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Rodriguez BN, Huang H, Chia JJ, Hoffmann A. The noncanonical NFκB pathway: Regulatory mechanisms in health and disease. WIREs Mech Dis 2024; 16:e1646. [PMID: 38634218 PMCID: PMC11486840 DOI: 10.1002/wsbm.1646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/29/2024] [Accepted: 04/01/2024] [Indexed: 04/19/2024]
Abstract
The noncanonical NFκB signaling pathway mediates the biological functions of diverse cell survival, growth, maturation, and differentiation factors that are important for the development and maintenance of hematopoietic cells and immune organs. Its dysregulation is associated with a number of immune pathologies and malignancies. Originally described as the signaling pathway that controls the NFκB family member RelB, we now know that noncanonical signaling also controls NFκB RelA and cRel. Here, we aim to clarify our understanding of the molecular network that mediates noncanonical NFκB signaling and review the human diseases that result from a deficient or hyper-active noncanonical NFκB pathway. It turns out that dysregulation of RelA and cRel, not RelB, is often implicated in mediating the resulting pathology. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Cancer > Molecular and Cellular Physiology Immune System Diseases > Stem Cells and Development.
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Affiliation(s)
- Benancio N. Rodriguez
- Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA; Molecular Biology Institute, Los Angeles, CA
| | - Helen Huang
- Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA; Institute for Quantitative and Computational Biosciences, Los Angeles, CA
| | - Jennifer J. Chia
- Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA; Molecular Biology Institute, Los Angeles, Calif; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA
| | - Alexander Hoffmann
- Department of Microbiology, Immunology, and Molecular Genetics; Molecular Biology Institute; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA
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2
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Amroodi MN, Maghsoudloo M, Amiri S, Mokhtari K, Mohseni P, Pourmarjani A, Jamali B, Khosroshahi EM, Asadi S, Tabrizian P, Entezari M, Hashemi M, Wan R. Unraveling the molecular and immunological landscape: Exploring signaling pathways in osteoporosis. Biomed Pharmacother 2024; 177:116954. [PMID: 38906027 DOI: 10.1016/j.biopha.2024.116954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/05/2024] [Accepted: 06/15/2024] [Indexed: 06/23/2024] Open
Abstract
Osteoporosis, characterized by compromised bone density and microarchitecture, represents a significant global health challenge, particularly in aging populations. This comprehensive review delves into the intricate signaling pathways implicated in the pathogenesis of osteoporosis, providing valuable insights into the pivotal role of signal transduction in maintaining bone homeostasis. The exploration encompasses cellular signaling pathways such as Wnt, Notch, JAK/STAT, NF-κB, and TGF-β, all of which play crucial roles in bone remodeling. The dysregulation of these pathways is a contributing factor to osteoporosis, necessitating a profound understanding of their complexities to unveil the molecular mechanisms underlying bone loss. The review highlights the pathological significance of disrupted signaling in osteoporosis, emphasizing how these deviations impact the functionality of osteoblasts and osteoclasts, ultimately resulting in heightened bone resorption and compromised bone formation. A nuanced analysis of the intricate crosstalk between these pathways is provided to underscore their relevance in the pathophysiology of osteoporosis. Furthermore, the study addresses some of the most crucial long non-coding RNAs (lncRNAs) associated with osteoporosis, adding an additional layer of academic depth to the exploration of immune system involvement in various types of osteoporosis. Finally, we propose that SKP1 can serve as a potential biomarker in osteoporosis.
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Affiliation(s)
- Morteza Nakhaei Amroodi
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, department of orthopedic, school of medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mazaher Maghsoudloo
- Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Shayan Amiri
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, department of orthopedic, school of medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Khatere Mokhtari
- Department of Cellular and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Parnaz Mohseni
- Department of Pediatrics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Azadeh Pourmarjani
- Department of Pediatrics, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Behdokht Jamali
- Department of microbiology and genetics, kherad Institute of higher education, Busheher, lran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Pouria Tabrizian
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, department of orthopedic, school of medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Runlan Wan
- Department of Oncology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China.
