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Osteoclastogenesis and Osteogenesis

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 52557

Special Issue Editor

Prof. Dr. Jung Eun Kim

E-Mail Website
Guest Editor
Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
Interests: osteoblast/osteoclast differentiation; bone remodeling; bone development and homeostasis; bone metastasis; musculoskeletal diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Welcome to the Special Issue of Biochemistry Section of the International Journal of Molecular Sciences, on “Osteoclastogenesis and Osteogenesis”.

Bone is a highly dynamic tissue that is continuously remodeled to attain and maintain optimal bone integrity, mass, and strength. Normal bone remodeling is tightly regulated by a balance between osteoclastic bone resorption and osteoblastic bone formation. However, the physiological condition can be changed by various factors, which lead to an imbalance of bone remodeling and develop bone diseases such as osteoporosis. Thus, osteoclastogenesis and osteogenesis are the most basic, but they are the most essential in bone biology. This Special Issue focuses on novel molecular mechanisms of osteoblasts and osteoclasts contributing to bone remodeling and provides a powerful platform for elucidating novel insights on bone pathophysiology. We very welcome the submission of original research articles and comprehensive reviews.

Prof. Dr. Jung Eun Kim
Guest Editor

Manuscript Submission Information

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Keywords

  • Osteoblast
  • Osteocyte
  • Osteoclast
  • Mesenchymal stem cell
  • Bone lining cell
  • Hematopoietic stem cell
  • Cell differentiation
  • Bone remodeling
  • Bone pathophysiology

Published Papers (16 papers)

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Editorial

Jump to: Research, Review

4 pages, 178 KiB  
Editorial
Osteoclastogenesis and Osteogenesis
by Jung-Eun Kim
Int. J. Mol. Sci. 2022, 23(12), 6659; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126659 - 15 Jun 2022
Viewed by 1499
Abstract
Bone is a highly dynamic tissue that is continuously remodeled to attain and maintain optimal bone integrity, mass, and strength [...] Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)

