang

Int. J. Mol. Sci. 2020, 21(17), 6095; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176095 - 24 Aug 2020

Cited by 15 | Viewed by 2569

Abstract

Osteosarcoma is the most common primary tumor of the skeletal system and is well-known to have an aggressive clinical outcome and high metastatic potential. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays a vital role in the development of several cancers. However, the effect of CXCL13 in the motility of osteosarcoma cells remains uncertain. Here, we found that CXCL13 increases the migration and invasion potential of three osteosarcoma cell lines. In addition, CXCL13 expression was upregulated in migration-prone MG-63 cells. Vascular cell adhesion molecule 1 (VCAM-1) siRNA and antibody demonstrated that CXCL13 promotes migration via increasing VCAM-1 production. We also show that CXCR5 receptor controls CXCL13-mediated VCAM-1 expression and cell migration. Our study identified that CXCL13/CXCR5 axis facilitate VCAM-1 production and cell migration in human osteosarcoma via the phospholipase C beta (PLCβ), protein kinase C α (PKCα), c-Src, and nuclear factor-κB (NF-κB) signaling pathways. CXCL13 and CXCR5 appear to be a novel therapeutic target in metastatic osteosarcoma. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

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14 pages, 7555 KiB

Open AccessArticle

Chondroitin Sulfate Prevents STZ Induced Diabetic Osteoporosis through Decreasing Blood Glucose, AntiOxidative Stress, Anti-Inflammation and OPG/RANKL Expression Regulation

by Hong Xing Zheng, De Jing Chen, Yue Xin Zu, En Zhu Wang and Shan Shan Qi

Int. J. Mol. Sci. 2020, 21(15), 5303; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155303 - 26 Jul 2020

Cited by 34 | Viewed by 3559

Abstract

Chondroitin sulfate (CS) has antioxidative, anti-inflammatory, anti-osteoarthritic and hypoglycemic effects. However, whether it has antidiabetic osteoporosis effects has not been reported. Therefore, in this study, we established a STZ-induced diabetic rat model; CS (500 mg kg⁻¹ d⁻¹) was orally administrated for eight weeks to study its preventive effects on diabetic osteoporosis. The results showed that eight weeks of CS treatment improved the symptoms of diabetes; the CS-treated group has increased body weight, decreased water or food intake, decreased blood glucose, increased bone-mineral density, repaired bone morphology and decreased femoral osteoclasts and tibia adipocytes numbers. After CS treatment, bone histomorphometric parameters returned to normal, the levels of serum inflammatory cytokines (IL-1β, IL-6 and TNF-α) decreased significantly, serum SOD, GPX and CAT activities increased and MDA level increased. In the CS-treated group, the levels of serum ALP, CTX-1, TRACP 5b, osteocalcin and RANKL decreased and the serum RUNX 2 and OPG levels increased. Bone immunohistochemistry results showed that CS can effectively increase the expression of OPG and RUNX2 and reduce the expression of RANKL in diabetic rats. All of these indicate that CS could prevent STZ induced diabetic osteoporosis—mainly through decreasing blood glucose, antioxidative stress, anti-inflammation and regulation of OPG/RANKL expression. CS can therefore effectively prevent bone loss caused by diabetes. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

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13 pages, 1369 KiB

Open AccessArticle

A Novel Peptide, CK2.3, Improved Bone Formation in Ovariectomized Sprague Dawley Rats

by Linda Sequeira, John Nguyen, Liyun Wang and Anja Nohe

Int. J. Mol. Sci. 2020, 21(14), 4874; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144874 - 10 Jul 2020

