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Osteoporosis: From Molecular Mechanisms to Therapies

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 March 2019) | Viewed by 114090

Special Issue Editor

Special Issue Information

Dear Colleagues,

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. Chih-Hsin Tang
Guest Editor

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Keywords

  • Osteoporosis
  • Treatment
  • Prevention
  • Molecular mechanisms
  • Signaling pathways

Published Papers (16 papers)

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Editorial

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3 pages, 170 KiB  
Editorial
Osteoporosis: From Molecular Mechanisms to Therapies
by Chih-Hsin Tang
Int. J. Mol. Sci. 2020, 21(3), 714; https://doi.org/10.3390/ijms21030714 - 22 Jan 2020
Cited by 12 | Viewed by 3088
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, while anabolic agents such as teriparatide stimulate [...] Read more.
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, while anabolic agents such as teriparatide stimulate bone formation and correct the characteristic changes in the trabecular microarchitecture. However, all of 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 fifteen articles published in the Special Issue, Osteoporosis: From Molecular Mechanisms to Therapies 2019, as part of the global picture of the current understanding of osteoporosis. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)

Research

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11 pages, 1756 KiB  
Article
CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts
by Po-Chun Chen, Ju-Fang Liu, Yi-Chin Fong, Yuan-Lin Huang, Chia-Chia Chao and Chih-Hsin Tang
Int. J. Mol. Sci. 2019, 20(13), 3300; https://doi.org/10.3390/ijms20133300 - 05 Jul 2019
Cited by 30 | Viewed by 4241
Abstract
CCN3, otherwise known as the nephroblastoma overexpressed (NOV) protein, is a cysteine-rich protein that belongs to the CCN family and regulates several cellular functions. Osteoblasts are major bone-forming cells that undergo proliferation, mineralization, renewal, and repair during the bone formation process. We have [...] Read more.
CCN3, otherwise known as the nephroblastoma overexpressed (NOV) protein, is a cysteine-rich protein that belongs to the CCN family and regulates several cellular functions. Osteoblasts are major bone-forming cells that undergo proliferation, mineralization, renewal, and repair during the bone formation process. We have previously reported that CCN3 increases bone morphogenetic protein 4 (BMP-4) production and bone mineralization in osteoblasts, although the role of CCN3 remains unclear with regard to osteogenic transcription factors (runt-related transcription factor 2 (Runx2) and osterix). Here, we used alizarin red-S and alkaline phosphatase staining to show that CCN3 enhances osteoblast differentiation. Stimulation of osteoblasts with CCN3 increases expression of osteogenic factors such as BMPs, Runx2, and osterix. Moreover, we found that the inhibition of miR-608 expression is involved in the effects of CCN3 and that incubation of osteoblasts with CCN3 promotes focal adhesion kinase (FAK) and Akt phosphorylation. Our results indicate that CCN3 promotes the expression of Runx2 and osterix in osteoblasts by inhibiting miR-608 expression via the FAK and Akt signaling pathways. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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18 pages, 3599 KiB  
Article
Petunidin, a B-ring 5′-O-Methylated Derivative of Delphinidin, Stimulates Osteoblastogenesis and Reduces sRANKL-Induced Bone Loss
by Masahiro Nagaoka, Toyonobu Maeda, Sawako Moriwaki, Atsushi Nomura, Yasumasa Kato, Shumpei Niida, Marlena C. Kruger and Keiko Suzuki
Int. J. Mol. Sci. 2019, 20(11), 2795; https://doi.org/10.3390/ijms20112795 - 07 Jun 2019
Cited by 22 | Viewed by 4149
Abstract
Several lines of evidence suggest that oxidative stress is one of the key pathogenic mechanisms of osteoporosis. We aimed to elucidate the bone protective effects of petunidin, one of the most common anthocyanidins, considering its potent antioxidative activity. Petunidin (>5 μg/mL) significantly inhibited [...] Read more.