Research

Jump to: Editorial, Review

15 pages, 2510 KiB  
Article
Hexosamine Biosynthetic Pathway-Derived O-GlcNAcylation Is Critical for RANKL-Mediated Osteoclast Differentiation
by Myoung Jun Kim, Hyuk Soon Kim, Sangyong Lee, Keun Young Min, Wahn Soo Choi and Jueng Soo You
Int. J. Mol. Sci. 2021, 22(16), 8888; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168888 - 18 Aug 2021
Cited by 12 | Viewed by 2826
Abstract
O-linked-N-acetylglucosaminylation (O-GlcNAcylation) performed by O-GlcNAc transferase (OGT) is a nutrient-responsive post-translational modification (PTM) via the hexosamine biosynthetic pathway (HBP). Various transcription factors (TFs) are O-GlcNAcylated, affecting their activities and significantly contributing to cellular processes ranging from survival to cellular differentiation. Given the pleiotropic [...] Read more.
O-linked-N-acetylglucosaminylation (O-GlcNAcylation) performed by O-GlcNAc transferase (OGT) is a nutrient-responsive post-translational modification (PTM) via the hexosamine biosynthetic pathway (HBP). Various transcription factors (TFs) are O-GlcNAcylated, affecting their activities and significantly contributing to cellular processes ranging from survival to cellular differentiation. Given the pleiotropic functions of O-GlcNAc modification, it has been studied in various fields; however, the role of O-GlcNAcylation during osteoclast differentiation remains to be explored. Kinetic transcriptome analysis during receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL)-mediated osteoclast differentiation revealed that the nexus of major nutrient metabolism, HBP was critical for this process. We observed that the critical genes related to HBP activation, including Nagk, Gfpt1, and Ogt, were upregulated, while the global O-GlcNAcylation was increased concomitantly during osteoclast differentiation. The O-GlcNAcylation inhibition by the small-molecule inhibitor OSMI-1 reduced osteoclast differentiation in vitro and in vivo by disrupting the translocation of NF-κB p65 and nuclear factor of activated T cells c1 (NFATc1) into the nucleus by controlling their PTM O-GlcNAcylation. Furthermore, OSMI-1 had a synergistic effect with bone target therapy on osteoclastogenesis. Lastly, knocking down Ogt with shRNA (shOgt) mimicked OSMI-1’s effect on osteoclastogenesis. Targeting O-GlcNAcylation during osteoclast differentiation may be a valuable therapeutic approach for osteoclast-activated bone diseases. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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11 pages, 2010 KiB  
Article
Protective Effect of Ciclopirox against Ovariectomy-Induced Bone Loss in Mice by Suppressing Osteoclast Formation and Function
by Hye Jung Ihn, Jiwon Lim, Kiryeong Kim, Sang-Hyeon Nam, Soomin Lim, Su Jeong Lee, Jong-Sup Bae, Tae Hoon Kim, Jung-Eun Kim, Moon-Chang Baek, Yong Chul Bae and Eui Kyun Park
Int. J. Mol. Sci. 2021, 22(15), 8299; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158299 - 02 Aug 2021
Cited by 2 | Viewed by 2134
Abstract
Postmenopausal osteoporosis is closely associated with excessive osteoclast formation and function, resulting in the loss of bone mass. Osteoclast-targeting agents have been developed to manage this disease. We examined the effects of ciclopirox on osteoclast differentiation and bone resorption in vitro and in [...] Read more.
Postmenopausal osteoporosis is closely associated with excessive osteoclast formation and function, resulting in the loss of bone mass. Osteoclast-targeting agents have been developed to manage this disease. We examined the effects of ciclopirox on osteoclast differentiation and bone resorption in vitro and in vivo. Ciclopirox significantly inhibited osteoclast formation from primary murine bone marrow macrophages (BMMs) in response to receptor activator of nuclear factor kappa B ligand (RANKL), and the expression of genes associated with osteoclastogenesis and function was decreased. The formation of actin rings and resorption pits was suppressed by ciclopirox. Analysis of RANKL-mediated early signaling events in BMMs revealed that ciclopirox attenuates IκBα phosphorylation without affecting mitogen-activated protein kinase activation. Furthermore, the administration of ciclopirox suppressed osteoclast formation and bone loss in ovariectomy-induced osteoporosis in mice and reduced serum levels of osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus. These results indicate that ciclopirox exhibits antiosteoclastogenic activity both in vitro and in vivo and represents a new candidate compound for protection against osteoporosis and other osteoclast-related bone diseases. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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12 pages, 4128 KiB  
Article
Overexpression of miR-125b in Osteoblasts Improves Age-Related Changes in Bone Mass and Quality through Suppression of Osteoclast Formation
by Shota Ito, Tomoko Minamizaki, Shohei Kohno, Yusuke Sotomaru, Yoshiaki Kitaura, Shinsuke Ohba, Toshie Sugiyama, Jane E. Aubin, Kotaro Tanimoto and Yuji Yoshiko