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3
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Wang Z, Luo W, Zhang G, Li H, Zhou F, Wang D, Feng X, Xiong Y, Wu Y. FoxO1 knockdown inhibits RANKL-induced osteoclastogenesis by blocking NLRP3 inflammasome activation. Oral Dis 2024; 30:3272-3285. [PMID: 37927112 DOI: 10.1111/odi.14800] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 11/07/2023]
Abstract
OBJECTIVES This study aimed to elucidate the connection between osteoclastic forkhead transcription factor O1 (FoxO1) and periodontitis and explore the underlying mechanism by which FoxO1 knockdown regulates osteoclast formation. MATERIALS AND METHODS A conventional ligature-induced periodontitis model was constructed to reveal the alterations in the proportion of osteoclastic FoxO1 in periodontitis via immunofluorescence staining. Additionally, RNA sequencing (RNA-seq) was performed to explore the underlying mechanisms of FoxO1 knockdown-mediated osteoclastogenesis, followed by western blotting, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. RESULTS FoxO1+ osteoclasts were enriched in the alveolar bone in experimental periodontitis. Moreover, FoxO1 knockdown led to impaired osteoclastogenesis with low expression of osteoclast differentiation-related genes, accompanied by an insufficient osteoclast maturation phenotype. Mechanistically, RNA-seq revealed that the nuclear factor kappa B (NF-κB) and nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways were inhibited in FoxO1-knockdown osteoclasts. Consistent with this, MCC950, an effective inhibitor of the NLRP3 inflammasome, substantially attenuated osteoclast formation. CONCLUSIONS FoxO1 knockdown contributed to the inhibition of osteoclastogenesis by effectively suppressing NF-κB signaling and NLRP3 inflammasome activation. This prospective study reveals the role of FoxO1 in mediating osteoclastogenesis and provides a viable therapeutic target for periodontitis treatment.
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Affiliation(s)
- Zhanqi Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wenxin Luo
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Guorui Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Haiyun Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Feng Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Dongyang Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xuan Feng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yi Xiong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yingying Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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4
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Liu S, Lu Q, Wang M, Guo H, Wang Y, Nong J, Wang S, Xia H, Xia T, Sun H. S-nitrosoglutathione reductase-dependent p65 denitrosation promotes osteoclastogenesis by facilitating recruitment of p65 to NFATc1 promoter. Bone 2024; 181:117036. [PMID: 38311303 DOI: 10.1016/j.bone.2024.117036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 12/26/2023] [Accepted: 02/01/2024] [Indexed: 02/10/2024]
Abstract
Osteoclasts, the exclusive bone resorptive cells, are indispensable for bone remodeling. Hence, understanding novel signaling modulators regulating osteoclastogenesis is clinically important. Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) is a master transcription factor in osteoclastogenesis, and binding of NF-κB p65 subunit to NFATc1 promoter is required for its expression. It is well-established that DNA binding activity of p65 can be regulated by various post-translational modifications, including S-nitrosation. Recent studies have demonstrated that S-nitrosoglutathione reductase (GSNOR)-mediated protein denitrosation participated in cell fate commitment by regulating gene transcription. However, the role of GSNOR in osteoclastogenesis remains unexplored and enigmatic. Here, we investigated the effect of GSNOR-mediated denitrosation of p65 on osteoclastogenesis. Our results revealed that GSNOR was up-regulated during osteoclastogenesis in vitro. Moreover, GSNOR inhibition with a chemical inhibitor impaired osteoclast differentiation, podosome belt formation, and bone resorption activity. Furthermore, GSNOR inhibition enhanced the S-nitrosation level of p65, precluded the binding of p65 to NFATc1 promoter, and suppressed NFATc1 expression. In addition, mouse model of lipopolysaccharides (LPS)-induced calvarial osteolysis was employed to evaluate the therapeutic effect of GSNOR inhibitor in vivo. Our results indicated that GSNOR inhibitor treatment alleviated the inflammatory bone loss by impairing osteoclast formation in mice. Taken together, these data have shown that GSNOR activity is required for osteoclastogenesis by facilitating binding of p65 to NFATc1 promoter via promoting p65 denitrosation, suggesting that GSNOR may be a potential therapeutic target in the treatment of osteolytic diseases.