Several lines of evidence suggest that oxidative stress is one of the key pathogenic mechanisms of osteoporosis. We aimed to elucidate the bone protective effects of petunidin, one of the most common anthocyanidins, considering its potent antioxidative activity. Petunidin (>5 μg/mL) significantly inhibited osteoclastogenesis and downregulated c-fos, Nfatc1, Mmp9, Ctsk, and Dc-stamp mRNA expression in RAW264.7 cells. Conversely, petunidin (>16 μg/mL) stimulated mineralized matrix formation and gene expression of Bmp2 and Ocn, whereas it suppressed Mmp13, Mmp2, and Mmp9 mRNA expression and proteolytic activities of MMP13 and MMP9 in MC3T3-E1 cells. Micro-CT and bone histomorphometry analyses of sRANKL-induced osteopenic C57BL/6J mice showed that daily oral administration of petunidin (7.5 mg/kg/day) increased bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), the ratio of osteoid volume to tissue volume (OV/TV), osteoid thickness (O.Th), the ratio of osteoid surface to bone surface (OS/BS), the ratio of osteoblast surface to bone surface (Ob.S/BS), and the number of osteoblast per unit of bone surface (N.Ob/BS), and decreased trabecular separation (Tb.Sp), the ratio of eroded surface to bone surface (ES/BS), the ratio of osteoclast surface to bone surface (Oc.S/BS), and number of osteoclast per unit of bone surface (N.Oc/BS), compared to untreated mice. Furthermore, histological sections of the femurs showed that oral administration of petunidin to sRANKL-induced osteopenic mice increased the size of osteoblasts located along the bone surface and the volume of osteoid was consistent with the in vitro osteoblast differentiation and MMP inhibition. These results suggest that petunidin is a promising natural agent to improve sRANKL-induced osteopenia in mice through increased osteoid formation, reflecting accelerated osteoblastogenesis, concomitant with suppressed bone resorption. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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14 pages, 1992 KiB  
Article
Anti-Osteoporotic Effects of Kukoamine B Isolated from Lycii Radicis Cortex Extract on Osteoblast and Osteoclast Cells and Ovariectomized Osteoporosis Model Mice
by Eunkuk Park, Jeonghyun Kim, Mun-Chang Kim, Subin Yeo, Jieun Kim, Seulbi Park, Miran Jo, Chun Whan Choi, Hyun-Seok Jin, Sang Woo Lee, Wan Yi Li, Ji-Won Lee, Jin-Hyok Park, Dam Huh and Seon-Yong Jeong
Int. J. Mol. Sci. 2019, 20(11), 2784; https://doi.org/10.3390/ijms20112784 - 06 Jun 2019
Cited by 21 | Viewed by 5023
Abstract
Osteoporosis is an abnormal bone remodeling condition characterized by decreased bone density, which leads to high risks of fracture. Previous study has demonstrated that Lycii Radicis Cortex (LRC) extract inhibits bone loss in ovariectomized (OVX) mice by enhancing osteoblast differentiation. A bioactive compound, [...] Read more.
Osteoporosis is an abnormal bone remodeling condition characterized by decreased bone density, which leads to high risks of fracture. Previous study has demonstrated that Lycii Radicis Cortex (LRC) extract inhibits bone loss in ovariectomized (OVX) mice by enhancing osteoblast differentiation. A bioactive compound, kukoamine B (KB), was identified from fractionation of an LRC extract as a candidate component responsible for an anti-osteoporotic effect. This study investigated the anti-osteoporotic effects of KB using in vitro and in vivo osteoporosis models. KB treatment significantly increased the osteoblastic differentiation and mineralized nodule formation of osteoblastic MC3T3-E1 cells, while it significantly decreased the osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. The effects of KB on osteoblastic and osteoclastic differentiations under more physiological conditions were also examined. In the co-culture of MC3T3-E1 cells and monocytes, KB promoted osteoblast differentiation but did not affect osteoclast differentiation. In vivo experiments revealed that KB significantly inhibited OVX-induced bone mineral density loss and restored the impaired bone structural properties in osteoporosis model mice. These results suggest that KB may be a potential therapeutic candidate for the treatment of osteoporosis. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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27 pages, 6691 KiB  
Article
Mechanism of CK2.3, a Novel Mimetic Peptide of Bone Morphogenetic Protein Receptor Type IA, Mediated Osteogenesis
by Vrathasha Vrathasha, Hilary Weidner and Anja Nohe
Int. J. Mol. Sci. 2019, 20(10), 2500; https://doi.org/10.3390/ijms20102500 - 21 May 2019
Cited by 11 | Viewed by 3926
Abstract
Background: Osteoporosis is a degenerative skeletal disease with a limited number of treatment options. CK2.3, a novel peptide, may be a potential therapeutic. It induces osteogenesis and bone formation in vitro and in vivo by acting downstream of BMPRIA through releasing CK2 from [...] Read more.