Int. J. Mol. Sci. 2021, 22(13), 6745; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136745 - 23 Jun 2021
Cited by 2 | Viewed by 1937
Abstract
We recently reported an unexpected role of osteoblast-derived matrix vesicles in the delivery of microRNAs to bone matrix. Of such microRNAs, we found that miR-125b inhibited osteoclast formation by targeting Prdm1 encoding a transcriptional repressor of anti-osteoclastogenesis factors. Transgenic (Tg) mice overexpressing miR-125b [...] Read more.
We recently reported an unexpected role of osteoblast-derived matrix vesicles in the delivery of microRNAs to bone matrix. Of such microRNAs, we found that miR-125b inhibited osteoclast formation by targeting Prdm1 encoding a transcriptional repressor of anti-osteoclastogenesis factors. Transgenic (Tg) mice overexpressing miR-125b in osteoblasts by using human osteocalcin promoter grow normally but exhibit high trabecular bone mass. We have now further investigated the effects of osteoblast-mediated miR-125b overexpression on skeletal morphogenesis and remodeling during development, aging and in a situation of skeletal repair, i.e., fracture healing. There were no significant differences in the growth plate, primary spongiosa or lateral (periosteal) bone formation and mineral apposition rate between Tg and wild-type (WT) mice during early bone development. However, osteoclast number and medial (endosteal) bone resorption were less in Tg compared to WT mice, concomitant with increased trabecular bone mass. Tg mice were less susceptible to age-dependent changes in bone mass, phosphate/amide I ratio and mechanical strength. In a femoral fracture model, callus formation progressed similarly in Tg and WT mice, but callus resorption was delayed, reflecting the decreased osteoclast numbers associated with the Tg callus. These results indicate that the decreased osteoclastogenesis mediated by miR-125b overexpression in osteoblasts leads to increased bone mass and strength, while preserving bone formation and quality. They also suggest that, in spite of the fact that single miRNAs may target multiple genes, the miR-125b axis may be an attractive therapeutic target for bone loss in various age groups. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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13 pages, 2937 KiB  
Article
S100 Calcium-Binding Protein P Secreted from Megakaryocytes Promotes Osteoclast Maturation
by Seung-Hoon Lee, Hye Jung Ihn, Eui Kyun Park and Jung-Eun Kim
Int. J. Mol. Sci. 2021, 22(11), 6129; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116129 - 07 Jun 2021
Cited by 7 | Viewed by 2307
Abstract
Megakaryocytes (MKs) differentiate from hematopoietic stem cells and produce platelets at the final stage of differentiation. MKs directly interact with bone cells during bone remodeling. However, whether MKs are involved in regulating bone metabolism through indirect regulatory effects on bone cells is unclear. [...] Read more.
Megakaryocytes (MKs) differentiate from hematopoietic stem cells and produce platelets at the final stage of differentiation. MKs directly interact with bone cells during bone remodeling. However, whether MKs are involved in regulating bone metabolism through indirect regulatory effects on bone cells is unclear. Here, we observed increased osteoclast differentiation of bone marrow-derived macrophages (BMMs) cultured in MK-cultured conditioned medium (MK CM), suggesting that this medium contains factors secreted from MKs that affect osteoclastogenesis. To identify the MK-secreted factor, DNA microarray analysis of the human leukemia cell line K562 and MKs was performed, and S100 calcium-binding protein P (S100P) was selected as a candidate gene affecting osteoclast differentiation. S100P was more highly expressed in MKs than in K562 cells, and showed higher levels in MK CM than in K562-cultured conditioned medium. In BMMs cultured in the presence of recombinant human S100P protein, osteoclast differentiation was promoted and marker gene expression was increased. The resorption area was significantly larger in S100P protein-treated osteoclasts, demonstrating enhanced resorption activity. Overall, S100P secreted from MKs promotes osteoclast differentiation and resorption activity, suggesting that MKs indirectly regulate osteoclast differentiation and activity through the paracrine action of S100P. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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12 pages, 2247 KiB  
Article
PTX3 Effects on Osteogenic Differentiation in Osteoporosis: An In Vitro Study
by Chiara Greggi, Ida Cariati, Federica Onorato, Riccardo Iundusi, Manuel Scimeca and Umberto Tarantino
Int. J. Mol. Sci. 2021, 22(11), 5944; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115944 - 31 May 2021
Cited by 5 | Viewed by 2174
Abstract
Pentraxin 3 (PTX3) is a glycoprotein belonging to the humoral arm of innate immunity that participates in the body’s defence mechanisms against infectious diseases. It has recently been defined as a multifunctional protein, given its involvement in numerous physiological and pathological processes, as [...] Read more.