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Affiliation(s)
- Shumin Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; School of Stomatology, Wuhan University, Wuhan 430079, China
| | - Qian Lu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; School of Stomatology, Wuhan University, Wuhan 430079, China
| | - Min Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral Implantology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Huilin Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Yiwen Wang
- School of Stomatology, Wuhan University, Wuhan 430079, China
| | - Jingwen Nong
- School of Stomatology, Wuhan University, Wuhan 430079, China
| | - Shuo Wang
- School of Stomatology, Wuhan University, Wuhan 430079, China
| | - Haibin Xia
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral Implantology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Ting Xia
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral Implantology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
| | - Huifang Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Center for Prosthodontics and Implant Dentistry, Optics Valley Branch, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
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Guo Q, Jin Y, Chen X, Ye X, Shen X, Lin M, Zeng C, Zhou T, Zhang J. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther 2024; 9:53. [PMID: 38433280 PMCID: PMC10910037 DOI: 10.1038/s41392-024-01757-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 03/05/2024] Open
Abstract
NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.
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Affiliation(s)
- Qing Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yizi Jin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xinyu Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, PR China
| | - Xiaomin Ye
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Xin Shen
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingxi Lin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cheng Zeng
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Teng Zhou
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jian Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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6
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Hasegawa Y, Asada S. DNA-dependent protein kinase catalytic subunit binds to the transactivation domain 1 of NF-κB p65. Biochem Biophys Rep 2023; 35:101538. [PMID: 37674974 PMCID: PMC10477060 DOI: 10.1016/j.bbrep.2023.101538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 08/27/2023] [Accepted: 08/28/2023] [Indexed: 09/08/2023] Open
Abstract
Nuclear factor-kappa B (NF-κB) is a transcriptional factor that binds to the ∼10-base-pair κB motif on target genes and acts as an inflammatory regulator. Since dysregulation of NF-κB is thought to be related to various diseases, it would be very important to elucidate its post-translational modifications and binding partners in detail and to deeply understand mechanisms of the NF-κB dysregulation. NF-κB p65 is known to interact with the basic transcription factor TFIID subunit hTAFII31/TAF9 through the ФXXФФ (Ф, hydrophobic amino acid; X, any amino acid) motif in a similar fashion to p53. MDM2 is known to inhibit p53 from binding to hTAFII31/TAF9 by masking p53's ФXXФФ motif. Here, as can be rationalized from this observation, we searched for novel nuclear proteins that interact with the transactivation domain 1 (TA1) of NF-κB p65 containing a ФXXФФ motif. We prepared a GST-tagged polypeptide, GST-p65532-550, from Phe532-Ser550 of the TA1 domain and found various U937 cell nuclear proteins that bound to GST-p65532-550. The largest bound protein the size of ∼400 kDa was subjected to mass spectrometric analysis and found to be DNA-dependent protein kinase catalytic subunit (DNA-PKcs). An immunoprecipitation experiment with an antibody against p65 and nuclear extracts from TNF-α-treated A549 cells suggested that NF-κB p65 indeed binds to DNA-PKcs in human cells. Furthermore, binding assays with a series of His-tagged DNA-PKcs fragments suggested that DNA-PKcs can bind to NF-κB p65 through the interaction of the TA1 domain with the region 541-750 in the N-HEAT domain or the region 2485-2576 in the M-HEAT domain.
