International Journal of Molecular Sciences

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11 pages, 2165 KiB

Open AccessArticle

Protocadherin-7 Regulates Osteoclast Differentiation through Intracellular SET-Binding Domain-Mediated RhoA and Rac1 Activation

by Hyunsoo Kim, Noriko Takegahara and Yongwon Choi

Int. J. Mol. Sci. 2021, 22(23), 13117; https://doi.org/10.3390/ijms222313117 - 4 Dec 2021

Cited by 6 | Viewed by 2257

Abstract

Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin δ1 subgroup of the cadherin superfamily. Although the cell-intrinsic role of Pcdh7 in osteoclast differentiation has been demonstrated, the molecular mechanisms of Pcdh7 regulating osteoclast differentiation remain to be determined. Here, we demonstrate that [...] Read more.

Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin δ1 subgroup of the cadherin superfamily. Although the cell-intrinsic role of Pcdh7 in osteoclast differentiation has been demonstrated, the molecular mechanisms of Pcdh7 regulating osteoclast differentiation remain to be determined. Here, we demonstrate that Pcdh7 contributes to osteoclast differentiation by regulating small GTPases, RhoA and Rac1, through its SET oncoprotein binding domain. Pcdh7 is associated with SET along with RhoA and Rac1 during osteoclast differentiation. Pcdh7-deficient (Pcdh7^−/−) cells showed abolished RANKL-induced RhoA and Rac1 activation, and impaired osteoclast differentiation. Impaired osteoclast differentiation in Pcdh7^−/− cells was restored by retroviral transduction of full-length Pcdh7 but not by a Pcdh7 mutant that lacks SET binding domain. The direct crosslink of the Pcdh7 intracellular region induced the activation of RhoA and Rac1, which was not observed when Pcdh7 lacks the SET binding domain. Additionally, retroviral transduction of the constitutively active form of RhoA and Rac1 completely restored the impaired osteoclast differentiation in Pcdh7^−/− cells. Collectively, these results demonstrate that Pcdh7 controls osteoclast differentiation by regulating RhoA and Rac1 activation through the SET binding domain. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms 2.0)

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13 pages, 33485 KiB

Open AccessArticle

How to Get Them off?—Assessment of Innovative Techniques for Generation and Detachment of Mature Osteoclasts for Biomaterial Resorption Studies

by Christiane Heinemann, Josephine Adam, Benjamin Kruppke, Vera Hintze, Hans-Peter Wiesmann and Thomas Hanke

Int. J. Mol. Sci. 2021, 22(3), 1329; https://doi.org/10.3390/ijms22031329 - 29 Jan 2021

Cited by 5 | Viewed by 2974

Abstract

The fusion process of mononuclear monocytes into multinuclear osteoclasts in vitro is an essential process for the study of osteoclastic resorption of biomaterials. Thereby biomaterials offer many influencing factors such as sample shape, material composition, and surface topography, which can have a decisive [...] Read more.

The fusion process of mononuclear monocytes into multinuclear osteoclasts in vitro is an essential process for the study of osteoclastic resorption of biomaterials. Thereby biomaterials offer many influencing factors such as sample shape, material composition, and surface topography, which can have a decisive influence on the fusion and thus the entire investigation. For the specific investigation of resorption, it can therefore be advantageous to skip the fusion on samples and use mature, predifferentiated osteoclasts directly. However, most conventional detachment methods (cell scraper, accutase), lead to a poor survival rate of osteoclasts or to a loss of function of the cells after their reseeding. In the present study different conventional and novel methods of detachment in combination with different culture surfaces were investigated to obtain optimal osteoclast differentiation, yield, and vitality rates without loss of function. The innovative method—using thermoresponsive surfaces for cultivation and detachment—was found to be best suited. This is in particular due to its ability to maintain osteoclast activity, as proven by TRAP 5b-, CTSK-activity and resorption pits on dentin discs and decellularized osteoblast-derived matrix plates. In conclusion, it is shown, that osteoclasts can be predifferentiated on cell culture dishes and transferred to a reference biomaterial under preservation of osteoclastic resorption activity, providing biomaterial researchers with a novel tool for material characterization. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms 2.0)

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16 pages, 1910 KiB

Open AccessArticle

Fusion Potential of Human Osteoclasts In Vitro Reflects Age, Menopause, and In Vivo Bone Resorption Levels of Their Donors—A Possible Involvement of DC-STAMP

by Anaïs M. J. Møller, Jean-Marie Delaissé, Jacob B. Olesen, Luisa M. Canto, Silvia R. Rogatto, Jonna S. Madsen and Kent Søe

Int. J. Mol. Sci. 2020, 21(17), 6368; https://doi.org/10.3390/ijms21176368 - 2 Sep 2020

Cited by 23 | Viewed by 3190

Abstract

It is well established that multinucleation is central for osteoclastic bone resorption. However, our knowledge on the mechanisms regulating how many nuclei an osteoclast will have is limited. The objective of this study was to investigate donor-related variations in the fusion potential of [...] Read more.

