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New Insights in Osteoclasts’ Biology
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New Insights in Osteoclasts’ Biology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 29762

Special Issue Editors

Prof. Dr. Sophie Roux

E-Mail Website
Guest Editor
Université de Sherbrooke, Sherbrooke, QC, Canada
Interests: osteoclast; bone resorption; autophagy; epigenetics; bone diseases; rheumatoid arthritis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Hugues Allard-Chamard

E-Mail Website
Guest Editor
Université de Sherbrooke, Sherbrooke, QC, Canada
Interests: lymphocytes; epigenetics; osteo-immunology; primary immunodeficiency; IgG4-related disease; arthritis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Following the explosion of knowledge triggered by the cloning of RANKL and its partners RANK and OPG in the late 1990s, the comprehension of osteoclasts’ physiology and its involvement in bone diseases characterized by hypersorption have grown steadily. The discovery of new signaling and trafficking pathways have challenged our understanding of bone homeostasis, and has opened the path for the emergence of new therapeutics. Moreover, knowledge about cell interactions has also been refined, particularly with immune T- or B-cells, leading to the definition of the osteoimmunology field. Translational research in bone diseases also benefits from the development of high-throughput screening techniques to refine our understanding of the genetic and epigenetic components involved in bone dysregulation.

This Special Issue on osteoclasts is therefore open to research articles and reviews, and aims to better understand the osteoclastic cell, from its activation to the signaling and regulatory pathways, as well as osteoclast dysfunctions in bone diseases.

You may choose our Joint Special Issue in Life.

Prof. Dr. Sophie Roux
Prof. Dr. Hugues Allard-Chamard
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

  • human osteoclast
  • mouse models
  • cell differentiation
  • multinucleation
  • trafficking
  • epigenetics
  • RANKL pathway
  • osteoprotegerin
  • cytokines
  • micro-RNAs
  • bone diseases

Published Papers (6 papers)

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Research

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16 pages, 2772 KiB  
Article
Kynurenine Promotes RANKL-Induced Osteoclastogenesis In Vitro by Activating the Aryl Hydrocarbon Receptor Pathway
by Nada H. Eisa, Sakamuri V. Reddy, Ahmed M. Elmansi, Galina Kondrikova, Dmitry Kondrikov, Xing-Ming Shi, Chad M. Novince, Mark W. Hamrick, Meghan E. McGee-Lawrence, Carlos M. Isales, Sadanand Fulzele and William D. Hill
Int. J. Mol. Sci. 2020, 21(21), 7931; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217931 - 26 Oct 2020
Cited by 26 | Viewed by 3170
Abstract
There is increasing evidence of the involvement of the tryptophan metabolite kynurenine (KYN) in disrupting osteogenesis and contributing to aging-related bone loss. Here, we show that KYN has an effect on bone resorption by increasing osteoclastogenesis. We have previously reported that in vivo [...] Read more.
There is increasing evidence of the involvement of the tryptophan metabolite kynurenine (KYN) in disrupting osteogenesis and contributing to aging-related bone loss. Here, we show that KYN has an effect on bone resorption by increasing osteoclastogenesis. We have previously reported that in vivo treatment with KYN significantly increased osteoclast number lining bone surfaces. Here, we report the direct effect of KYN on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis in Raw 264.7 macrophage cells, and we propose a potential mechanism for these KYN-mediated effects. We show that KYN/RANKL treatment results in enhancement of RANKL-induced osteoclast differentiation. KYN drives upregulation and activation of the key osteoclast transcription factors, c-fos and NFATc1 resulting in an increase in the number of multinucleated TRAP+ osteoclasts, and in hydroxyapatite bone resorptive activity. Mechanistically, the KYN receptor, aryl hydrocarbon receptor (AhR), plays an important role in the induction of osteoclastogenesis. We show that blocking AhR signaling using an AhR antagonist, or AhR siRNA, downregulates the KYN/RANKL-mediated increase in c-fos and NFATc1 and inhibits the formation of multinucleated TRAP + osteoclasts. Altogether, this work highlights that the novelty of the KYN and AhR pathways might have a potential role in helping to regulate osteoclast function with age and supports pursuing additional research to determine if they are potential therapeutic targets for the prevention or treatment of osteoporosis. Full article
(This article belongs to the Special Issue New Insights in Osteoclasts’ Biology)
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18 pages, 3409 KiB  
Article
Osteoclasts’ Ability to Generate Trenches Rather Than Pits Depends on High Levels of Active Cathepsin K and Efficient Clearance of Resorption Products
by Xenia G. Borggaard, Dinisha C. Pirapaharan, Jean-Marie Delaissé and Kent Søe
Int. J. Mol. Sci. 2020, 21(16), 5924; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165924 - 18 Aug 2020
Cited by 19 | Viewed by 3454
Abstract
Until recently, it was well-accepted that osteoclasts resorb bone according to the resorption cycle model. This model is based on the assumption that osteoclasts are immobile during bone erosion, allowing the actin ring to be firmly attached and thereby provide an effective seal [...] Read more.
Until recently, it was well-accepted that osteoclasts resorb bone according to the resorption cycle model. This model is based on the assumption that osteoclasts are immobile during bone erosion, allowing the actin ring to be firmly attached and thereby provide an effective seal encircling the resorptive compartment. However, through time-lapse, it was recently documented that osteoclasts making elongated resorption cavities and trenches move across the bone surface while efficiently resorbing bone. However, it was also shown that osteoclasts making rounded cavities and pits indeed resorb bone while they are immobile. Only little is known about what distinguishes these two different resorption modes. This is of both basic and clinical interest because these resorption modes are differently sensitive to drugs and are affected by the gender as well as age of the donor. In the present manuscript we show that: 1. levels of active cathepsin K determine the switch from pit to trench mode; 2. pit and trench mode depend on clathrin-mediated endocytosis; and 3. a mechanism integrating release of resorption products and membrane/integrin recycling is required for prolongation of trench mode. Our study therefore contributes to an improved understanding of the molecular and cellular determinants for the two osteoclastic bone resorption modes. Full article
(This article belongs to the Special Issue New Insights in Osteoclasts’ Biology)
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Review