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Affiliation(s)
- Yuta Hasegawa
- Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Higashijima 265-1, Akiha-ku, Niigata, Niigata, 956-8603, Japan
| | - Shinichi Asada
- Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Higashijima 265-1, Akiha-ku, Niigata, Niigata, 956-8603, Japan
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Chakraborty S, Schneider J, Mitra DK, Kubatzky KF. Mechanistic insight of interleukin-9 induced osteoclastogenesis. Immunology 2023; 169:309-322. [PMID: 36732282 PMCID: PMC7615986 DOI: 10.1111/imm.13630] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 01/03/2023] [Indexed: 02/04/2023] Open
Abstract
Interleukin (IL)-9 is an emerging player in the pathogenesis of various chronic inflammatory diseases including bone disorders like rheumatoid arthritis (RA) and psoriatic arthritis. Recently, IL-9 was shown to enhance the osteoclast formation and their function in RA. However, the mechanisms by which IL-9 influences osteoclastogenesis are not known. Therefore, in this study we aimed to unravel the direct and indirect ways by which IL-9 can influence osteoclast formation. We used mouse bone marrow precursor cells for checking the effect of IL-9 on osteoclast differentiation and its function. Next, IL-9 induced signalling pathway were checked in the process of osteoclastogenesis. T cells play an important role in enhancing osteoclastogenesis in inflammatory conditions. We used splenic T cells to understand the impact of IL-9 on the functions of T effector (Teff) and regulatory T (Treg) cells. Furthermore, the effect of IL-9 mediated modulation of the T cell response on osteoclasts was checked using a coculture model of T cells with osteoclast precursors. We showed that IL-9 enhanced osteoclast formation and its function. We found that IL-9 activates STAT3, P38 MAPK, ERK1/2, NFκB and we hypothesize that it mediates the effect on osteoclastogenesis by accelerating mitochondrial biogenesis. Additionally, IL-9 was observed to facilitate the functions of pro-osteoclastogenic IL-17 producing T cells, but inhibits the function of anti-osteoclastogenic Treg cells. Our observations suggest that IL-9 can influence osteoclastogenesis directly by modulating the signalling cascade in the precursor cells; indirectly by enhancing IL-17 producing T cells and by reducing the functions of Treg cells.
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Affiliation(s)
- Sushmita Chakraborty
- Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University, Heidelberg, Germany
- Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
| | - Jakob Schneider
- Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University, Heidelberg, Germany
| | - Dipendra Kumar Mitra
- Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
| | - Katharina F. Kubatzky
- Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University, Heidelberg, Germany
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8
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Rajpar I, Kumar G, Fortina P, Tomlinson RE. Toll-like receptor 4 signaling in osteoblasts is required for load-induced bone formation in mice. iScience 2023; 26:106304. [PMID: 36950122 PMCID: PMC10025993 DOI: 10.1016/j.isci.2023.106304] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 01/06/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
In mature bone, NGF is produced by osteoblasts following mechanical loading and signals through resident sensory nerves expressing its high affinity receptor, neurotrophic tyrosine kinase receptor type 1 (TrkA), to support bone formation. Here, we investigated whether osteoblastic expression of Toll-like receptor 4 (TLR4), a key receptor in the NF-κB signaling pathway, is required to initiate NGF-TrkA signaling required for load-induced bone formation. Although Tlr4 conditional knockout mice have normal skeletal mass and strength in adulthood, the loss of TLR4 signaling significantly reduced lamellar bone formation following loading. Inhibition of TLR4 signaling reduced Ngf expression in primary osteoblasts and RNA sequencing of bones from Tlr4 conditional knockout mice and wild-type littermates revealed dysregulated inflammatory signaling three days after osteogenic mechanical loading. In total, our study reveals an important role for osteoblastic TLR4 in the skeletal adaptation of bone to mechanical forces.