It is well established that multinucleation is central for osteoclastic bone resorption. However, our knowledge on the mechanisms regulating how many nuclei an osteoclast will have is limited. The objective of this study was to investigate donor-related variations in the fusion potential of in vitro-generated osteoclasts. Therefore, CD14⁺ monocytes were isolated from 49 healthy female donors. Donor demographics were compared to the in vivo bone biomarker levels and their monocytes’ ability to differentiate into osteoclasts, showing that: (1) C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels increase with age, (2) the number of nuclei per osteoclast in vitro increases with age, and (3) there is a positive correlation between the number of nuclei per osteoclast in vitro and CTX levels in vivo. Furthermore, the expression levels of the gene encoding dendritic cell-specific transmembrane protein (DCSTAMP) of osteoclasts in vitro correlated positively with the number of nuclei per osteoclast, CTX levels in vivo, and donor age. Our results furthermore suggest that these changes in gene expression may be mediated through age-related changes in DNA methylation levels. We conclude that both intrinsic factors and age-induced increase in fusion potential of osteoclasts could be contributing factors for the enhanced bone resorption in vivo, possibly caused by increased expression levels of DCSTAMP. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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16 pages, 1156 KiB

Open AccessArticle

HIV-1-Infected Human Macrophages, by Secreting RANK-L, Contribute to Enhanced Osteoclast Recruitment

by Rémi Mascarau, Florent Bertrand, Arnaud Labrousse, Isabelle Gennero, Renaud Poincloux, Isabelle Maridonneau-Parini, Brigitte Raynaud-Messina and Christel Vérollet

Int. J. Mol. Sci. 2020, 21(9), 3154; https://doi.org/10.3390/ijms21093154 - 30 Apr 2020

Cited by 8 | Viewed by 3650

Abstract

HIV-1 infection is frequently associated with low bone density, which can progress to osteoporosis leading to a high risk of fractures. Only a few mechanisms have been proposed to explain the enhanced osteolysis in the context of HIV-1 infection. As macrophages are involved [...] Read more.

HIV-1 infection is frequently associated with low bone density, which can progress to osteoporosis leading to a high risk of fractures. Only a few mechanisms have been proposed to explain the enhanced osteolysis in the context of HIV-1 infection. As macrophages are involved in bone homeostasis and are critical host cells for HIV-1, we asked whether HIV-1-infected macrophages could participate in bone degradation. Upon infection, human macrophages acquired some osteoclast features: they became multinucleated, upregulated the osteoclast markers RhoE and β3 integrin, and organized their podosomes as ring superstructures resembling osteoclast sealing zones. However, HIV-1-infected macrophages were not fully differentiated in osteoclasts as they did not upregulate NFATc-1 transcription factor and were unable to degrade bone. Investigating whether infected macrophages participate indirectly to virus-induced osteolysis, we showed that they produce RANK-L, the key osteoclastogenic cytokine. RANK-L secreted by HIV-1-infected macrophages was not sufficient to stimulate multinucleation, but promoted the protease-dependent migration of osteoclast precursors. In conclusion, we propose that, by stimulating RANK-L secretion, HIV-1-infected macrophages contribute to create a microenvironment that favors the recruitment of osteoclasts, participating in bone disorders observed in HIV-1 infected patients. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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12 pages, 2987 KiB

Open AccessArticle

CD44 Can Compensate for IgSF11 Deficiency by Associating with the Scaffold Protein PSD-95 during Osteoclast Differentiation

by Hyunsoo Kim, Noriko Takegahara, Matthew C. Walsh and Yongwon Choi

Int. J. Mol. Sci. 2020, 21(7), 2646; https://doi.org/10.3390/ijms21072646 - 10 Apr 2020

Cited by 6 | Viewed by 3206

Abstract

Differentiation of osteoclasts, which are specialized multinucleated macrophages capable of bone resorption, is driven primarily by receptor activator of NF-κB ligand (RANKL). Additional signaling from cell surface receptors, such as cell adhesion molecules (CAMs), is also required for osteoclast maturation. Previously, we have [...] Read more.