Pentraxin 3 (PTX3) is a glycoprotein belonging to the humoral arm of innate immunity that participates in the body’s defence mechanisms against infectious diseases. It has recently been defined as a multifunctional protein, given its involvement in numerous physiological and pathological processes, as well as in the pathogenesis of age-related diseases such as osteoporosis. Based on this evidence, the aim of our study was to investigate the possible role of PTX3 in both the osteoblastic differentiation and calcification process: to this end, primary osteoblast cultures from control and osteoporotic patients were incubated with human recombinant PTX3 (hrPTX3) for 72 h. Standard osteinduction treatment, consisting of β-glycerophosphate, dexamethasone and ascorbic acid, was used as control. Our results showed that treatment with hrPTX3, as well as with the osteogenic cocktail, induced cell differentiation towards the osteoblastic lineage. We also observed that the treatment not only promoted an increase in cell proliferation, but also the formation of calcification-like structures, especially in primary cultures from osteoporotic patients. In conclusion, the results reported here suggest the involvement of PTX3 in osteogenic differentiation, highlighting its osteoinductive capacity, like the standard osteoinduction treatment. Therefore, this study opens new and exciting perspectives about the possible role of PTX3 as biomarker and therapeutic agent for osteoporosis. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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12 pages, 2248 KiB  
Article
Austalide K from the Fungus Penicillium rudallense Prevents LPS-Induced Bone Loss in Mice by Inhibiting Osteoclast Differentiation and Promoting Osteoblast Differentiation
by Kwang-Jin Kim, Jusung Lee, Weihong Wang, Yongjin Lee, Eunseok Oh, Kyu-Hyung Park, Chanyoon Park, Gee-Eun Woo, Young-Jin Son and Heonjoong Kang
Int. J. Mol. Sci. 2021, 22(11), 5493; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115493 - 23 May 2021
Cited by 8 | Viewed by 2631
Abstract
Osteoporosis is a chronic disease that has become a serious public health problem due to the associated reduction in quality of life and its increasing financial burden. It is known that inhibiting osteoclast differentiation and promoting osteoblast formation prevents osteoporosis. As there is [...] Read more.
Osteoporosis is a chronic disease that has become a serious public health problem due to the associated reduction in quality of life and its increasing financial burden. It is known that inhibiting osteoclast differentiation and promoting osteoblast formation prevents osteoporosis. As there is no drug with this dual activity without clinical side effects, new alternatives are needed. Here, we demonstrate that austalide K, isolated from the marine fungus Penicillium rudallenes, has dual activities in bone remodeling. Austalide K inhibits the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and improves bone morphogenetic protein (BMP)-2-mediated osteoblast differentiation in vitro without cytotoxicity. The nuclear factor of activated T cells c1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), dendritic cell-specific transmembrane protein (DC-STAMP), and cathepsin K (CTSK) osteoclast-formation-related genes were reduced and alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and osteopontin (OPN) (osteoblast activation-related genes) were simultaneously upregulated by treatment with austalide K. Furthermore, austalide K showed good efficacy in an LPS-induced bone loss in vivo model. Bone volume, trabecular separation, trabecular thickness, and bone mineral density were recovered by austalide K. On the basis of these results, austalide K may lead to new drug treatments for bone diseases such as osteoporosis. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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16 pages, 7281 KiB  
Article
Osteogenesis of 3D-Printed PCL/TCP/bdECM Scaffold Using Adipose-Derived Stem Cells Aggregates; An Experimental Study in the Canine Mandible
by Joon Seok Lee, Tae Hyun Park, Jeong Yeop Ryu, Dong Kyu Kim, Eun Jung Oh, Hyun Mi Kim, Jin-Hyung Shim, Won-Soo Yun, Jung Bo Huh, Sung Hwan Moon, Seong Soo Kang and Ho Yun Chung
Int. J. Mol. Sci. 2021, 22(11), 5409; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115409 - 21 May 2021
Cited by 22 | Viewed by 3980
Abstract
Three-dimensional (3D) printing is perceived as an innovative tool for change in tissue engineering and regenerative medicine based on research outcomes on the development of artificial organs and tissues. With advances in such technology, research is underway into 3D-printed artificial scaffolds for tissue [...] Read more.