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30 pages, 2035 KiB  
Review
The V-ATPase a3 Subunit: Structure, Function and Therapeutic Potential of an Essential Biomolecule in Osteoclastic Bone Resorption
by Anh Chu, Ralph A. Zirngibl and Morris F. Manolson
Int. J. Mol. Sci. 2021, 22(13), 6934; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136934 - 28 Jun 2021
Cited by 16 | Viewed by 4145
Abstract
This review focuses on one of the 16 proteins composing the V-ATPase complex responsible for resorbing bone: the a3 subunit. The rationale for focusing on this biomolecule is that mutations in this one protein account for over 50% of osteopetrosis cases, highlighting [...] Read more.
This review focuses on one of the 16 proteins composing the V-ATPase complex responsible for resorbing bone: the a3 subunit. The rationale for focusing on this biomolecule is that mutations in this one protein account for over 50% of osteopetrosis cases, highlighting its critical role in bone physiology. Despite its essential role in bone remodeling and its involvement in bone diseases, little is known about the way in which this subunit is targeted and regulated within osteoclasts. To this end, this review is broadened to include the three other mammalian paralogues (a1, a2 and a4) and the two yeast orthologs (Vph1p and Stv1p). By examining the literature on all of the paralogues/orthologs of the V-ATPase a subunit, we hope to provide insight into the molecular mechanisms and future research directions specific to a3. This review starts with an overview on bone, highlighting the role of V-ATPases in osteoclastic bone resorption. We then cover V-ATPases in other location/functions, highlighting the roles which the four mammalian a subunit paralogues might play in differential targeting and/or regulation. We review the ways in which the energy of ATP hydrolysis is converted into proton translocation, and go in depth into the diverse role of the a subunit, not only in proton translocation but also in lipid binding, cell signaling and human diseases. Finally, the therapeutic implication of targeting a3 specifically for bone diseases and cancer is discussed, with concluding remarks on future directions. Full article
(This article belongs to the Special Issue New Insights in Osteoclasts’ Biology)
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16 pages, 1318 KiB  
Review
Rab GTPases in Osteoclastic Bone Resorption and Autophagy
by Michèle Roy and Sophie Roux
Int. J. Mol. Sci. 2020, 21(20), 7655; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207655 - 16 Oct 2020
Cited by 13 | Viewed by 6845
Abstract
Small guanosine triphosphate hydrolases (GTPases) of the Rab family are involved in plasma membrane delivery, fusion events, and lysosomal and autophagic degradation pathways, thereby regulating signaling pathways and cell differentiation and function. Osteoclasts are bone-resorbing cells that maintain bone homeostasis. Polarized vesicular trafficking [...] Read more.
Small guanosine triphosphate hydrolases (GTPases) of the Rab family are involved in plasma membrane delivery, fusion events, and lysosomal and autophagic degradation pathways, thereby regulating signaling pathways and cell differentiation and function. Osteoclasts are bone-resorbing cells that maintain bone homeostasis. Polarized vesicular trafficking pathways result in the formation of the ruffled border, the osteoclast’s resorptive organelle, which also assists in transcytosis. Here, we reviewed the different roles of Rab GTPases in the endomembrane machinery of osteoclasts and in bone diseases caused by the dysfunction of these proteins, with a particular focus on autophagy and bone resorption. Understanding the molecular mechanisms underlying osteoclast-related bone disease development is critical for developing and improving therapies. Full article