Differentiation of osteoclasts, which are specialized multinucleated macrophages capable of bone resorption, is driven primarily by receptor activator of NF-κB ligand (RANKL). Additional signaling from cell surface receptors, such as cell adhesion molecules (CAMs), is also required for osteoclast maturation. Previously, we have demonstrated that immunoglobulin superfamily 11 (IgSF11), a member of the immunoglobulin-CAM (IgCAM) family, plays an important role in osteoclast differentiation through association with the scaffold protein postsynaptic density protein 95 (PSD-95). Here, we demonstrate that the osteoclast-expressed CAM CD44 can compensate for IgSF11 deficiency when cell–cell interaction conditions are suboptimal by associating with PSD-95. Impaired osteoclast differentiation in IgSF11-deficient (IgSF11^−/−) cultures was rescued by antibody-mediated stimulation of CD44 or by treatment with low-molecular-weight hyaluronan (LMW-HA), a CD44 ligand. Biochemical analysis revealed that PSD-95, which is required for osteoclast differentiation, associates with CD44 in osteoclasts regardless of the presence or absence of IgSF11. RNAi-mediated knockdown of PSD-95 abrogated the effects of either CD44 stimulation or LMW-HA treatment on osteoclast differentiation, suggesting that CD44, similar to IgSF11, is functionally associated with PSD-95 during osteoclast differentiation. Taken together, these results reveal that CD44 can compensate for IgSF11 deficiency in osteoclasts through association with PSD-95. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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19 pages, 3673 KiB

Open AccessArticle

TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression

by Tadahiro Tokunaga, Sho Mokuda, Hiroki Kohno, Kazutoshi Yukawa, Tatsuomi Kuranobu, Katsuhiro Oi, Yusuke Yoshida, Shintaro Hirata and Eiji Sugiyama

Int. J. Mol. Sci. 2020, 21(3), 800; https://doi.org/10.3390/ijms21030800 - 25 Jan 2020

Cited by 24 | Viewed by 6935

Abstract

Osteoclasts are multinucleated giant cells responsible for bone resorption. Various mediators involved in osteoclast differentiation have been investigated as possible therapeutic targets for osteoporosis and rheumatoid arthritis (RA). Although transforming growth factor beta1 (TGFβ1) has been described as one such multifunctional cytokine essential [...] Read more.

Osteoclasts are multinucleated giant cells responsible for bone resorption. Various mediators involved in osteoclast differentiation have been investigated as possible therapeutic targets for osteoporosis and rheumatoid arthritis (RA). Although transforming growth factor beta1 (TGFβ1) has been described as one such multifunctional cytokine essential for bone remodeling, its effect on osteoclastogenesis remains controversial. Therefore, we sought to examine the effect of TGFβ1 on osteoclast generation induced by receptor activator of nuclear factor (NF)-κB ligand (RANKL) in humans. Peripheral blood monocytes, isolated using magnetic bead sorting, were cultured with macrophage-colony stimulating factor (M-CSF) or RANKL with or without TGFβ1. Tartrate-resistant acid phosphatase (TRAP) staining, as well as bone resorption assays, revealed that TGFβ1 suppressed RANKL-mediated human osteoclast development. Real-time reverse transcription PCR and Western blotting revealed that TGFβ1 reduced the gene and protein expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), the master regulator of osteoclast differentiation, respectively. Luciferase assays indicated that TGFβ1 inhibited the NF-κB p65-stimulated promoter activity of NFATc1. Immunofluorescence analysis demonstrated that TGFβ1 abrogated RANKL-induced nuclear translocation of p65. Thus, TGFβ1 regulates human RANKL-induced osteoclastogenesis via downregulation of NFATc1 by blocking nuclear translocation of NF-κB, suggesting that TGFβ1 may be a potential therapeutic target for RA. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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19 pages, 3421 KiB

Open AccessArticle

A Sub-Clone of RAW264.7-Cells Form Osteoclast-Like Cells Capable of Bone Resorption Faster than Parental RAW264.7 through Increased De Novo Expression and Nuclear Translocation of NFATc1

by Laia Mira-Pascual, Anh N. Tran, Göran Andersson, Tuomas Näreoja and Pernilla Lång

Int. J. Mol. Sci. 2020, 21(2), 538; https://doi.org/10.3390/ijms21020538 - 14 Jan 2020

Cited by 7 | Viewed by 5075

Abstract

The murine macrophage cell line RAW264.7 is extensively used as a progenitor to study osteoclast (OC) differentiation. RAW264.7 is a heterogeneous cell line, containing sub-clones with different abilities to form OCs. The aim of this study was to identify characteristics within the heterogeneous [...] Read more.