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Affiliation(s)
- Ibtesam Rajpar
- Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Gaurav Kumar
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Paolo Fortina
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Ryan E. Tomlinson
- Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA
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9
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Wang X, Shao L, Richardson KK, Ling W, Warren A, Krager K, Aykin-Burns N, Hromas R, Zhou D, Almeida M, Kim HN. Hematopoietic cytoplasmic adaptor protein Hem1 promotes osteoclast fusion and bone resorption in mice. J Biol Chem 2023; 299:102841. [PMID: 36574841 PMCID: PMC9867982 DOI: 10.1016/j.jbc.2022.102841] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/25/2022] Open
Abstract
Hem1 (hematopoietic protein 1), a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins, is essential for lymphopoiesis and innate immunity as well as for the transition of hematopoiesis from the fetal liver to the bone marrow. However, the role of Hem1 in bone cell differentiation and bone remodeling is unknown. Here, we show that deletion of Hem1 resulted in a markedly increase in bone mass because of defective bone resorption in mice of both sexes. Hem1-deficient osteoclast progenitors were able to differentiate into osteoclasts, but the osteoclasts exhibited impaired osteoclast fusion and decreased bone-resorption activity, potentially because of decreased mitogen-activated protein kinase and tyrosine kinase c-Abl activity. Transplantation of bone marrow hematopoietic stem and progenitor cells from wildtype into Hem1 knockout mice increased bone resorption and normalized bone mass. These findings indicate that Hem1 plays a pivotal role in the maintenance of normal bone mass.
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Affiliation(s)
- Xiaoyan Wang
- Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Lijian Shao
- Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Kimberly K Richardson
- Division of Endocrinology, Department of Internal Medicine, Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Wen Ling
- Division of Endocrinology, Department of Internal Medicine, Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Aaron Warren
- Division of Endocrinology, Department of Internal Medicine, Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA
| | - Kimberly Krager
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Nukhet Aykin-Burns
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Robert Hromas
- Department of Medicine, The Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Daohong Zhou
- Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Department of Pharmacodynamics, University of Florida, Gainesville, Florida, USA
| | - Maria Almeida
- Division of Endocrinology, Department of Internal Medicine, Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA; Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Ha-Neui Kim
- Division of Endocrinology, Department of Internal Medicine, Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.
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10
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Zhang J, Wu YJ, Hu XX, Wei W. New insights into the Lck-NF-κB signaling pathway. Front Cell Dev Biol 2023; 11:1120747. [PMID: 36910149 PMCID: PMC9999026 DOI: 10.3389/fcell.2023.1120747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 02/15/2023] [Indexed: 03/14/2023] Open
Abstract
Lck is essential for the development, activity, and proliferation of T cells, which may contribute to pathological progression and development of human diseases, such as autoimmune disorders and cancers when functioning aberrantly. Nuclear factor-κB (NF-κB) was initially discovered as a factor bound to the κ light-chain immunoglobulin enhancer in the nuclei of activated B lymphocytes. Activation of the nuclear factor-κB pathway controls expression of several genes that are related to cell survival, apoptosis, and inflammation. Abnormal expression of Lck and nuclear factor-κB has been found in autoimmune diseases and malignancies, including rheumatoid arthritis, systemic lupus erythematosus, acute T cell lymphocytic leukemia, and human chronic lymphocytic leukemia, etc. Nuclear factor-κB inhibition is effective against autoimmune diseases and malignancies through blocking inflammatory responses, although it may lead to serious adverse reactions that are unexpected and unwanted. Further investigation of the biochemical and functional interactions between nuclear factor-κB and other signaling pathways may be helpful to prevent side-effects. This review aims to clarify the Lck-nuclear factor-κB signaling pathway, and provide a basis for identification of new targets and therapeutic approaches against autoimmune diseases and malignancies.