Background: Osteoporosis is a degenerative skeletal disease with a limited number of treatment options. CK2.3, a novel peptide, may be a potential therapeutic. It induces osteogenesis and bone formation in vitro and in vivo by acting downstream of BMPRIA through releasing CK2 from the receptor. However, the detailed signaling pathways, the time frame of signaling, and genes activated remain largely unknown. Methods: Using a newly developed fluorescent CK2.3 analog, specific inhibitors for the BMP signaling pathways, Western blot, and RT-qPCR, we determined the mechanism of CK2.3 in C2C12 cells. We then confirmed the results in primary BMSCs. Results: Using these methods, we showed that CK2.3 stimulation activated OSX, ALP, and OCN. CK2.3 stimulation induced time dependent release of CK2β from BMPRIA and concurrently CK2.3 colocalized with CK2α. Furthermore, CK2.3 induced BMP signaling depends on ERK1/2 and Smad1/5/8 signaling pathways. Conclusion: CK2.3 is a novel peptide that drives osteogenesis, and we detailed the molecular sequence of events that are triggered from the stimulation of CK2.3 until the induction of mineralization. This knowledge can be applied in the development of future therapeutics for osteoporosis. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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14 pages, 1349 KiB  
Article
Exercise Alleviates Osteoporosis in Rats with Mild Chronic Kidney Disease by Decreasing Sclerostin Production
by Hung-Wei Liao, Tsang-Hai Huang, Yi-Han Chang, Hung-Hsiang Liou, Yu-Hsien Chou, Yuh-Mou Sue, Peir-Haur Hung, Yu-Tzu Chang, Pei-Chuan Ho and Kuen-Jer Tsai
Int. J. Mol. Sci. 2019, 20(8), 2044; https://doi.org/10.3390/ijms20082044 - 25 Apr 2019
Cited by 14 | Viewed by 4425
Abstract
Chronic kidney disease–mineral bone disorder (CKD–MBD), comprising mineral, hormonal, and bone metabolic imbalance, is a major CKD-related issue; it causes osteoporosis prevalence in CKD patients. Osteocyte-derived sclerostin inhibits the osteogenic Wnt/β-catenin signaling pathway; its levels rise when kidney function declines. Exercise modulates the [...] Read more.