The murine macrophage cell line RAW264.7 is extensively used as a progenitor to study osteoclast (OC) differentiation. RAW264.7 is a heterogeneous cell line, containing sub-clones with different abilities to form OCs. The aim of this study was to identify characteristics within the heterogeneous RAW264.7 cells that define sub-clones with an augmented ability to form bone-resorbing OCs (H9), as well as sub-clones representing non-OCs (J8). RAW264.7 sub-clones were isolated by single cell cloning. Selection was based on TRAP/cathepsin K expression in sub-clone cultures without added RANKL. Sub-clones before and after differentiation with RANKL were assayed for multiple OC-characteristics. Sub-clone H9 cells presented a higher expression of OC-markers in cultures without added RANKL compared to the parental RAW264.7. After 6 days of RANKL stimulation, sub-clone H9 cells had equal expression levels of OC-markers with RAW264.7 and formed OCs able to demineralize hydroxyapatite. However, sub-clone H9 cells displayed rapid differentiation of OC already at Day 2 compared to Day 4 from parental RAW264.7, and when cultured on plastic and on bone they were more efficient in resorption. This rapid differentiation was likely due to high initial expression/nuclear translocation of OC master transcription factor, NFATc1. In contrast to H9, J8 cells expressed initially very low levels of OC-markers, and they did not respond to RANKL-stimulation by developing OC-characteristics/OC-marker expression. Hence, H9 is an additional clone suitable for experimental setup requiring rapid differentiation of large numbers of OCs. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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12 pages, 3065 KiB

Open AccessArticle

Pisidium coreanum Inhibits Multinucleated Osteoclast Formation and Prevents Estrogen-Deficient Osteoporosis

by Mun Hwan Choi, Kyunghee Lee, Mi Yeong Kim, Hong-In Shin and Daewon Jeong

Int. J. Mol. Sci. 2019, 20(23), 6076; https://doi.org/10.3390/ijms20236076 - 2 Dec 2019

Cited by 6 | Viewed by 3383

Abstract

Mollusks have served as important sources of human food and medicine for a long time. Raw Pisidium coreanum, a freshwater bivalve of the phylum Mollusca, is used in traditional therapies in parts of Asia. However, the therapeutic effects of Pisidium coreanum on [...] Read more.

Mollusks have served as important sources of human food and medicine for a long time. Raw Pisidium coreanum, a freshwater bivalve of the phylum Mollusca, is used in traditional therapies in parts of Asia. However, the therapeutic effects of Pisidium coreanum on bone diseases are not known. We investigated the functional roles of Pisidium coreanum in osteoporotic bone diseases. Pisidium coreanum inhibited the differentiation of bone marrow-derived monocytic cells into mature osteoclasts in vitro. The ovariectomized mice that received oral administration of Pisidium coreanum showed improvements in both trabecular and cortical bones. This preventive activity of Pisidium coreanum against bone loss was due to limited osteoclast maturation with reduced osteoclast surface extent in trabecular bone tissue. The formation of large multinucleated osteoclasts in vitro was significantly decreased in response to Pisidium coreanum, consistent with the reduced expression levels of osteoclast markers and fusion-related genes, such as NFATc1, p65, integrin αvβ3, DC-STAMP, OC-STAMP, Atp6v0d2, FAK, CD44, and MFR. These data suggest that Pisidium coreanum inhibits osteoclast differentiation by negatively regulating the fusion of mononuclear osteoclast precursors. Thus, our data demonstrate the ability of Pisidium coreanum to effectively prevent estrogen-deficient osteoporosis through inhibition of multinucleated osteoclast formation. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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16 pages, 2712 KiB

Open AccessArticle

Osteoclast-Like Cells in Aneurysmal Disease Exhibit an Enhanced Proteolytic Phenotype

by Matthew J. Kelly, Kimihiro Igari and Dai Yamanouchi

Int. J. Mol. Sci. 2019, 20(19), 4689; https://doi.org/10.3390/ijms20194689 - 21 Sep 2019

Cited by 7 | Viewed by 4269

Abstract

Abdominal aortic aneurysm (AAA) is among the top 20 causes of death in the United States. Surgical repair is the gold standard for AAA treatment, therefore, there is a need for non-invasive therapeutic interventions. Aneurysms are more closely associated with the osteoclast-like catabolic [...] Read more.