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Affiliation(s)
- Jing Zhang
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Yu-Jing Wu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Xiao-Xi Hu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Wei Wei
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
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11
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Zhang H, Qin S, Zhang X, Du P, Zhu Y, Huang Y, Michiels J, Zeng Q, Chen W. Dietary resistant starch alleviates Escherichia coli-induced bone loss in meat ducks by promoting short-chain fatty acid production and inhibiting Malt1/NF-κB inflammasome activation. J Anim Sci Biotechnol 2022; 13:92. [PMID: 35927754 PMCID: PMC9354418 DOI: 10.1186/s40104-022-00739-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 06/05/2022] [Indexed: 11/16/2022] Open
Abstract
Background Escherichia coli (E. coli) infection in humans and animals usually comes with gut dysbiosis, which is potential culprit to skeletal health, it is still unclear to whether diet interfered gut microbiome changes can be a protective strategy to bone loss development. Here, the effects of resistant starch from raw potato starch (RPS), a type of prebiotic, on E. coli-induced bone loss and gut microbial composition in meat ducks were evaluated. Results The results showed that dietary 12% RPS treatment improved bone quality, depressed bone resorption, and attenuated the pro-inflammatory reaction in both ileum and bone marrow. Meanwhile, the 12% RPS diet also increased the abundance of Firmicutes in E. coli-treated birds, along with higher production of short-chain fatty acids (SCFAs) especially propionate and butyrate. Whereas addition of β-acid, an inhibitor of bacterial SCFAs production, to the drinking water of ducks fed 12% RPS diet significantly decreased SCFAs level in cecum content and eliminated RPS-induced tibial mass improvement. Further, treatment with MI-2 to abrogate mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) activity replicated the protective role of dietary 12% RPS in E. coli-induced bone loss including reduced the inhibition on nuclear factor κB (NF-κB) inflammasome activation, decreased bone resorption, and improved bone quality, which were correlated with comparable and higher regulatory T cells (Treg) frequency in MI-2 and 12% RPS group, respectively. Conclusions These findings suggested that the diet with 12% RPS could alleviate E. coli-induced bone loss in meat ducks by changing the gut microbial composition and promoting concomitant SCFAs production, and consequently inhibiting Malt1/NF-κB inflammasome activation and Treg cells expansion. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s40104-022-00739-7.
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Affiliation(s)
- Huaiyong Zhang
- College of Animal Science and Technology, Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, 450046, China.,Laboratory for Animal Nutrition and Animal Product Quality, Department of Animal Sciences and Aquatic Ecology, Ghent University, 9000, Ghent, Belgium
| | - Simeng Qin
- Institute of Animal Nutrition, Key Laboratory for Animal Disease-Resistance Nutrition of China, Ministry of Education, Sichuan Agricultural University, Chengdu, 611130, China
| | - Xiangli Zhang
- College of Animal Science and Technology, Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, 450046, China
| | - Pengfei Du
- College of Animal Science and Technology, Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, 450046, China
| | - Yao Zhu
- College of Animal Science and Technology, Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, 450046, China
| | - Yanqun Huang
- College of Animal Science and Technology, Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, 450046, China
| | - Joris Michiels
- Laboratory for Animal Nutrition and Animal Product Quality, Department of Animal Sciences and Aquatic Ecology, Ghent University, 9000, Ghent, Belgium
| | - Quifeng Zeng
- Institute of Animal Nutrition, Key Laboratory for Animal Disease-Resistance Nutrition of China, Ministry of Education, Sichuan Agricultural University, Chengdu, 611130, China.
| | - Wen Chen
- College of Animal Science and Technology, Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, 450046, China.
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12
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Wang WJ, He JW, Fu WZ, Wang C, Zhang ZL. Genetic Polymorphisms of Nuclear Factor-κB Family Affect the Bone Mineral Density Response to Zoledronic Acid Therapy in Postmenopausal Chinese Women. Genes (Basel) 2022; 13:genes13081343. [PMID: 36011257 PMCID: PMC9407517 DOI: 10.3390/genes13081343] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 07/06/2022] [Accepted: 07/22/2022] [Indexed: 02/04/2023] Open
Abstract
The aim of this study was to explore the allelic association between genetic polymorphisms of the NF-κB pathway and the variance of clinical effects of zoledronic in postmenopausal Chinese women with osteoporosis. In the study, 110 Chinese postmenopausal women with osteoporosis were recruited. Every patient received zoledronic once a year. BMD was measured at baseline and after one year of treatment. The 13 tagger SNPs of five genes in the NF-κB pathway were genotyped. In the study, 101 subjects completed the one-year follow-up. The ITCTG and DTCTG haplotypes, which are constituted of rs28362491, rs3774937, rs230521, rs230510 and rs4648068 of the NF-κB1 gene, were associated with improvement in BMD at L1-4 and femoral neck (p < 0.001, p = 0.008, respectively). The CGC haplotype, which is constituted of rs7119750, rs2306365 and rs11820062 of the RELA gene, was associated with improvement in BMD at total hip (p < 0.001). After Bonferroni correction, haplotypes ITCTG and CGC still showed significant association with the % change of BMD at L1-4 and total hip. Therefore, NF-κB1 and RELA gene were significantly associated with bone response to the treatment of zoledronic in postmenopausal Chinese women with osteoporosis.