Cited by 4 | Viewed by 2591

Abstract

Osteoporosis is a bone disease that has no definite cure. Current treatments for osteoporosis are divided into two categories: anti-resorptive and anabolic. However, these treatments are not perfect and have considerable risks. In addition, bone quality often declines over time with these treatments. We designed a peptide, CK2.3, that has both anabolic and anti-resorptive effects on bone. We reported that CK2.3 induced osteoblastic mineralization, promoted bone formation, and suppressed osteoclastogenesis in vivo. The effect of CK2.3 to rescue an osteoporosis phenotype model has never been shown. In this study, we demonstrated the effect of CK2.3 in ovariectomized rats, a standard model of osteoporosis. We systemically injected CK2.3 at 2.3 µg/kg each day for five consecutive days. Micro-computed tomography indicated that CK2.3 increased bone mineral density, (bone volume/tissue volume) BV/TV and (trabecular number) TbN, and decreased (trabecular space) TbSp in the femoral head. Similarly, single photon absorptiometry showed that treatment with CK2.3 increased bone mineral density in the lumbar spine and the pelvis. Additionally, we observed increased femoral shaft stiffness with ovariectomized rats treated with CK2.3. We also detected no significant changes in the weight of organs such as the heart, lung, liver, kidney, and spleen. An advantage of CK2.3 over current treatments was that it not only promoted bone formation but also improved fracture resistance. In conclusion, we demonstrated CK2.3 as a new anabolic treatment for osteoporosis. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

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15 pages, 3010 KiB

Open AccessArticle

Therapeutic Potential of Tauroursodeoxycholic Acid for the Treatment of Osteoporosis

by Tae-Keun Ahn, Kyoung-Tae Kim, Hari Prasad Joshi, Kwang Hwan Park, Jae Won Kyung, Un-Yong Choi, Seil Sohn, Seung-Hun Sheen, Dong-Eun Shin, Soo-Hong Lee and In-Bo Han

Int. J. Mol. Sci. 2020, 21(12), 4274; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124274 - 16 Jun 2020

Cited by 17 | Viewed by 3537

Abstract

Tauroursodeoxycholic acid (TUDCA) is a US FDA-approved hydrophilic bile acid for the treatment of chronic cholestatic liver disease. In the present study, we investigate the effects of TUDCA on the proliferation and differentiation of osteoblasts and its therapeutic effect on a mice model of osteoporosis. Following treatment with different concentrations of TUDCA, cell viability, differentiation, and mineralization were measured. Three-month-old female C57BL/6 mice were randomly divided into three groups (n = 8 mice per group): (i) normal mice as the control group, (ii) ovariectomy (OVX) group (receiving phosphate-buffered saline (PBS) treatment every other day for 4 weeks), and (iii) OVX group with TUDCA (receiving TUDCA treatment every other day for 4 weeks starting 6 weeks after OVX). At 11 weeks post-surgery, serum levels of procollagen type I N-terminal propeptides (PINP) and type I collagen crosslinked C-telopeptides (CTX) were measured, and all mice were sacrificed to examine the distal femur by micro-computed tomography (CT) scans and histology. TUDCA (100 nM, 1 µM) significantly increased the proliferation and viability of osteoblasts and osteoblast differentiation and mineralization when used in vitro. Furthermore, TUDCA neutralized the detrimental effects of methylprednisolone (methylprednisolone-induced osteoblast apoptosis). In the TUDCA treatment group the PINP level was higher and the CTX level was lower, but these levels were not significantly different compared to the PBS treatment group. Micro-CT and histology showed that the TUDCA treatment group preserved more trabecular structures in the distal femur compared to the PBS treatment group. In addition, the TUDCA treatment group increased the percentage bone volume with respect to the total bone volume, bone mineral density, and mice distal femur trabeculae compared with the PBS treatment group. Taken together, our findings suggest that TUDCA may provide a favorable effect on bones and could be used for the prevention and treatment of osteoporosis. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

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Review

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22 pages, 1054 KiB

Open AccessReview

Molecular Mechanisms and Emerging Therapeutics for Osteoporosis

by Ji-Yoon Noh, Young Yang and Haiyoung Jung

Int. J. Mol. Sci. 2020, 21(20), 7623; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207623 - 15 Oct 2020