Chronic kidney disease–mineral bone disorder (CKD–MBD), comprising mineral, hormonal, and bone metabolic imbalance, is a major CKD-related issue; it causes osteoporosis prevalence in CKD patients. Osteocyte-derived sclerostin inhibits the osteogenic Wnt/β-catenin signaling pathway; its levels rise when kidney function declines. Exercise modulates the physiological functions of osteocytes, potentially altering sclerostin production. It may aid bone and mineral electrolyte homeostasis in CKD. Mild CKD was induced in rats by partial nephrectomy. They were divided into: sham (no CKD), CKD, and CKD + exercise (8 weeks of treadmill running) groups. Micro-CT scanning demonstrated that the CKD + exercise-group rats had a higher bone mineral density (BMD) of the spine and femoral metaphysis and higher femoral trabecular bone volume than the CKD-group rats. Bone formation rates were not significantly different. The CKD + exercise-group rats had lower serum sclerostin (157.1 ± 21.1 vs 309 ± 38.1 pg/mL, p < 0.05) and CTX-1 (bone resorption marker) levels. Immunohistochemistry revealed higher tibial β-catenin concentrations in the CKD + exercise-group rats. Serum FGF-23, intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), calcium, and phosphate levels showed no significant differences between these groups. Thus, exercise improves BMD and bone microstructure in mild CKD by inhibiting sclerostin production, but does not alter serum minerals. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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17 pages, 2458 KiB  
Article
Activation of PPARs Modulates Signalling Pathways and Expression of Regulatory Genes in Osteoclasts Derived from Human CD14+ Monocytes
by Abe Kasonga, Marlena C. Kruger and Magdalena Coetzee
Int. J. Mol. Sci. 2019, 20(7), 1798; https://doi.org/10.3390/ijms20071798 - 11 Apr 2019
Cited by 20 | Viewed by 3769
Abstract
Osteoclasts are the sole bone resorbing cell in the body and their over activity is key in the development of osteoporosis. Osteoclastogenesis is mediated by receptor activator of nuclear factor κB ligand (RANKL) signalling pathways. Unsaturated fatty acids (UFA) are known to inhibit [...] Read more.
Osteoclasts are the sole bone resorbing cell in the body and their over activity is key in the development of osteoporosis. Osteoclastogenesis is mediated by receptor activator of nuclear factor κB ligand (RANKL) signalling pathways. Unsaturated fatty acids (UFA) are known to inhibit osteoclastogenesis by targeting RANKL signalling. However, the mechanisms of action remain unclear. Peroxisome proliferator activated receptors (PPARs) are a family of nuclear receptors, with three known isoforms (PPAR-α, PPAR-β/δ and PPAR-γ), that are known to bind UFAs and are expressed in osteoclasts. In this study, we aimed to determine how different families of UFAs activate PPARs and how PPAR activation influences osteoclast signalling. Human CD14+ monocytes were seeded into cluster plates with RANKL and macrophage colony stimulating factor (M-CSF) in the presence of PPAR agonists or different types of UFAs. All the PPAR agonists were shown to upregulate the activity of their respective receptors. Polyunsaturated fatty acids increased PPAR-α to a greater extent than monounsaturated fatty acids (MUFAs), which favoured PPAR-β/δ activation. All PPAR agonists inhibited osteoclastogenesis. The activation of RANKL signalling pathways and expression of key osteoclast genes were downregulated by PPAR agonists. This study reveals that PPAR activation can inhibit osteoclastogenesis through modulation of RANKL signalling. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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18 pages, 16673 KiB  
Article
Interaction among Calcium Diet Content, PTH (1-34) Treatment and Balance of Bone Homeostasis in Rat Model: The Trabecular Bone as Keystone
by Marzia Ferretti, Francesco Cavani, Laura Roli, Marta Checchi, Maria Sara Magarò, Jessika Bertacchini and Carla Palumbo
Int. J. Mol. Sci. 2019, 20(3), 753; https://doi.org/10.3390/ijms20030753 - 11 Feb 2019
Cited by 9 | Viewed by 3836
Abstract
The present study is the second step (concerning normal diet restoration) of the our previous study (concerning the calcium-free diet) to determine whether normal diet restoration, with/without concomitant PTH (1-34) administration, can influence amounts and deposition sites of the total bone mass. Histomorphometric [...] Read more.