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13
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Shen G, Liu X, Lei W, Duan R, Yao Z. Plumbagin is a NF-κB-inducing kinase inhibitor with dual anabolic and antiresorptive effects that prevents menopausal-related osteoporosis in mice. J Biol Chem 2022; 298:101767. [PMID: 35235833 PMCID: PMC8958545 DOI: 10.1016/j.jbc.2022.101767] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 12/03/2022] Open
Abstract
Osteoporosis is caused by enhanced bone resorption and relatively reduced bone formation. There is an unmet need to develop new agents with both antiresorptive and anabolic effects to treat osteoporosis, although drugs with either effect alone are available. A small molecular compound, plumbagin, was reported to inhibit receptor activator of nuclear factor kappa-B ligand-induced osteoclast (OC) differentiation by inhibiting IκBα phosphorylation-mediated canonical NF-κB activation. However, the key transcriptional factor RelA/p65 in canonical NF-κB pathway functions to promote OC precursor survival but not terminal OC differentiation. Here, we found that plumbagin inhibited the activity of NF-κB inducing kinase, the key molecule that controls noncanonical NF-κB signaling, in an ATP/ADP-based kinase assay. Consistent with this, plumbagin inhibited processing of NF-κB2 p100 to p52 in the progenitor cells of both OCs and osteoblasts (OBs). Interestingly, plumbagin not only inhibited OC but also stimulated OB differentiation in vitro. Importantly, plumbagin prevented trabecular bone loss in ovariectomized mice. This was associated with decreased OC surfaces on trabecular surface and increased parameters of OBs, including OB surface on trabecular surface, bone formation rate, and level of serum osteocalcin, compared to vehicle-treated mice. In summary, we conclude that plumbagin is a NF-κB-inducing kinase inhibitor with dual anabolic and antiresorptive effects on bone and could represent a new class of agent for the prevention and treatment of osteoporosis.
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Affiliation(s)
- Gengyang Shen
- Department of Pathology and Laboratory Medicine, and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Xin Liu
- Department of Pathology and Laboratory Medicine, and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Wei Lei
- Department of Pathology and Laboratory Medicine, and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Rong Duan
- Department of Pathology and Laboratory Medicine, and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Zhenqiang Yao
- Department of Pathology and Laboratory Medicine, and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA.
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14
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Davis JL, Pokhrel NK, Cox L, Rohatgi N, Faccio R, Veis DJ. Conditional loss of IKKα in Osterix + cells has no effect on bone but leads to age-related loss of peripheral fat. Sci Rep 2022; 12:4915. [PMID: 35318397 PMCID: PMC8940989 DOI: 10.1038/s41598-022-08914-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/10/2022] [Indexed: 11/09/2022] Open
Abstract
NF-κB has been reported to both promote and inhibit bone formation. To explore its role in osteolineage cells, we conditionally deleted IKKα, an upstream kinase required for non-canonical NF-κB activation, using Osterix (Osx)-Cre. Surprisingly, we found no effect on either cancellous or cortical bone, even following mechanical loading. However, we noted that IKKα conditional knockout (cKO) mice began to lose body weight after 6 months of age with severe reductions in fat mass and lower adipocyte size in geriatric animals. qPCR analysis of adipogenic markers in fat pads of cKO mice indicated no difference in early differentiation, but instead markedly lower leptin with age. We challenged young mice with a high fat diet finding that cKO mice gained less weight and showed improved glucose metabolism. Low levels of recombination at the IKKα locus were detected in fat pads isolated from old cKO mice. To determine whether recombination occurs in adipocytes, we examined fat pads in Osx-Cre;TdT reporter mice; these showed increasing Osx-Cre-mediated expression in peripheral adipocytes from 6 weeks to 18 months. Since Osx-Cre drives recombination in peripheral adipocytes with age, we conclude that fat loss in cKO mice is most likely caused by progressive deficits of IKKα in adipocytes.