(This article belongs to the Special Issue New Insights in Osteoclasts’ Biology)
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54 pages, 3687 KiB  
Review
Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions
by Jessica Jann, Suzanne Gascon, Sophie Roux and Nathalie Faucheux
Int. J. Mol. Sci. 2020, 21(20), 7597; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207597 - 14 Oct 2020
Cited by 64 | Viewed by 7803
Abstract
The balance between bone forming cells (osteoblasts/osteocytes) and bone resorbing cells (osteoclasts) plays a crucial role in tissue homeostasis and bone repair. Several hormones, cytokines, and growth factors—in particular the members of the TGF-β superfamily such as the bone morphogenetic proteins—not only regulate [...] Read more.
The balance between bone forming cells (osteoblasts/osteocytes) and bone resorbing cells (osteoclasts) plays a crucial role in tissue homeostasis and bone repair. Several hormones, cytokines, and growth factors—in particular the members of the TGF-β superfamily such as the bone morphogenetic proteins—not only regulate the proliferation, differentiation, and functioning of these cells, but also coordinate the communication between them to ensure an appropriate response. Therefore, this review focuses on TGF-β superfamily and its influence on bone formation and repair, through the regulation of osteoclastogenesis, osteogenic differentiation of stem cells, and osteoblasts/osteoclasts balance. After introducing the main types of bone cells, their differentiation and cooperation during bone remodeling and fracture healing processes are discussed. Then, the TGF-β superfamily, its signaling via canonical and non-canonical pathways, as well as its regulation by Wnt/Notch or microRNAs are described and discussed. Its important role in bone homeostasis, repair, or disease is also highlighted. Finally, the clinical therapeutic uses of members of the TGF-β superfamily and their associated complications are debated. Full article
(This article belongs to the Special Issue New Insights in Osteoclasts’ Biology)
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14 pages, 2043 KiB  
Review
Ostm1 from Mouse to Human: Insights into Osteoclast Maturation
by Jean Vacher, Michael Bruccoleri and Monica Pata
Int. J. Mol. Sci. 2020, 21(16), 5600; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165600 - 05 Aug 2020
Cited by 7 | Viewed by 3550
Abstract
The maintenance of bone mass is a dynamic process that requires a strict balance between bone formation and resorption. Bone formation is controlled by osteoblasts, while osteoclasts are responsible for resorption of the bone matrix. The opposite functions of these cell types have [...] Read more.
The maintenance of bone mass is a dynamic process that requires a strict balance between bone formation and resorption. Bone formation is controlled by osteoblasts, while osteoclasts are responsible for resorption of the bone matrix. The opposite functions of these cell types have to be tightly regulated not only during normal bone development, but also during adult life, to maintain serum calcium homeostasis and sustain bone integrity to prevent bone fractures. Disruption of the control of bone synthesis or resorption can lead to an over accumulation of bone tissue in osteopetrosis or conversely to a net depletion of the bone mass in osteoporosis. Moreover, high levels of bone resorption with focal bone formation can cause Paget’s disease. Here, we summarize the steps toward isolation and characterization of the osteopetrosis associated trans-membrane protein 1 (Ostm1) gene and protein, essential for proper osteoclast maturation, and responsible when mutated for the most severe form of osteopetrosis in mice and humans. Full article
(This article belongs to the Special Issue New Insights in Osteoclasts’ Biology)
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