Abdominal aortic aneurysm (AAA) is among the top 20 causes of death in the United States. Surgical repair is the gold standard for AAA treatment, therefore, there is a need for non-invasive therapeutic interventions. Aneurysms are more closely associated with the osteoclast-like catabolic degradation of the artery, rather than the osteoblast-like anabolic processes of arterial calcification. We have reported the presence of osteoclast-like cells (OLCs) in human and mouse aneurysmal tissues. The aim of this study was to examine OLCs from aneurysmal tissues as a source of degenerative proteases. Aneurysmal and control tissues from humans, and from the mouse CaPO₄ and angiotensin II (AngII) disease models, were analyzed via flow cytometry and immunofluorescence for the expression of osteoclast markers. We found higher expression of the osteoclast markers tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinase-9 (MMP-9), and cathepsin K, and the signaling molecule, hypoxia-inducible factor-1α (HIF-1α), in aneurysmal tissue compared to controls. Aneurysmal tissues also contained more OLCs than controls. Additionally, more OLCs from aneurysms express HIF-1α, and produce more MMP-9 and cathepsin K, than myeloid cells from the same tissue. These data indicate that OLCs are a significant source of proteases known to be involved in aortic degradation, in which the HIF-1α signaling pathway may play an important role. Our findings suggest that OLCs may be an attractive target for non-surgical suppression of aneurysm formation due to their expression of degradative proteases. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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Review

Jump to: Research

15 pages, 8126 KiB

Open AccessReview

Targeting S1PRs as a Therapeutic Strategy for Inflammatory Bone Loss Diseases—Beyond Regulating S1P Signaling

by Hong Yu

Int. J. Mol. Sci. 2021, 22(9), 4411; https://doi.org/10.3390/ijms22094411 - 23 Apr 2021

Cited by 11 | Viewed by 3636

Abstract

As G protein coupled receptors, sphingosine-1-phosphate receptors (S1PRs) have recently gained attention for their role in modulating inflammatory bone loss diseases. Notably, in murine studies inhibiting S1PR2 by its specific inhibitor, JTE013, alleviated osteoporosis induced by RANKL and attenuated periodontal alveolar bone loss [...] Read more.

As G protein coupled receptors, sphingosine-1-phosphate receptors (S1PRs) have recently gained attention for their role in modulating inflammatory bone loss diseases. Notably, in murine studies inhibiting S1PR2 by its specific inhibitor, JTE013, alleviated osteoporosis induced by RANKL and attenuated periodontal alveolar bone loss induced by oral bacterial inflammation. Treatment with a multiple S1PRs modulator, FTY720, also suppressed ovariectomy-induced osteoporosis, collagen or adjuvant-induced arthritis, and apical periodontitis in mice. However, most previous studies and reviews have focused mainly on how S1PRs manipulate S1P signaling pathways, subsequently affecting various diseases. In this review, we summarize the underlying mechanisms associated with JTE013 and FTY720 in modulating inflammatory cytokine release, cell chemotaxis, and osteoclastogenesis, subsequently influencing inflammatory bone loss diseases. Studies from our group and from other labs indicate that S1PRs not only control S1P signaling, they also regulate signaling pathways induced by other stimuli, including bacteria, lipopolysaccharide (LPS), bile acid, receptor activator of nuclear factor κB ligand (RANKL), IL-6, and vitamin D. JTE013 and FTY720 alleviate inflammatory bone loss by decreasing the production of inflammatory cytokines and chemokines, reducing chemotaxis of inflammatory cells from blood circulation to bone and soft tissues, and suppressing RANKL-induced osteoclast formation. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms 2.0)

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17 pages, 707 KiB

Open AccessReview

Osteoclast Fusion: Physiological Regulation of Multinucleation through Heterogeneity—Potential Implications for Drug Sensitivity

by Kent Søe

Int. J. Mol. Sci. 2020, 21(20), 7717; https://doi.org/10.3390/ijms21207717 - 19 Oct 2020

Cited by 30 | Viewed by 4898

Abstract

Classically, osteoclast fusion consists of four basic steps: (1) attraction/migration, (2) recognition, (3) cell–cell adhesion, and (4) membrane fusion. In theory, this sounds like a straightforward simple linear process. However, it is not. Osteoclast fusion has to take place in a well-coordinated manner—something [...] Read more.

