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Metabolic Bone Diseases: Pathophysiology and Molecular Biology

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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 October 2019) | Viewed by 56757

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Special Issue Editors

Prof. Dr. Andreas K. Nüssler

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Guest Editor

Siegfried-Weller Institute for Trauma Research, BG Trauma Center, University of Tuebingen, Schnarrenbergstrasse 95, 72070 Tuebingen, Germany
Interests: bone metabolic diseases; bone biology; stem cell; bone tissue; osteogenic differentiation
Special Issues, Collections and Topics in MDPI journals

Dr. Sabrina Ehnert

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Guest Editor

Department of Trauma and Reconstructive Surgery, Siegfried Weller Research Institute, Eberhard Karls University Tuebingen, BG Trauma Center Tuebingen, 72076 Tuebingen, Germany
Interests: bone biology; stem cell; bone tissue; osteogenic differentiation; musculoskeletal
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nowadays dramatic demographic changes towards an aging society along with a quiescent lifestyle results in a raised incidence of metabolic diseases worldwide, such as diabetes mellitus type 2. Many of these diseases affect bone metabolism. Indeed, there are more than 70 diseases and health conditions reported causing so-called metabolic bone diseases—characterized by bone pain, altered posture, and poor bone quality (e.g. osteopenia or osteoporosis), and consequently an increased fracture risk. In the case of a fracture, patient-centered care is a great challenge, including fixing the fracture, handling of the surrounding soft tissue and the patients’ mobilization. Despite all the medical progress, these patients often face delayed/impaired bone healing rich in complications.

All this forces society to tackle the existing gaps in the knowledge of metabolic bone disorders. Most metabolic bone diseases have in common an imbalance in osteoblast and osteoclast function, resulting in poor bone quality. However, the mechanisms leading to metabolic bone diseases are far from being elucidated.

This Special Issue will contain a collection of manuscripts that describe investigations into the different stages of bone metabolic diseases, reflecting our current knowledge and describing several diseases and the underlying molecular mechanisms, molecular diagnostics, and novel molecular treatment/therapeutic options.

Prof. Dr. Andreas K. Nüssler
Dr. Sabrina Ehnert
Guest Editors

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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

bone
bone microenvironment
metabolic bone diseases
molecular mechanisms
aging
diabetic osteopathy
hepatic osteodystrophy
osteoblast
bone density
osteoclast

Published Papers (6 papers)

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Research

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16 pages, 2649 KiB

Open AccessArticle

The Rho GTPase RAC1 in Osteoblasts Controls Their Function

by Katrin Huck, Carla Sens, Carina Wuerfel, Caren Zoeller and Inaam A. Nakchbandi

Int. J. Mol. Sci. 2020, 21(2), 385; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020385 - 08 Jan 2020

Cited by 10 | Viewed by 3777

Abstract

The regulation of the differentiation of the bone-forming cells, the osteoblasts, is complex. Many signaling pathways converge on the master regulator of osteoblast differentiation Runx2. The role of molecules that integrate several signaling pathways such as the Rho GTPases need to be better understood. We, therefore, asked at which stage Rac1, one of the Rho GTPase, is needed for osteoblast differentiation and whether it is involved in two pathways, the anabolic response to parathyroid hormone and the stimulatory effect of fibronectin isoforms on integrins. Genetic deletion of Rac1 in preosteoblasts using the osterix promoter diminished osteoblast differentiation in vitro. This effect was however similar to the presence of the promoter by itself. We, therefore, applied a Rac1 inhibitor and confirmed a decrease in differentiation. In vivo, Rac1 deletion using the osterix promoter decreased bone mineral density as well as histomorphometric measures of osteoblast function. In contrast, deleting Rac1 in differentiating osteoblasts using the collagen α1(I) promoter had no effects. We then evaluated whether intermittent parathyroid hormone (PTH) was able to affect bone mineral density in the absence of Rac1 in preosteoblasts. The increase in bone mineral density was similar in control animals and in mice in which Rac1 was deleted using the osterix promoter. Furthermore, stimulation of integrin by integrin isoforms was able to enhance osteoblast differentiation, despite the deletion of Rac1. In summary, Rac1 in preosteoblasts is required for normal osteoblast function and bone density, but it is neither needed for PTH-mediated anabolic effects nor for integrin-mediated enhancement of differentiation. Full article

(This article belongs to the Special Issue Metabolic Bone Diseases: Pathophysiology and Molecular Biology)