Three-dimensional (3D) printing is perceived as an innovative tool for change in tissue engineering and regenerative medicine based on research outcomes on the development of artificial organs and tissues. With advances in such technology, research is underway into 3D-printed artificial scaffolds for tissue recovery and regeneration. In this study, we fabricated artificial scaffolds by coating bone demineralized and decellularized extracellular matrix (bdECM) onto existing 3D-printed polycaprolactone/tricalcium phosphate (PCL/TCP) to enhance osteoconductivity and osteoinductivity. After injecting adipose-derived stem cells (ADSCs) in an aggregate form found to be effective in previous studies, we examined the effects of the scaffold on ossification during mandibular reconstruction in beagle dogs. Ten beagles were divided into two groups: group A (PCL/TCP/bdECM + ADSC injection; n = 5) and group B (PCL/TCP/bdECM; n = 5). The results were analyzed four and eight weeks after intervention. Computed tomography (CT) findings showed that group A had more diffuse osteoblast tissue than group B. Evidence of infection or immune rejection was not detected following histological examination. Goldner trichrome (G/T) staining revealed rich ossification in scaffold pores. ColI, Osteocalcin, and Runx2 gene expressions were determined using real-time polymerase chain reaction. Group A showed greater expression of these genes. Through Western blotting, group A showed a greater expression of genes that encode ColI, Osteocalcin, and Runx2 proteins. In conclusion, intervention group A, in which the beagles received the additional ADSC injection together with the 3D-printed PCL/TCP coated with bdECM, showed improved mandibular ossification in and around the pores of the scaffold. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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16 pages, 3173 KiB  
Article
Metallothionein 3 Promotes Osteoblast Differentiation in C2C12 Cells via Reduction of Oxidative Stress
by Santie Li, Myeong-Ji Kim, Sung-Ho Lee, Litai Jin, Weitao Cong, Hye-Gwang Jeong and Kwang-Youl Lee
Int. J. Mol. Sci. 2021, 22(9), 4312; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094312 - 21 Apr 2021
Cited by 9 | Viewed by 2731
Abstract
Metallothioneins (MTs) are intracellular cysteine-rich proteins, and their expressions are enhanced under stress conditions. MTs are recognized as having the ability to regulate redox balance in living organisms; however, their role in regulating osteoblast differentiation is still unclear. In this research, we found [...] Read more.
Metallothioneins (MTs) are intracellular cysteine-rich proteins, and their expressions are enhanced under stress conditions. MTs are recognized as having the ability to regulate redox balance in living organisms; however, their role in regulating osteoblast differentiation is still unclear. In this research, we found that the expression of MT3, one member of the MT protein family, was specifically upregulated in the differentiation process of C2C12 myoblasts treated with bone morphogenetic protein 4 (BMP4). Transfection with MT3-overexpressing plasmids in C2C12 cells enhanced their differentiation to osteoblasts, together with upregulating the protein expression of bone specific transcription factors runt-related gene 2 (Runx2), Osterix, and distal-less homeobox 5 (Dlx5). Additionally, MT3 knockdown performed the opposite. Further studies revealed that overexpression of MT3 decreased reactive oxygen species (ROS) production in C2C12 cells treated with BMP4, and MT3 silencing enhanced ROS production. Treating C2C12 cells with antioxidant N-acetylcysteine also promoted osteoblast differentiation, and upregulated Runx2/Osterix/Dlx5, while ROS generator antimycin A treatment performed the opposite. Finally, antimycin A treatment inhibited osteoblast differentiation and Runx2/Osterix/Dlx5 expression in MT3-overexpressing C2C12 cells. These findings identify the role of MT3 in osteoblast differentiation and indicate that MT3 may have interesting potential in the field of osteogenesis research. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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18 pages, 3824 KiB  
Article
Biological Evaluation and Transcriptomic Analysis of Corylin as an Inhibitor of Osteoclast Differentiation
by Anna Xiao-Dan Yu, Jian Xiao, Shi-Zheng Zhao, Xiang-Peng Kong, Kenneth Kin-Leung Kwan, Brody Zhong-Yu Zheng, Kevin Qi-Yun Wu, Tina Ting-Xia Dong and Karl Wah-Keung Tsim
Int. J. Mol. Sci. 2021, 22(7), 3540; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073540 - 29 Mar 2021
Cited by 7 | Viewed by 2744
Abstract
Corylin, a flavonoid isolated from the fruit of Psoralea corylifolia, has an osteogenic effect on osteoblasts in vitro and bone micromass ex vivo. However, the effect and mechanism of corylin in regulating osteoclastogenesis remain unknown. By using murine bone marrow macrophages as [...] Read more.
