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Osteoporosis: From Molecular Mechanisms to Therapies 3.0

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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 (30 June 2022) | Viewed by 34993

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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 2.0" (https://www.mdpi.com/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

Manuscript Submission Information

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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

Osteoporosis
Treatment
Prevention
Molecular mechanisms
Signaling pathways

Published Papers (10 papers)

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Editorial

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2 pages, 155 KiB

Open AccessEditorial

Osteoporosis: From Molecular Mechanisms to Therapies 3.0

by Chih-Hsin Tang

Int. J. Mol. Sci. 2021, 22(23), 12725; https://doi.org/10.3390/ijms222312725 - 25 Nov 2021

Cited by 2 | Viewed by 1741

Abstract

Osteoporosis is a common skeletal disorder that occurs 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 six articles published in our Special Issue “Osteoporosis: From Molecular Mechanisms to Therapies 3.0”, a continuation of our 2020 Special Issue "Osteoporosis: From Molecular Mechanisms to Therapies". 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 3.0)

Research

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11 pages, 857 KiB

Open AccessArticle

Assessment of Bone Microstructure by Micro CT in C57BL/6J Mice for Sex-Specific Differentiation

by Katharina Kerschan-Schindl, Maria Papageorgiou, Ursula Föger-Samwald, Maria Butylina, Michael Weber and Peter Pietschmann

Int. J. Mol. Sci. 2022, 23(23), 14585; https://doi.org/10.3390/ijms232314585 - 23 Nov 2022

Cited by 4 | Viewed by 2205

Abstract

It remains uncertain which skeletal sites and parameters should be analyzed in rodent studies evaluating bone health and disease. In this cross-sectional mouse study using micro-computed tomography (µCT), we explored: (1) which microstructural parameters can be used to discriminate female from male bones and (2) whether it is meaningful to evaluate more than one bone site. Microstructural parameters of the trabecular and/or cortical compartments of the femur, tibia, thoracic and lumbar vertebral bodies, and skull were evaluated by µCT in 10 female and 10 male six-month-old C57BL/6J mice. The trabecular number (TbN) was significantly higher, while the trabecular separation (TbSp) was significantly lower in male compared to female mice at all skeletal sites assessed. Overall, bone volume/tissue volume (BV/TV) was also significantly higher in male vs. female mice (except for the thoracic spine, which did not differ by sex). Most parameters of the cortical bone microstructure did not differ between male and female mice. BV/TV, TbN, and TbSp at the femur, and TbN and TbSp at the tibia and lumbar spine could fully (100%) discriminate female from male bones. Cortical thickness (CtTh) at the femur was the best parameter to detect sex differences in the cortical compartment (AUC = 0.914). In 6-month-old C57BL/6J mice, BV/TV, TbN, and TbSp can be used to distinguish male from female bones. Whenever it is not possible to assess multiple bone sites, we propose to evaluate the bone microstructure of the femur for detecting potential sex differences. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 3.0)

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14 pages, 38394 KiB

Open AccessArticle

MicroRNA-29a in Osteoblasts Represses High-Fat Diet-Mediated Osteoporosis and Body Adiposis through Targeting Leptin

by Wei-Shiung Lian, Re-Wen Wu, Yu-Shan Chen, Jih-Yang Ko, Shao-Yu Wang, Holger Jahr and Feng-Sheng Wang

Int. J. Mol. Sci. 2021, 22(17), 9135; https://doi.org/10.3390/ijms22179135 - 24 Aug 2021

Cited by 11 | Viewed by 2605

Abstract

Skeletal tissue involves systemic adipose tissue metabolism and energy expenditure. MicroRNA signaling controls high-fat diet (HFD)-induced bone and fat homeostasis dysregulation remains uncertain. This study revealed that transgenic overexpression of miR-29a under control of osteocalcin promoter in osteoblasts (miR-29aTg) attenuated HFD-mediated body overweight, hyperglycemia, and hypercholesterolemia. HFD-fed miR-29aTg mice showed less bone mass loss, fatty marrow, and visceral fat mass together with increased subscapular brown fat mass than HFD-fed wild-type mice. HFD-induced O₂ underconsumption, respiratory quotient repression, and heat underproduction were attenuated in miR-29aTg mice. In vitro, miR-29a overexpression repressed transcriptomic landscapes of the adipocytokine signaling pathway, fatty acid metabolism, and lipid transport, etc., of bone marrow mesenchymal progenitor cells. Forced miR-29a expression promoted osteogenic differentiation but inhibited adipocyte formation. miR-29a signaling promoted brown/beige adipocyte markers Ucp-1, Pgc-1α, P2rx5, and Pat2 expression and inhibited white adipocyte markers Tcf21 and Hoxc9 expression. The microRNA also reduced peroxisome formation and leptin expression during adipocyte formation and downregulated HFD-induced leptin expression in bone tissue. Taken together, miR-29a controlled leptin signaling and brown/beige adipocyte formation of osteogenic progenitor cells to preserve bone anabolism, which reversed HFD-induced energy underutilization and visceral fat overproduction. This study sheds light on a new molecular mechanism by which bone integrity counteracts HFD-induced whole-body fat overproduction. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 3.0)