Classically, osteoclast fusion consists of four basic steps: (1) attraction/migration, (2) recognition, (3) cell–cell adhesion, and (4) membrane fusion. In theory, this sounds like a straightforward simple linear process. However, it is not. Osteoclast fusion has to take place in a well-coordinated manner—something that is not simple. In vivo, the complex regulation of osteoclast formation takes place within the bone marrow—in time and space. The present review will focus on considering osteoclast fusion in the context of physiology and pathology. Special attention is given to: (1) regulation of osteoclast fusion in vivo, (2) heterogeneity of osteoclast fusion partners, (3) regulation of multi-nucleation, (4) implications for physiology and pathology, and (5) implications for drug sensitivity and side effects. The review will emphasize that more attention should be given to the human in vivo reality when interpreting the impact of in vitro and animal studies. This should be done in order to improve our understanding of human physiology and pathology, as well as to improve anti-resorptive treatment and reduce side effects. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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22 pages, 2175 KiB

Open AccessReview

Pathogenic Mechanisms of Myeloma Bone Disease and Possible Roles for NRF2

by Chia-Hung Yen, Chin-Mu Hsu, Samuel Yien Hsiao and Hui-Hua Hsiao

Int. J. Mol. Sci. 2020, 21(18), 6723; https://doi.org/10.3390/ijms21186723 - 14 Sep 2020

Cited by 21 | Viewed by 4568

Abstract

Osteolytic bone lesions are one of the central features of multiple myeloma (MM) and lead to bone pain, fractures, decreased quality of life, and decreased survival. Dysfunction of the osteoclast (OC)/osteoblast (OB) axis plays a key role in the development of myeloma-associated osteolytic [...] Read more.

Osteolytic bone lesions are one of the central features of multiple myeloma (MM) and lead to bone pain, fractures, decreased quality of life, and decreased survival. Dysfunction of the osteoclast (OC)/osteoblast (OB) axis plays a key role in the development of myeloma-associated osteolytic lesions. Many signaling pathways and factors are associated with myeloma bone diseases (MBDs), including the RANKL/OPG and NF-κB pathways. NRF2, a master regulator of inflammatory signaling, might play a role in the regulation of bone metabolism via anti-inflammatory signaling and decreased reactive oxygen species (ROS) levels. The loss of NRF2 expression in OCs reduced bone mass via the RANK/RANKL pathway and other downstream signaling pathways that affect osteoclastogenesis. The NRF2 level in OBs could interfere with interleukin (IL)-6 expression, which is associated with bone metabolism and myeloma cells. In addition to direct impact on OCs and OBs, the activity of NRF2 on myeloma cells and mesenchymal stromal cells influences the inflammatory stress/ROS level in these cells, which has an impact on OCs, OBs, and osteocytes. The interaction between these cells and OCs affects the osteoclastogenesis of myeloma bone lesions associated with NRF2. Therefore, we have reviewed the effects of NRF2 on OCs and OBs in MBDs. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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24 pages, 1262 KiB

Open AccessReview

Heterogeneity and Actin Cytoskeleton in Osteoclast and Macrophage Multinucleation

by Jiro Takito and Masanori Nakamura

Int. J. Mol. Sci. 2020, 21(18), 6629; https://doi.org/10.3390/ijms21186629 - 10 Sep 2020

Cited by 26 | Viewed by 5532

Abstract

Osteoclast signatures are determined by two transcriptional programs, the lineage-determining transcription pathway and the receptor activator of nuclear factor kappa-B ligand (RANKL)-dependent differentiation pathways. During differentiation, mononuclear precursors become multinucleated by cell fusion. Recently, live-cell imaging has revealed a high level of heterogeneity [...] Read more.