The present study is the second step (concerning normal diet restoration) of the our previous study (concerning the calcium-free diet) to determine whether normal diet restoration, with/without concomitant PTH (1-34) administration, can influence amounts and deposition sites of the total bone mass. Histomorphometric evaluations and immunohistochemical analysis for Sclerostin expression were conducted on the vertebral bodies and femurs in the rat model. The final goals are (i) to define timing and manners of bone mass changes when calcium is restored to the diet, (ii) to analyze the different involvement of the two bony architectures having different metabolism (i.e., trabecular versus cortical bone), and (iii) to verify the eventual role of PTH (1-34) administration. Results evidenced the greater involvement of the trabecular bone with respect to the cortical bone, in response to different levels of calcium content in the diet, and the effect of PTH, mostly in the recovery of trabecular bony architecture. The main findings emerged from the present study are (i) the importance of the interplay between mineral homeostasis and skeletal homeostasis in modulating and guiding bone’s response to dietary/metabolic alterations and (ii) the evidence that the more involved bony architecture is the trabecular bone, the most susceptible to the dynamical balance of the two homeostases. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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Review

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27 pages, 1579 KiB  
Review
Bone Diseases in Patients with Chronic Liver Disease
by Hae Min Jeong and Dong Joon Kim
Int. J. Mol. Sci. 2019, 20(17), 4270; https://doi.org/10.3390/ijms20174270 - 31 Aug 2019
Cited by 54 | Viewed by 11194
Abstract
Osteoporosis is a frequently observed complication in patients with chronic liver disease, particularly liver cirrhosis and cholestatic liver diseases. In addition, osteoporosis is critical in patients receiving a liver transplant. Nevertheless, few studies have evaluated bone diseases in patients with more frequently observed [...] Read more.
Osteoporosis is a frequently observed complication in patients with chronic liver disease, particularly liver cirrhosis and cholestatic liver diseases. In addition, osteoporosis is critical in patients receiving a liver transplant. Nevertheless, few studies have evaluated bone diseases in patients with more frequently observed chronic liver disease, such as chronic viral hepatitis, nonalcoholic fatty liver disease and alcoholic liver disease. Osteoporosis is a disease caused by an imbalance in the activities of osteoblasts and osteoclasts. Over the last few decades, many advances have improved our knowledge of the pathogenesis of osteoporosis. Importantly, activated immune cells affect the progression of osteoporosis, and chronic inflammation may exert an additional effect on the existing pathophysiology of osteoporosis. The microbiota of the intestinal tract may also affect the progression of bone loss in patients with chronic liver disease. Recently, studies regarding the effects of chronic inflammation on dysbiosis in bone diseases have been conducted. However, mechanisms underlying osteoporosis in patients with chronic liver disease are complex and precise mechanisms remain unknown. The following special considerations in patients with chronic liver disease are reviewed: bone diseases in patients who underwent a liver transplant, the association between chronic hepatitis B virus infection treatment and bone diseases, the association between sarcopenia and bone diseases in patients with chronic liver disease, and the association between chronic liver disease and avascular necrosis of the hip. Few guidelines are currently available for the management of low bone mineral density or bone diseases in patients with chronic liver disease. Due to increased life expectancy and therapeutic advances in chronic liver disease, the importance of managing osteoporosis and other bone diseases in patients with chronic liver disease is expected to increase. Consequently, specific guidelines need to be established in the near future. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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24 pages, 725 KiB  
Review
Molecular-Based Treatment Strategies for Osteoporosis: A Literature Review
by Yuichiro Ukon, Takahiro Makino, Joe Kodama, Hiroyuki Tsukazaki, Daisuke Tateiwa, Hideki Yoshikawa and Takashi Kaito
Int. J. Mol. Sci. 2019, 20(10), 2557; https://doi.org/10.3390/ijms20102557 - 24 May 2019
Cited by 76 | Viewed by 12966
Abstract
Osteoporosis is an unavoidable public health problem in an aging or aged society. Anti-resorptive agents (calcitonin, estrogen, and selective estrogen-receptor modulators, bisphosphonates, anti-receptor activator of nuclear factor κB ligand antibody along with calcium and vitamin D supplementations) and anabolic agents (parathyroid hormone and [...] Read more.