Corylin, a flavonoid isolated from the fruit of Psoralea corylifolia, has an osteogenic effect on osteoblasts in vitro and bone micromass ex vivo. However, the effect and mechanism of corylin in regulating osteoclastogenesis remain unknown. By using murine bone marrow macrophages as the osteoclast precursor, corylin was found to inhibit the receptor activator of nuclear factor (NF) κB ligand (RANKL)-induced osteoclast differentiation via down-regulating osteoclastic marker genes. In parallel, F-actin formation and osteoclast migration were diminished in corylin-treated cultured osteoclasts, and subsequently the expressions of osteoclastic proteins were suppressed: the suppression of protein expression was further illustrated by transcriptomic analysis. Furthermore, corylin inhibited the nuclear translocation of p65, giving rise to a restraint in osteoclastic differentiation through the attenuation of transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor of activated T cells c1 (NFATc1). There was no obvious change in apoptosis when the RANKL-induce osteoclasts were cultured in the presence of corylin. The finding supports the potential development of corylin as an osteoclast inhibitor against osteoporosis. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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16 pages, 3740 KiB  
Article
Increased Presence of Complement Factors and Mast Cells in Alveolar Bone and Tooth Resorption
by Kathrin Luntzer, Ina Lackner, Birte Weber, Yvonne Mödinger, Anita Ignatius, Florian Gebhard, Susann-Yvonne Mihaljevic, Melanie Haffner-Luntzer and Miriam Kalbitz
Int. J. Mol. Sci. 2021, 22(5), 2759; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052759 - 09 Mar 2021
Cited by 3 | Viewed by 2325
Abstract
Periodontitis is the inflammatory destruction of the tooth-surrounding and -supporting tissue, resulting at worst in tooth loss. Another locally aggressive disease of the oral cavity is tooth resorption (TR). This is associated with the destruction of the dental mineralized tissue. However, the underlying [...] Read more.
Periodontitis is the inflammatory destruction of the tooth-surrounding and -supporting tissue, resulting at worst in tooth loss. Another locally aggressive disease of the oral cavity is tooth resorption (TR). This is associated with the destruction of the dental mineralized tissue. However, the underlying pathomechanisms remain unknown. The complement system, as well as mast cells (MCs), are known to be involved in osteoclastogenesis and bone loss. The complement factors C3 and C5 were previously identified as key players in periodontal disease. Therefore, we hypothesize that complement factors and MCs might play a role in alveolar bone and tooth resorption. To investigate this, we used the cat as a model because of the naturally occurring high prevalence of both these disorders in this species. Teeth, gingiva samples and serum were collected from domestic cats, which had an appointment for dental treatment under anesthesia, as well as from healthy cats. Histological analyses, immunohistochemical staining and the CH-50 and AH-50 assays revealed increased numbers of osteoclasts and MCs, as well as complement activity in cats with TR. Calcifications score in the gingiva was highest in animals that suffer from TR. This indicates that MCs and the complement system are involved in the destruction of the mineralized tissue in this condition. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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14 pages, 6674 KiB  
Article
Influence of Cu2+ on Osteoclast Formation and Activity In Vitro
by Anne Bernhardt, Jana Bacova, Uwe Gbureck and Michael Gelinsky
Int. J. Mol. Sci. 2021, 22(5), 2451; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052451 - 28 Feb 2021
Cited by 20 | Viewed by 2890
Abstract
Background: Copper-containing biomaterials are increasingly applied for bone regeneration due to their pro-angiogenetic, pro-osteogenetic and antimicrobial properties. Therefore, the effect of Cu2+ on osteoclasts, which play a major role in bone remodeling was studied in detail. Methods: Human primary osteoclasts, differentiated from [...] Read more.
Background: Copper-containing biomaterials are increasingly applied for bone regeneration due to their pro-angiogenetic, pro-osteogenetic and antimicrobial properties. Therefore, the effect of Cu2+ on osteoclasts, which play a major role in bone remodeling was studied in detail. Methods: Human primary osteoclasts, differentiated from human monocytes were differentiated or cultivated in the presence of Cu2+. Osteoclast formation and activity were analyzed by measurement of osteoclast-specific enzyme activities, gene expression analysis and resorption assays. Furthermore, the glutathione levels of the cells were checked to evaluate oxidative stress induced by Cu2+. Results: Up to 8 µM Cu2+ did not induce cytotoxic effects. Activity of tartrate-resistant acid phosphatase (TRAP) was significantly increased, while other osteoclast specific enzyme activities were not affected. However, gene expression of TRAP was not upregulated. Resorptive activity of osteoclasts towards dentin was not changed in the presence of 8 µM Cu2+ but decreased in the presence of extracellular bone matrix. When Cu2+ was added to mature osteoclasts TRAP activity was not increased and resorption decreased only moderately. The glutathione level of both differentiating and mature osteoclasts was significantly decreased in the presence of Cu2+. Conclusions: Differentiating and mature osteoclasts react differently to Cu2+. High TRAP activities are not necessarily related to high resorption. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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12 pages, 3569 KiB  