Cited by 116 | Viewed by 17537

Abstract

Osteoporosis is the most common chronic metabolic bone disease. It has been estimated that more than 10 million people in the United States and 200 million men and women worldwide have osteoporosis. Given that the aging population is rapidly increasing in many countries, osteoporosis could become a global challenge with an impact on the quality of life of the affected individuals. Osteoporosis can be defined as a condition characterized by low bone density and increased risk of fractures due to the deterioration of the bone architecture. Thus, the major goal of treatment is to reduce the risk for fractures. There are several treatment options, mostly medications that can control disease progression in risk groups, such as postmenopausal women and elderly men. Recent studies on the basic molecular mechanisms and clinical implications of osteoporosis have identified novel therapeutic targets. Emerging therapies targeting novel disease mechanisms could provide powerful approaches for osteoporosis management in the future. Here, we review the etiology of osteoporosis and the molecular mechanism of bone remodeling, present current pharmacological options, and discuss emerging therapies targeting novel mechanisms, investigational treatments, and new promising therapeutic approaches. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

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21 pages, 1298 KiB

Open AccessReview

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

by Umani S. Walallawita, Frances M. Wolber, Ayelet Ziv-Gal, Marlena C. Kruger and Julian A. Heyes

Int. J. Mol. Sci. 2020, 21(19), 7119; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197119 - 27 Sep 2020

Cited by 16 | Viewed by 5072

Abstract

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. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

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24 pages, 1383 KiB

Open AccessReview

Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review

by Chia-Yu Hsu, Li-Ru Chen and Kuo-Hu Chen

Int. J. Mol. Sci. 2020, 21(18), 6846; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186846 - 18 Sep 2020

Cited by 70 | Viewed by 11216

Abstract

Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. Among CKD patients, adynamic bone disease or low bone turnover is the most common type of renal osteodystrophy. The consequences of CKD-MBD include increased fracture risk, greater morbidity, and mortality. Thus, the goal is to prevent the occurrences of fractures by means of alleviating CKD-induced MBD and treating subsequent osteoporosis. Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD. CKD-MBD includes abnormalities of calcium, phosphorus, PTH, and/or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and/or vascular or other soft tissue calcification. In patients with CKD-MBD, using either DXA or FRAX to screen fracture risk should be considered. Biomarkers such as bALP and iPTH may assist to assess bone turnover. Before initiating an antiresorptive or anabolic agent to treat osteoporosis in CKD patients, lifestyle modifications, such as exercise, calcium, and vitamin D supplementation, smoking cessation, and avoidance of excessive alcohol intake are important. Managing hyperphosphatemia and SHPT are also crucial. Understanding the complex pathogenesis of CKD-MBD is crucial in improving one’s short- and long-term outcomes. Treatment strategies for CKD-associated osteoporosis should be patient-centered to determine the type of renal osteodystrophy. This review focuses on the mechanism, evaluation and management of patients with CKD-MBD. However, further studies are needed to explore more details regarding the underlying pathophysiology and to assess the safety and efficacy of agents for treating CKD-MBD. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

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37 pages, 3200 KiB

Open AccessReview

Quercetin as an Agent for Protecting the Bone: A Review of the Current Evidence

by Sok Kuan Wong, Kok-Yong Chin and Soelaiman Ima-Nirwana

Int. J. Mol. Sci. 2020, 21(17), 6448; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176448 - 03 Sep 2020

Cited by 113 | Viewed by 7894

Abstract

Quercetin is a flavonoid abundantly found in fruits and vegetables. It possesses a wide spectrum of biological activities, thus suggesting a role in disease prevention and health promotion. The present review aimed to uncover the bone-sparing effects of quercetin and its mechanism of action. Animal studies have found that the action of quercetin on bone is largely protective, with a small number of studies reporting negative outcomes. Quercetin was shown to inhibit RANKL-mediated osteoclastogenesis, osteoblast apoptosis, oxidative stress and inflammatory response while promoting osteogenesis, angiogenesis, antioxidant expression, adipocyte apoptosis and osteoclast apoptosis. The possible underlying mechanisms involved are regulation of Wnt, NF-κB, Nrf2, SMAD-dependent, and intrinsic and extrinsic apoptotic pathways. On the other hand, quercetin was shown to exert complex and competing actions on the MAPK signalling pathway to orchestrate bone metabolism, resulting in both stimulatory and inhibitory effects on bone in parallel. The overall interaction is believed to result in a positive effect on bone. Considering the important contributions of quercetin in regulating bone homeostasis, it may be considered an economical and promising agent for improving bone health. The documented preclinical findings await further validation from human clinical trials. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 2.0)

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