Osteoporosis is an unavoidable public health problem in an aging or aged society. Anti-resorptive agents (calcitonin, estrogen, and selective estrogen-receptor modulators, bisphosphonates, anti-receptor activator of nuclear factor κB ligand antibody along with calcium and vitamin D supplementations) and anabolic agents (parathyroid hormone and related peptide analogs, sclerostin inhibitors) have major roles in current treatment regimens and are used alone or in combination based on the pathological condition. Recent advancements in the molecular understanding of bone metabolism and in bioengineering will open the door to future treatment paradigms for osteoporosis, including antibody agents, stem cells, and gene therapies. This review provides an overview of the molecular mechanisms, clinical evidence, and potential adverse effects of drugs that are currently used or under development for the treatment of osteoporosis to aid clinicians in deciding how to select the best treatment option. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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21 pages, 559 KiB  
Review
Medical Treatment for Osteoporosis: From Molecular to Clinical Opinions
by Li-Ru Chen, Nai-Yu Ko and Kuo-Hu Chen
Int. J. Mol. Sci. 2019, 20(9), 2213; https://doi.org/10.3390/ijms20092213 - 06 May 2019
Cited by 91 | Viewed by 9405
Abstract
Osteoporosis is a major concern all over the world. With aging, a gradual loss of bone mass results in osteopenia and osteoporosis. Heritable factors account for 60–80% of optimal bone mineralization. Modifiable factors, such as weight-bearing exercise, nutrition, body mass, and hormonal milieu, [...] Read more.
Osteoporosis is a major concern all over the world. With aging, a gradual loss of bone mass results in osteopenia and osteoporosis. Heritable factors account for 60–80% of optimal bone mineralization. Modifiable factors, such as weight-bearing exercise, nutrition, body mass, and hormonal milieu, play an important role in the development of osteopenia and osteoporosis in adulthood. Currently, anti-resorptive agents, including estrogen, bisphosphonates, and selective estrogen receptor modulators (SERMs), are the drugs of choice for osteoporosis. Other treatments include parathyroid hormone (PTH) as well as the nutritional support of calcium and vitamin D. New treatments such as tissue-selective estrogen receptor complexes (TSECs) are currently in use too. This review, which is based on a systematic appraisal of the current literature, provides current molecular and genetic opinions on osteoporosis and its medical treatment. It offers evidence-based information to help researchers and clinicians with osteoporosis assessment. However, many issues regarding osteoporosis and its treatment remain unknown or controversial and warrant future investigation. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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15 pages, 964 KiB  
Review
The Role of Macrophage in the Pathogenesis of Osteoporosis
by Deng-Ho Yang and Meng-Yin Yang
Int. J. Mol. Sci. 2019, 20(9), 2093; https://doi.org/10.3390/ijms20092093 - 28 Apr 2019
Cited by 75 | Viewed by 11801
Abstract
Osteoporosis is a systemic disease with progressive bone loss. The bone loss is associated with an imbalance between bone resorption via osteoclasts and bone formation via osteoblasts. Other cells including T cells, B cells, macrophages, and osteocytes are also involved in the pathogenesis [...] Read more.
Osteoporosis is a systemic disease with progressive bone loss. The bone loss is associated with an imbalance between bone resorption via osteoclasts and bone formation via osteoblasts. Other cells including T cells, B cells, macrophages, and osteocytes are also involved in the pathogenesis of osteoporosis. Different cytokines from activated macrophages can regulate or stimulate the development of osteoclastogenesis-associated bone loss. The fusion of macrophages can form multinucleated osteoclasts and, thus, cause bone resorption via the expression of IL-4 and IL-13. Different cytokines, endocrines, and chemokines are also expressed that may affect the presentation of macrophages in osteoporosis. Macrophages have an effect on bone formation during fracture-associated bone repair. However, activated macrophages may secrete proinflammatory cytokines that induce bone loss by osteoclastogenesis, and are associated with the activation of bone resorption. Targeting activated macrophages at an appropriate stage may help inhibit or slow the progression of bone loss in patients with osteoporosis. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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14 pages, 765 KiB  
Review
The Endocannabinoid/Endovanilloid System in Bone: From Osteoporosis to Osteosarcoma
by Francesca Rossi, Chiara Tortora, Francesca Punzo, Giulia Bellini, Maura Argenziano, Alessandra Di Paola, Marco Torella and Silverio Perrotta
Int. J. Mol. Sci. 2019, 20(8), 1919; https://doi.org/10.3390/ijms20081919 - 18 Apr 2019
Cited by 51 | Viewed by 6611
Abstract
Bone is a dynamic tissue, whose homeostasis is maintained by a fine balance between osteoclast (OC) and osteoblast (OB) activity. The endocannabinoid/endovanilloid (EC/EV) system’s receptors are the cannabinoid receptor type 1 (CB1), the cannabinoid receptor type 2 (CB2), and the transient receptor potential [...] Read more.