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19 pages, 2535 KiB

Open AccessArticle

Cigarette Smoke Induces the Risk of Metabolic Bone Diseases: Transforming Growth Factor Beta Signaling Impairment via Dysfunctional Primary Cilia Affects Migration, Proliferation, and Differentiation of Human Mesenchymal Stem Cells

by Romina H. Aspera-Werz, Tao Chen, Sabrina Ehnert, Sheng Zhu, Theresa Fröhlich and Andreas K. Nussler

Int. J. Mol. Sci. 2019, 20(12), 2915; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20122915 - 14 Jun 2019

Cited by 34 | Viewed by 4471

Abstract

It is well established that smoking has detrimental effects on bone integrity and is a preventable risk factor for metabolic bone disorders. Following orthopedic surgeries, smokers frequently show delayed fracture healing associated with many complications, which results in prolonged hospital stays. One crucial factor responsible for fracture repair is the recruitment and differentiation of mesenchymal stem cells (MSCs) at early stages, a mechanism mediated by transforming growth factor β (TGF-β). Although it is known that smokers frequently have decreased TGF-β levels, little is known about the actual signaling occurring in these patients. We investigated the effect of cigarette smoke on TGF-β signaling in MSCs to evaluate which step in the pathway is affected by cigarette smoke extract (CSE). Single-cell-derived human mesenchymal stem cell line (SCP-1 cells) were treated with CSE concentrations associated with smoking up to 20 cigarettes a day. TGF-β signaling was analyzed using an adenovirus-based reporter assay system. Primary cilia structure and downstream TGF-β signaling modulators (Smad2, Smad3, and Smad4) were analyzed by Western blot and immunofluorescence staining. CSE exposure significantly reduced TGF-β signaling. Intriguingly, we observed that protein levels of phospho-Smad2/3 (active forms) as well as nuclear translocation of the phospho-Smad3/4 complex decreased after CSE exposure, phenomena that affected signal propagation. CSE exposure reduced the activation of TGF-β modulators under constitutive activation of TGF-β receptor type I (ALK5), evidencing that CSE affects signaling downstream of the ALK5 receptor but not the binding of the cytokine to the receptor itself. CSE-mediated TGF-β signaling impaired MSC migration, proliferation, and differentiation and ultimately affected endochondral ossification. Thus, we conclude that CSE-mediated disruption of TGF-β signaling in MSCs is partially responsible for delayed fracture healing in smokers. Full article

(This article belongs to the Special Issue Metabolic Bone Diseases: Pathophysiology and Molecular Biology)

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Review

Jump to: Research

31 pages, 736 KiB

Open AccessReview

Cytokines in Inflammatory Disease

by Shinwan Kany, Jan Tilmann Vollrath and Borna Relja

Int. J. Mol. Sci. 2019, 20(23), 6008; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20236008 - 28 Nov 2019

Cited by 993 | Viewed by 30074

Abstract

This review aims to briefly discuss a short list of a broad variety of inflammatory cytokines. Numerous studies have implicated that inflammatory cytokines exert important effects with regard to various inflammatory diseases, yet the reports on their specific roles are not always consistent. They can be used as biomarkers to indicate or monitor disease or its progress, and also may serve as clinically applicable parameters for therapies. Yet, their precise role is not always clearly defined. Thus, in this review, we focus on the existing literature dealing with the biology of cytokines interleukin (IL)-6, IL-1, IL-33, tumor necrosis factor-alpha (TNF-α), IL-10, and IL-8. We will briefly focus on the correlations and role of these inflammatory mediators in the genesis of inflammatory impacts (e.g., shock, trauma, immune dysregulation, osteoporosis, and/or critical illness). Full article

(This article belongs to the Special Issue Metabolic Bone Diseases: Pathophysiology and Molecular Biology)

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18 pages, 1591 KiB

Open AccessReview

From Osteoclast Differentiation to Osteonecrosis of the Jaw: Molecular and Clinical Insights

by Alexandre Anesi, Luigi Generali, Laura Sandoni, Samantha Pozzi and Alexis Grande

Int. J. Mol. Sci. 2019, 20(19), 4925; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194925 - 04 Oct 2019