Article
PF-3845, a Fatty Acid Amide Hydrolase Inhibitor, Directly Suppresses Osteoclastogenesis through ERK and NF-κB Pathways In Vitro and Alveolar Bone Loss In Vivo
by Hye-Jung Ihn, Yi-Seul Kim, Soomin Lim, Jong-Sup Bae, Jae-Chang Jung, Yeo-Hyang Kim, Jin-Woo Park, Zhao Wang, Jeong-Tae Koh, Yong-Chul Bae, Moon-Chang Baek and Eui-Kyun Park
Int. J. Mol. Sci. 2021, 22(4), 1915; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041915 - 15 Feb 2021
Cited by 12 | Viewed by 2673
Abstract
Alveolar bone loss, the major feature of periodontitis, results from the activation of osteoclasts, which can consequently cause teeth to become loose and fall out; the development of drugs capable of suppressing excessive osteoclast differentiation and function is beneficial for periodontal disease patients. [...] Read more.
Alveolar bone loss, the major feature of periodontitis, results from the activation of osteoclasts, which can consequently cause teeth to become loose and fall out; the development of drugs capable of suppressing excessive osteoclast differentiation and function is beneficial for periodontal disease patients. Given the difficulties associated with drug discovery, drug repurposing is an efficient approach for identifying alternative uses of commercially available compounds. Here, we examined the effects of PF-3845, a selective fatty acid amide hydrolase (FAAH) inhibitor, on receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclastogenesis, its function, and the therapeutic potential for the treatment of alveolar bone destruction in experimental periodontitis. PF-3845 significantly suppressed osteoclast differentiation and decreased the induction of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific markers. Actin ring formation and osteoclastic bone resorption were also reduced by PF-3845, and the anti-osteoclastogenic and anti-resorptive activities were mediated by the suppression of phosphorylation of rapidly accelerated fibrosarcoma (RAF), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase, (ERK) and nuclear factor κB (NF-κB) inhibitor (IκBα). Furthermore, the administration of PF-3845 decreased the number of osteoclasts and the amount of alveolar bone destruction caused by ligature placement in experimental periodontitis in vivo. The present study provides evidence that PF-3845 is able to suppress osteoclastogenesis and prevent alveolar bone loss, and may give new insights into its role as a treatment for osteoclast-related diseases. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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17 pages, 2567 KiB  
Article
Bisphosphonates Reduce Smoking-Induced Osteoporotic-Like Alterations by Regulating RANKL/OPG in an Osteoblast and Osteoclast Co-Culture Model
by Sheng Zhu, Victor Häussling, Romina H. Aspera-Werz, Tao Chen, Bianca Braun, Weidong Weng, Tina Histing and Andreas K. Nussler
Int. J. Mol. Sci. 2021, 22(1), 53; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010053 - 23 Dec 2020
Cited by 16 | Viewed by 3652
Abstract
Co-culture models have become mandatory for obtaining better insights into bone homeostasis, which relies on the balance between osteoblasts and osteoclasts. Cigarette smoking (CS) has been proven to increase the risk of osteoporosis; however, there is currently no proven treatment for osteoporosis in [...] Read more.
Co-culture models have become mandatory for obtaining better insights into bone homeostasis, which relies on the balance between osteoblasts and osteoclasts. Cigarette smoking (CS) has been proven to increase the risk of osteoporosis; however, there is currently no proven treatment for osteoporosis in smokers excluding cessation. Bisphosphonates (BPs) are classical anti-osteoclastic drugs that are commonly used in examining the suitability of bone co-culture systems in vitro as well as to verify the response to osteoporotic stimuli. In the present study, we tested the effects of BPs on cigarette smoke extract (CSE)-affected cells in the co-culture of osteoblasts and osteoclasts. Our results showed that BPs were able to reduce CSE-induced osteoporotic alterations in the co-culture of osteoblasts and osteoclasts such as decreased matrix remodeling, enhanced osteoclast activation, and an up-regulated receptor activator of nuclear factor (NF)-kB-ligand (RANKL)/osteoprotegerin (OPG) ratio. In summary, BPs may be an effective alternative therapy for reversing osteoporotic alterations in smokers, and the potential mechanism is through modulation of the RANKL/OPG ratio. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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Review