Bone is a dynamic tissue, whose homeostasis is maintained by a fine balance between osteoclast (OC) and osteoblast (OB) activity. The endocannabinoid/endovanilloid (EC/EV) system’s receptors are the cannabinoid receptor type 1 (CB1), the cannabinoid receptor type 2 (CB2), and the transient receptor potential cation channel subfamily V member 1 (TRPV1). Their stimulation modulates bone formation and bone resorption. Bone diseases are very common worldwide. Osteoporosis is the principal cause of bone loss and it can be caused by several factors such as postmenopausal estrogen decrease, glucocorticoid (GC) treatments, iron overload, and chemotherapies. Studies have demonstrated that CB1 and TRPV1 stimulation exerts osteoclastogenic effects, whereas CB2 stimulation has an anti-osteoclastogenic role. Moreover, the EC/EV system has been demonstrated to have a role in cancer, favoring apoptosis and inhibiting cell proliferation. In particular, in bone cancer, the modulation of the EC/EV system not only reduces cell growth and enhances apoptosis but it also reduces cell invasion and bone pain in mouse models. Therefore, EC/EV receptors may be a useful pharmacological target in the prevention and treatment of bone diseases. More studies to better investigate the biochemical mechanisms underlining the EC/EV system effects in bone are needed, but the synthesis of hybrid molecules, targeting these receptors and capable of oppositely regulating bone homeostasis, seems to be a promising and encouraging prospective in bone disease management. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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11 pages, 599 KiB  
Review
Regulation of Proliferation, Differentiation and Functions of Osteoblasts by Runx2
by Toshihisa Komori
Int. J. Mol. Sci. 2019, 20(7), 1694; https://doi.org/10.3390/ijms20071694 - 04 Apr 2019
Cited by 451 | Viewed by 17828
Abstract
Runx2 is essential for osteoblast differentiation and chondrocyte maturation. During osteoblast differentiation, Runx2 is weakly expressed in uncommitted mesenchymal cells, and its expression is upregulated in preosteoblasts, reaches the maximal level in immature osteoblasts, and is down-regulated in mature osteoblasts. Runx2 enhances the [...] Read more.
Runx2 is essential for osteoblast differentiation and chondrocyte maturation. During osteoblast differentiation, Runx2 is weakly expressed in uncommitted mesenchymal cells, and its expression is upregulated in preosteoblasts, reaches the maximal level in immature osteoblasts, and is down-regulated in mature osteoblasts. Runx2 enhances the proliferation of osteoblast progenitors by directly regulating Fgfr2 and Fgfr3. Runx2 enhances the proliferation of suture mesenchymal cells and induces their commitment into osteoblast lineage cells through the direct regulation of hedgehog (Ihh, Gli1, and Ptch1), Fgf (Fgfr2 and Fgfr3), Wnt (Tcf7, Wnt10b, and Wnt1), and Pthlh (Pthr1) signaling pathway genes, and Dlx5. Runx2 heterozygous mutation causes open fontanelle and sutures because more than half of the Runx2 gene dosage is required for the induction of these genes in suture mesenchymal cells. Runx2 regulates the proliferation of osteoblast progenitors and their differentiation into osteoblasts via reciprocal regulation with hedgehog, Fgf, Wnt, and Pthlh signaling molecules, and transcription factors, including Dlx5 and Sp7. Runx2 induces the expression of major bone matrix protein genes, including Col1a1, Spp1, Ibsp, Bglap2, and Fn1, in vitro. However, the functions of Runx2 in differentiated osteoblasts in the expression of these genes in vivo require further investigation. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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26 pages, 3402 KiB  
Review
The Molecular Mechanism of Vitamin E as a Bone-Protecting Agent: A Review on Current Evidence
by Sok Kuan Wong, Nur-Vaizura Mohamad, Nurul ‘Izzah Ibrahim, Kok-Yong Chin, Ahmad Nazrun Shuid and Soelaiman Ima-Nirwana
Int. J. Mol. Sci. 2019, 20(6), 1453; https://doi.org/10.3390/ijms20061453 - 22 Mar 2019
Cited by 52 | Viewed by 4585
Abstract
Bone remodelling is a tightly-coordinated and lifelong process of replacing old damaged bone with newly-synthesized healthy bone. In the bone remodelling cycle, bone resorption is coupled with bone formation to maintain the bone volume and microarchitecture. This process is a result of communication [...] Read more.