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15 pages, 3715 KiB

Open AccessArticle

Visfatin Promotes the Metastatic Potential of Chondrosarcoma Cells by Stimulating AP-1-Dependent MMP-2 Production in the MAPK Pathway

by Shih-Ya Hung, Chih-Yang Lin, Cheng-Chieh Yu, Hsien-Te Chen, Ming-Yu Lien, Yu-Wen Huang, Yi-Chin Fong, Ju-Fang Liu, Shih-Wei Wang, Wei-Cheng Chen and Chih-Hsin Tang

Int. J. Mol. Sci. 2021, 22(16), 8642; https://doi.org/10.3390/ijms22168642 - 11 Aug 2021

Cited by 11 | Viewed by 2017

Abstract

Chondrosarcoma is a malignant bone tumor that is characterized by high metastatic potential and marked resistance to radiation and chemotherapy. The knowledge that adipokines facilitate the initiation, progression, metastasis, and treatment resistance of various tumors has driven several in vitro and in vivo investigations into the effects of adipokines resistin, leptin, and adiponectin upon the development and progression of chondrosarcomas. Another adipokine, visfatin, is known to regulate tumor progression and metastasis, although how this molecule may affect chondrosarcoma metastasis is unclear. Here, we found that visfatin facilitated cellular migration via matrix metalloproteinase-2 (MMP-2) production in human chondrosarcoma cells and overexpression of visfatin enhanced lung metastasis in a mouse model of chondrosarcoma. Visfatin-induced stimulation of MMP-2 synthesis and activation of the AP-1 transcription factor facilitated chondrosarcoma cell migration via the ERK, p38, and JNK signaling pathways. This evidence suggests that visfatin is worth targeting in the treatment of metastatic chondrosarcoma. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 3.0)

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14 pages, 3147 KiB

Open AccessArticle

Biological Mechanisms of Paeonoside in the Differentiation of Pre-Osteoblasts and the Formation of Mineralized Nodules

by Kyung-Ran Park, Joon Yeop Lee, Myounglae Cho, Jin Tae Hong and Hyung-Mun Yun

Int. J. Mol. Sci. 2021, 22(13), 6899; https://doi.org/10.3390/ijms22136899 - 27 Jun 2021

Cited by 10 | Viewed by 2474

Abstract

Paeonia suffruticosa is a magnificent and long-lived woody plant that has traditionally been used to treat various diseases including inflammatory, neurological, cancer, and cardiovascular diseases. In the present study, we demonstrated the biological mechanisms of paeonoside (PASI) isolated from the dried roots of P. suffruticosa in pre-osteoblasts. Herein, we found that PASI has no cytotoxic effects on pre-osteoblasts. Migration assay showed that PASI promoted wound healing and transmigration in osteoblast differentiation. PASI increased early osteoblast differentiation and mineralized nodule formation. In addition, PASI enhanced the expression of Wnt3a and bone morphogenetic protein 2 (BMP2) and activated their downstream molecules, Smad1/5/8 and β-catenin, leading to increases in runt-related transcription factor 2 (RUNX2) expression during osteoblast differentiation. Furthermore, PASI-mediated osteoblast differentiation was attenuated by inhibiting the BMP2 and Wnt3a pathways, which was accompanied by reduction in the expression of RUNX2 in the nucleus. Taken together, our findings provide evidence that PASI enhances osteoblast differentiation and mineralized nodules by regulating RUNX2 expression through the BMP2 and Wnt3a pathways, suggesting a potential role for PASI targeting osteoblasts to treat bone diseases including osteoporosis and periodontitis. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 3.0)

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14 pages, 3140 KiB

Open AccessArticle

Inhibition of RANKL-Induced Osteoclastogenesis by Novel Mutant RANKL

by Yuria Jang, Hong Moon Sohn, Young Jong Ko, Hoon Hyun and Wonbong Lim

Int. J. Mol. Sci. 2021, 22(1), 434; https://doi.org/10.3390/ijms22010434 - 04 Jan 2021

Cited by 12 | Viewed by 3078

Abstract

Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 3.0)

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Review

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24 pages, 1285 KiB

Open AccessReview

Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments

by Kazuhiro Maeda, Ken Yoshida, Tetsuro Nishizawa, Kazuhiro Otani, Yu Yamashita, Hinako Okabe, Yuka Hadano, Tomohiro Kayama, Daitaro Kurosaka and Mitsuru Saito

Int. J. Mol. Sci. 2022, 23(5), 2871; https://doi.org/10.3390/ijms23052871 - 06 Mar 2022