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25 pages, 819 KiB  
Review
The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis
by Kevin D. Seely, Cody A. Kotelko, Hannah Douglas, Brandon Bealer and Amanda E. Brooks
Int. J. Mol. Sci. 2021, 22(17), 9452; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179452 - 31 Aug 2021
Cited by 62 | Viewed by 9410
Abstract
An expanding body of research asserts that the gut microbiota has a role in bone metabolism and the pathogenesis of osteoporosis. This review considers the human gut microbiota composition and its role in osteoclastogenesis and the bone healing process, specifically in the case [...] Read more.
An expanding body of research asserts that the gut microbiota has a role in bone metabolism and the pathogenesis of osteoporosis. This review considers the human gut microbiota composition and its role in osteoclastogenesis and the bone healing process, specifically in the case of osteoporosis. Although the natural physiologic processes of bone healing and the pathogenesis of osteoporosis and bone disease are now relatively well known, recent literature suggests that a healthy microbiome is tied to bone homeostasis. Nevertheless, the mechanism underlying this connection is still somewhat enigmatic. Based on the literature, a relationship between the microbiome, osteoblasts, osteoclasts, and receptor activator of nuclear factor-kappa-Β ligand (RANKL) is contemplated and explored in this review. Studies have proposed various mechanisms of gut microbiome interaction with osteoclastogenesis and bone health, including micro-RNA, insulin-like growth factor 1, and immune system mediation. However, alterations to the gut microbiome secondary to pharmaceutical and surgical interventions cannot be discounted and are discussed in the context of clinical therapeutic consideration. The literature on probiotics and their mechanisms of action is examined in the context of bone healing. The known and hypothesized interactions of common osteoporosis drugs and the human gut microbiome are examined. Since dysbiosis in the gut microbiota can function as a biomarker of bone metabolic activity, it may also be a pharmacological and nutraceutical (i.e., pre- and probiotics) therapeutic target to promote bone homeostasis. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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22 pages, 2860 KiB  
Review
Regulation of Bone Cell Differentiation and Activation by Microbe-Associated Molecular Patterns
by Yeongkag Kwon, Chaeyeon Park, Jueun Lee, Dong Hyun Park, Sungho Jeong, Cheol-Heui Yun, Ok-Jin Park and Seung Hyun Han
Int. J. Mol. Sci. 2021, 22(11), 5805; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115805 - 28 May 2021
Cited by 20 | Viewed by 4794
Abstract
Gut microbiota has emerged as an important regulator of bone homeostasis. In particular, the modulation of innate immunity and bone homeostasis is mediated through the interaction between microbe-associated molecular patterns (MAMPs) and the host pattern recognition receptors including Toll-like receptors and nucleotide-binding oligomerization [...] Read more.
Gut microbiota has emerged as an important regulator of bone homeostasis. In particular, the modulation of innate immunity and bone homeostasis is mediated through the interaction between microbe-associated molecular patterns (MAMPs) and the host pattern recognition receptors including Toll-like receptors and nucleotide-binding oligomerization domains. Pathogenic bacteria such as Porphyromonas gingivalis and Staphylococcus aureus tend to induce bone destruction and cause various inflammatory bone diseases including periodontal diseases, osteomyelitis, and septic arthritis. On the other hand, probiotic bacteria such as Lactobacillus and Bifidobacterium species can prevent bone loss. In addition, bacterial metabolites and various secretory molecules such as short chain fatty acids and cyclic nucleotides can also affect bone homeostasis. This review focuses on the regulation of osteoclast and osteoblast by MAMPs including cell wall components and secretory microbial molecules under in vitro and in vivo conditions. MAMPs could be used as potential molecular targets for treating bone-related diseases such as osteoporosis and periodontal diseases. Full article
(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis)
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