Osteoclast signatures are determined by two transcriptional programs, the lineage-determining transcription pathway and the receptor activator of nuclear factor kappa-B ligand (RANKL)-dependent differentiation pathways. During differentiation, mononuclear precursors become multinucleated by cell fusion. Recently, live-cell imaging has revealed a high level of heterogeneity in osteoclast multinucleation. This heterogeneity includes the difference in the differentiation states and the mobility of the fusion precursors, as well as the mode of fusion among the fusion precursors with different numbers of nuclei. In particular, fusion partners often form morphologically distinct actin-based linkages that allow two cells to exchange lipids and proteins before membrane fusion. However, the origin of this heterogeneity remains elusive. On the other hand, osteoclast multinucleation is sensitive to the environmental cues. Such cues promote the reorganization of the actin cytoskeleton, especially the formation and transformation of the podosome, an actin-rich punctate adhesion. This review covers the heterogeneity of osteoclast multinucleation at the pre-fusion stage with reference to the environment-dependent signaling pathway responsible for reorganizing the actin cytoskeleton. Furthermore, we compare osteoclast multinucleation with macrophage fusion, which results in multinucleated giant macrophages. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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19 pages, 1099 KiB

Open AccessReview

The Influence of Radiation on Bone and Bone Cells—Differential Effects on Osteoclasts and Osteoblasts

by Anna-Jasmina Donaubauer, Lisa Deloch, Ina Becker, Rainer Fietkau, Benjamin Frey and Udo S. Gaipl

Int. J. Mol. Sci. 2020, 21(17), 6377; https://doi.org/10.3390/ijms21176377 - 2 Sep 2020

Cited by 51 | Viewed by 8483

Abstract

The bone is a complex organ that is dependent on a tight regulation between bone formation by osteoblasts (OBs) and bone resorption by osteoclasts (OCs). These processes can be influenced by environmental factors such as ionizing radiation (IR). In cancer therapy, IR is [...] Read more.

The bone is a complex organ that is dependent on a tight regulation between bone formation by osteoblasts (OBs) and bone resorption by osteoclasts (OCs). These processes can be influenced by environmental factors such as ionizing radiation (IR). In cancer therapy, IR is applied in high doses, leading to detrimental effects on bone, whereas radiation therapy with low doses of IR is applied for chronic degenerative and inflammatory diseases, with a positive impact especially on bone homeostasis. Moreover, the effects of IR are of particular interest in space travel, as astronauts suffer from bone loss due to space radiation and microgravity. This review summarizes the current state of knowledge on the effects of IR on bone with a special focus on the influence on OCs and OBs, as these cells are essential in bone remodeling. In addition, the influence of IR on the bone microenvironment is discussed. In summary, the effects of IR on bone and bone remodeling cells strongly depend on the applied radiation dose, as differential results are provided from in vivo as well as in vitro studies with varying doses of IR. Furthermore, the isolated effects of IR on a single cell type are difficult to determine, as the bone cells and bone microenvironment are building a tightly regulated network, influencing on one another. Therefore, future research is necessary in order to elucidate the influence of different bone cells on the overall radiation-induced effects on bone. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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30 pages, 2799 KiB

Open AccessReview

Learning from Monocyte-Macrophage Fusion and Multinucleation: Potential Therapeutic Targets for Osteoporosis and Rheumatoid Arthritis

by Laura Gambari, Francesco Grassi, Livia Roseti, Brunella Grigolo and Giovanna Desando

Int. J. Mol. Sci. 2020, 21(17), 6001; https://doi.org/10.3390/ijms21176001 - 20 Aug 2020

Cited by 26 | Viewed by 5565

Abstract

Excessive bone resorption by osteoclasts (OCs) covers an essential role in developing bone diseases, such as osteoporosis (OP) and rheumatoid arthritis (RA). Monocytes or macrophages fusion and multinucleation (M-FM) are key processes for generating multinucleated mature cells with essential roles in bone remodelling. [...] Read more.

Excessive bone resorption by osteoclasts (OCs) covers an essential role in developing bone diseases, such as osteoporosis (OP) and rheumatoid arthritis (RA). Monocytes or macrophages fusion and multinucleation (M-FM) are key processes for generating multinucleated mature cells with essential roles in bone remodelling. Depending on the phenotypic heterogeneity of monocyte/macrophage precursors and the extracellular milieu, two distinct morphological and functional cell types can arise mature OCs and giant cells (GCs). Despite their biological relevance in several physiological and pathological responses, many gaps exist in our understanding of their formation and role in bone, including the molecular determinants of cell fusion and multinucleation. Here, we outline fusogenic molecules during M-FM involved in OCs and GCs formation in healthy conditions and during OP and RA. Moreover, we discuss the impact of the inflammatory milieu on modulating macrophages phenotype and their differentiation towards mature cells. Methodological approach envisaged searches on Scopus, Web of Science Core Collection, and EMBASE databases to select relevant studies on M-FM, osteoclastogenesis, inflammation, OP, and RA. This review intends to give a state-of-the-art description of mechanisms beyond osteoclastogenesis and M-FM, with a focus on OP and RA, and to highlight potential biological therapeutic targets to prevent extreme bone loss. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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35 pages, 1429 KiB