Cited by 44 | Viewed by 6685

Abstract

Bone physiology relies on the delicate balance between resorption and formation of its tissue. Bone resorption depends on a process called osteoclastogenesis in which bone-resorbing cells, i.e., osteoclasts, are produced by the differentiation of more undifferentiated progenitors and precursors. This process is governed by two main factors, monocyte-colony stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). While the former exerts a proliferating effect on progenitors/precursors, the latter triggers a differentiation effect on more mature cells of the same lineage. Bone homeostasis requires a perfect space–time coordination of the involved signals. When osteoclastogenesis is poorly balanced with the differentiation of the bone forming counterparts, i.e., osteoblasts, physiological bone remodelling can turn into a pathological state, causing the systematic disruption of bone tissue which results in osteopenia or osteolysis. Examples of these conditions are represented by osteoporosis, Paget’s disease, bone metastasis, and multiple myeloma. Therefore, drugs targeting osteoclastogenesis, such as bisphosphonates and an anti-RANKL monoclonal antibody, have been developed and are currently used in the treatment of such diseases. Despite their demonstrated therapeutic efficacy, these agents are unfortunately not devoid of side effects. In this regard, a condition called osteonecrosis of the jaw (ONJ) has been recently correlated with anti-resorptive therapy. In this review we will address the involvement of osteoclasts and osteoclast-related factors in the pathogenesis of ONJ. It is to be hoped that a better understanding of the biological mechanisms underlying bone remodelling will help in the design a medical therapeutic approach for ONJ as an alternative to surgical procedures. Full article

(This article belongs to the Special Issue Metabolic Bone Diseases: Pathophysiology and Molecular Biology)

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11 pages, 743 KiB

Open AccessReview

The Endocrine Function of Osteocalcin Regulated by Bone Resorption: A Lesson from Reduced and Increased Bone Mass Diseases

by Michela Rossi, Giulia Battafarano, Jessica Pepe, Salvatore Minisola and Andrea Del Fattore

Int. J. Mol. Sci. 2019, 20(18), 4502; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184502 - 11 Sep 2019

Cited by 27 | Viewed by 4827

Abstract

Bone is a peculiar tissue subjected to a continuous process of self-renewal essential to assure the integrity of the skeleton and to explicate the endocrine functions. The study of bone diseases characterized by increased or reduced bone mass due to osteoclast alterations has been essential to understand the great role played by osteocalcin in the endocrine functions of the skeleton. The ability of osteoclasts to regulate the decarboxylation of osteocalcin and to control glucose metabolism, male fertility, and cognitive functions was demonstrated by the use of animal models. In this review we described how diseases characterized by defective and increased bone resorption activity, as osteopetrosis and osteoporosis, were essential to understand the involvement of bone tissue in whole body physiology. To translate this knowledge into humans, recently published reports on patients were described, but further studies should be performed to confirm this complex hormonal regulation in humans. Full article

(This article belongs to the Special Issue Metabolic Bone Diseases: Pathophysiology and Molecular Biology)

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31 pages, 3443 KiB

Open AccessReview

Hepatic Osteodystrophy—Molecular Mechanisms Proposed to Favor Its Development

by Sabrina Ehnert, Romina H. Aspera-Werz, Marc Ruoß, Steven Dooley, Jan G. Hengstler, Silvio Nadalin, Borna Relja, Andreas Badke and Andreas K. Nussler

Int. J. Mol. Sci. 2019, 20(10), 2555; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102555 - 24 May 2019

Cited by 46 | Viewed by 6263

Abstract

Almost all patients with chronic liver diseases (CLD) show altered bone metabolism. Depending on the etiology, this manifests in a severe osteoporosis in up to 75% of the affected patients. Due to high prevalence, the generic term hepatic osteodystrophy (HOD) evolved, describing altered bone metabolism, decreased bone mineral density, and deterioration of bone structure in patients with CLD. Once developed, HOD is difficult to treat and increases the risk of fragility fractures. Existing fractures affect the quality of life and, more importantly, long-term prognosis of these patients, which presents with increased mortality. Thus, special care is required to support the healing process. However, for early diagnosis (reduce fracture risk) and development of adequate treatment strategies (support healing of existing fractures), it is essential to understand the underlying mechanisms that link disturbed liver function with this bone phenotype. In the present review, we summarize proposed molecular mechanisms favoring the development of HOD and compromising the healing of associated fractures, including alterations in vitamin D metabolism and action, disbalances in transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signaling with histone deacetylases (HDACs) as secondary regulators, as well as alterations in the receptor activator of nuclear factor kappa B ligand (RANKL)–osteoprotegerin (OPG) system mediated by sclerostin. Based on these mechanisms, we give an overview on the limitations of early diagnosis of HOD with established serum markers. Full article

(This article belongs to the Special Issue Metabolic Bone Diseases: Pathophysiology and Molecular Biology)

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