Bone remodelling is a tightly-coordinated and lifelong process of replacing old damaged bone with newly-synthesized healthy bone. In the bone remodelling cycle, bone resorption is coupled with bone formation to maintain the bone volume and microarchitecture. This process is a result of communication between bone cells (osteoclasts, osteoblasts, and osteocytes) with paracrine and endocrine regulators, such as cytokines, reactive oxygen species, growth factors, and hormones. The essential signalling pathways responsible for osteoclastic bone resorption and osteoblastic bone formation include the receptor activator of nuclear factor kappa-B (RANK)/receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG), Wnt/β-catenin, and oxidative stress signalling. The imbalance between bone formation and degradation, in favour of resorption, leads to the occurrence of osteoporosis. Intriguingly, vitamin E has been extensively reported for its anti-osteoporotic properties using various male and female animal models. Thus, understanding the underlying cellular and molecular mechanisms contributing to the skeletal action of vitamin E is vital to promote its use as a potential bone-protecting agent. This review aims to summarize the current evidence elucidating the molecular actions of vitamin E in regulating the bone remodelling cycle. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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20 pages, 1498 KiB  
Review
The Role of Tocotrienol in Preventing Male Osteoporosis—A Review of Current Evidence
by Kok-Yong Chin and Soelaiman Ima-Nirwana
Int. J. Mol. Sci. 2019, 20(6), 1355; https://doi.org/10.3390/ijms20061355 - 18 Mar 2019
Cited by 23 | Viewed by 6032
Abstract
Male osteoporosis is a significant but undetermined healthcare problem. Men suffer from a higher mortality rate post-fracture than women and they are marginalized in osteoporosis treatment. The current prophylactic agents for osteoporosis are limited. Functional food components such as tocotrienol may be an [...] Read more.
Male osteoporosis is a significant but undetermined healthcare problem. Men suffer from a higher mortality rate post-fracture than women and they are marginalized in osteoporosis treatment. The current prophylactic agents for osteoporosis are limited. Functional food components such as tocotrienol may be an alternative option for osteoporosis prevention in men. This paper aims to review the current evidence regarding the skeletal effects of tocotrienol in animal models of male osteoporosis and its potential antiosteoporotic mechanism. The efficacy of tocotrienol of various sources (single isoform, palm and annatto vitamin E mixture) had been tested in animal models of bone loss induced by testosterone deficiency (orchidectomy and buserelin), metabolic syndrome, nicotine, alcoholism, and glucocorticoid. The treated animals showed improvements ranging from bone microstructural indices, histomorphometric indices, calcium content, and mechanical strength. The bone-sparing effects of tocotrienol may be exerted through its antioxidant, anti-inflammatory, and mevalonate-suppressive pathways. However, information pertaining to its mechanism of actions is superficial and warrants further studies. As a conclusion, tocotrienol could serve as a functional food component to prevent male osteoporosis, but its application requires validation from a clinical trial in men. Full article
(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)
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