Open AccessReview

Osteoclast Multinucleation: Review of Current Literature

by Joe Kodama and Takashi Kaito

Int. J. Mol. Sci. 2020, 21(16), 5685; https://doi.org/10.3390/ijms21165685 - 8 Aug 2020

Cited by 106 | Viewed by 10095

Abstract

Multinucleation is a hallmark of osteoclast maturation. The unique and dynamic multinucleation process not only increases cell size but causes functional alterations through reconstruction of the cytoskeleton, creating the actin ring and ruffled border that enable bone resorption. Our understanding of the molecular [...] Read more.

Multinucleation is a hallmark of osteoclast maturation. The unique and dynamic multinucleation process not only increases cell size but causes functional alterations through reconstruction of the cytoskeleton, creating the actin ring and ruffled border that enable bone resorption. Our understanding of the molecular mechanisms underlying osteoclast multinucleation has advanced considerably in this century, especially since the identification of DC-STAMP and OC-STAMP as “master fusogens”. Regarding the molecules and pathways surrounding these STAMPs, however, only limited progress has been made due to the absence of their ligands. Various molecules and mechanisms other than the STAMPs are involved in osteoclast multinucleation. In addition, several preclinical studies have explored chemicals that may be able to target osteoclast multinucleation, which could enable us to control pathogenic bone metabolism more precisely. In this review, we will focus on recent discoveries regarding the STAMPs and other molecules involved in osteoclast multinucleation. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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At the Crossroads of the Adipocyte and Osteoclast Differentiation Programs: Future Therapeutic Perspectives

by Shanmugam Muruganandan, Andreia M. Ionescu and Christopher J. Sinal

Int. J. Mol. Sci. 2020, 21(7), 2277; https://doi.org/10.3390/ijms21072277 - 26 Mar 2020

Cited by 54 | Viewed by 7311

Abstract

The coordinated development and function of bone-forming (osteoblasts) and bone-resorbing (osteoclasts) cells is critical for the maintenance of skeletal integrity and calcium homeostasis. An enhanced adipogenic versus osteogenic potential of bone marrow mesenchymal stem cells (MSCs) has been linked to bone loss associated [...] Read more.

The coordinated development and function of bone-forming (osteoblasts) and bone-resorbing (osteoclasts) cells is critical for the maintenance of skeletal integrity and calcium homeostasis. An enhanced adipogenic versus osteogenic potential of bone marrow mesenchymal stem cells (MSCs) has been linked to bone loss associated with diseases such as diabetes mellitus, as well as aging and postmenopause. In addition to an inherent decrease in bone formation due to reduced osteoblast numbers, recent experimental evidence indicates that an increase in bone marrow adipocytes contributes to a disproportionate increase in osteoclast formation. Therefore, a potential strategy for therapeutic intervention in chronic bone loss disorders such as osteoporosis is to interfere with the pro-osteoclastogenic influence of marrow adipocytes. However, application of this approach is limited by the extremely complex regulatory processes in the osteoclastogenic program. For example, key regulators of osteoclastogenesis such as the receptor activator of nuclear factor-kappaB ligand (RANKL) and the soluble decoy receptor osteoprotegerin (OPG) are not only secreted by both osteoblasts and adipocytes, but are also regulated through several cytokines produced by these cell types. In this context, biologically active signaling molecules secreted from bone marrow adipocytes, such as chemerin, adiponectin, leptin, visfatin and resistin, can have a profound influence on the osteoclast differentiation program of hematopoietic stem cells (HSCs), and thus, hold therapeutic potential under disease conditions. In addition to these paracrine signals, adipogenic transcription factors including CCAAT/enhancer binding protein alpha (C/EBPα), C/EBP beta (C/EBPβ) and peroxisome proliferator-associated receptor gamma (PPARγ) are also expressed by osteoclastogenic cells. However, in contrast to MSCs, activation of these adipogenic transcription factors in HSCs promotes the differentiation of osteoclast precursors into mature osteoclasts. Herein, we discuss the molecular mechanisms that link adipogenic signaling molecules and transcription factors to the osteoclast differentiation program and highlight therapeutic strategies targeting these mechanisms for promoting bone homeostasis. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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