Cited by 41 | Viewed by 6517

Abstract

Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients’ quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 3.0)

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17 pages, 366 KiB

Open AccessReview

Bone Health in Patients with Dyslipidemias: An Underestimated Aspect

by Panagiotis Anagnostis, Matilda Florentin, Sarantis Livadas, Irene Lambrinoudaki and Dimitrios G. Goulis

Int. J. Mol. Sci. 2022, 23(3), 1639; https://doi.org/10.3390/ijms23031639 - 31 Jan 2022

Cited by 34 | Viewed by 4665

Abstract

Beyond being aging-related diseases, atherosclerosis and osteoporosis share common pathogenetic pathways implicated in bone and vascular mineralization. However, the contributory role of dyslipidemia in this interplay is less documented. The purpose of this narrative review is to provide epidemiological evidence regarding the prevalence of bone disease (osteoporosis, fracture risk) in patients with dyslipidemias and to discuss potential common pathophysiological mechanisms linking osteoporosis and atherosclerosis. The effect of hypolipidemic therapy on bone metabolism is also discussed. Despite the high data heterogeneity and the variable quality of studies, dyslipidemia, mainly elevated total and low-density lipoprotein cholesterol concentrations, is associated with low bone mass and increased fracture risk. This effect may be mediated directly by the increased oxidative stress and systemic inflammation associated with dyslipidemia, leading to increased osteoclastic activity and reduced bone formation. Moreover, factors such as estrogen, vitamin D and K deficiency, and increased concentrations of parathyroid hormone, homocysteine and lipid oxidation products, can also contribute. Regarding the effect of hypolipidemic medications on bone metabolism, statins may slightly increase BMD and reduce fracture risk, although the evidence is not robust, as it is for omega-3 fatty acids. No evidence exists for the effects of ezetimibe, fibrates, and niacin. In any case, more prospective studies are needed further to elucidate the association between lipids and bone strength. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 3.0)

19 pages, 1088 KiB

Open AccessReview

Melatonin Inhibits Osteoclastogenesis and Osteolytic Bone Metastasis: Implications for Osteoporosis

by Iona J. MacDonald, Hsiao-Chi Tsai, An-Chen Chang, Chien-Chung Huang, Shun-Fa Yang and Chih-Hsin Tang

Int. J. Mol. Sci. 2021, 22(17), 9435; https://doi.org/10.3390/ijms22179435 - 30 Aug 2021

Cited by 15 | Viewed by 4572

Abstract

Osteoblasts and osteoclasts are major cellular components in the bone microenvironment and they play a key role in the bone turnover cycle. Many risk factors interfere with this cycle and contribute to bone-wasting diseases that progressively destroy bone and markedly reduce quality of life. Melatonin (N-acetyl-5-methoxy-tryptamine) has demonstrated intriguing therapeutic potential in the bone microenvironment, with reported effects that include the regulation of bone metabolism, acceleration of osteoblastogenesis, inhibition of osteoclastogenesis and the induction of apoptosis in mature osteoclasts, as well as the suppression of osteolytic bone metastasis. This review aims to shed light on molecular and clinical evidence that points to possibilities of melatonin for the treatment of both osteoporosis and osteolytic bone metastasis. It appears that the therapeutic qualities of melatonin supplementation may enable existing antiresorptive osteoporotic drugs to treat osteolytic metastasis. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 3.0)

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18 pages, 2013 KiB

Open AccessReview

Roles of MicroRNAs in Osteogenesis or Adipogenesis Differentiation of Bone Marrow Stromal Progenitor Cells

by Ya-Li Zhang, Liang Liu, Yaser Peymanfar, Paul Anderson and Cory J. Xian

Int. J. Mol. Sci. 2021, 22(13), 7210; https://doi.org/10.3390/ijms22137210 - 05 Jul 2021

Cited by 21 | Viewed by 3735

Abstract

Bone marrow stromal cells (BMSCs) are multipotent cells which can differentiate into chondrocytes, osteoblasts, and fat cells. Under pathological stress, reduced bone formation in favour of fat formation in the bone marrow has been observed through a switch in the differentiation of BMSCs. The bone/fat switch causes bone growth defects and disordered bone metabolism in bone marrow, for which the mechanisms remain unclear, and treatments are lacking. Studies suggest that small non-coding RNAs (microRNAs) could participate in regulating BMSC differentiation by disrupting the post-transcription of target genes, leading to bone/fat formation changes. This review presents an emerging concept of microRNA regulation in the bone/fat formation switch in bone marrow, the evidence for which is assembled mainly from in vivo and in vitro human or animal models. Characterization of changes to microRNAs reveals novel networks that mediate signalling and factors in regulating bone/fat switch and homeostasis. Recent advances in our understanding of microRNAs in their control in BMSC differentiation have provided valuable insights into underlying mechanisms and may have significant potential in development of new therapeutics. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies 3.0)

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