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Affiliation(s)
- Jennifer L Davis
- Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Nitin Kumar Pokhrel
- Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Linda Cox
- Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Nidhi Rohatgi
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Roberta Faccio
- Musculoskeletal Research Center, Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA.,Shriners Hospitals for Children, St. Louis, MO, 63110, USA
| | - Deborah J Veis
- Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, 63110, USA. .,Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA. .,Shriners Hospitals for Children, St. Louis, MO, 63110, USA.
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15
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Regulation of TNF-Induced Osteoclast Differentiation. Cells 2021; 11:cells11010132. [PMID: 35011694 PMCID: PMC8750957 DOI: 10.3390/cells11010132] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/24/2021] [Accepted: 12/28/2021] [Indexed: 12/27/2022] Open
Abstract
Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.
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16
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Kim I, Kim JH, Kim K, Seong S, Lee KB, Kim N. IRF2 enhances RANKL-induced osteoclast differentiation via regulating NF-κB/NFATc1 signaling. BMB Rep 2021. [PMID: 34488926 PMCID: PMC8505232 DOI: 10.5483/bmbrep.2021.54.9.070] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Interferon regulatory factors (IRFs) play roles in various biological processes including cytokine signaling, cell growth regulation and hematopoietic development. Although it has been reported that several IRFs are involved in bone metabolism, the role of IRF2 in bone cells has not been elucidated. Here, we investigated the involvement of IRF2 in RANKL-induced osteoclast differentiation. IRF2 overexpression in osteoclast pre-cursor cells enhanced osteoclast differentiation by regulating the expression of NFATc1, a master regulator of osteoclasto-genesis. Conversely, IRF2 knockdown inhibited osteoclast differentiation and decreased the NFATc1 expression. Moreover, IRF2 increased the translocation of NF-κB subunit p65 to the nucleus in response to RANKL and subsequently induced the expression of NFATc1. IRF2 plays an important role in RANKL-induced osteoclast differentiation by regulating NF-κB/NFATc1 signaling pathway. Taken together, we demonstrated the molecular mechanism of IRF2 in osteoclast differentiation, and provide a molecular basis for potential therapeutic targets for the treatment of bone diseases characterized by excessive bone resorption.
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Affiliation(s)
- Inyoung Kim
- Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Korea
| | - Jung Ha Kim
- Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Korea
| | - Kabsun Kim
- Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Korea
| | - Semun Seong
- Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Korea
| | - Keun-Bae Lee
- Department of Orthopedic Surgery, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea
| | - Nacksung Kim
- Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Korea
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17
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Mockenhaupt K, Gonsiewski A, Kordula T. RelB and Neuroinflammation. Cells 2021; 10:1609. [PMID: 34198987 PMCID: PMC8307460 DOI: 10.3390/cells10071609] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/23/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022] Open
Abstract
Neuroinflammation within the central nervous system involves multiple cell types that coordinate their responses by secreting and responding to a plethora of inflammatory mediators. These factors activate multiple signaling cascades to orchestrate initial inflammatory response and subsequent resolution. Activation of NF-κB pathways in several cell types is critical during neuroinflammation. In contrast to the well-studied role of p65 NF-κB during neuroinflammation, the mechanisms of RelB activation in specific cell types and its roles during neuroinflammatory response are less understood. In this review, we summarize the mechanisms of RelB activation in specific cell types of the CNS and the specialized effects this transcription factor exerts during neuroinflammation.
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Affiliation(s)
| | | | - Tomasz Kordula
- Department of Biochemistry and Molecular Biology, School of Medicine and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VI 23298, USA; (K.M.); (A.G.)
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18
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Alexandre-Moreno S, Bonet-Fernández JM, Atienzar-Aroca R, Aroca-Aguilar JD, Escribano J. Null cyp1b1 Activity in Zebrafish Leads to Variable Craniofacial Defects Associated with Altered Expression of Extracellular Matrix and Lipid Metabolism Genes. Int J Mol Sci 2021; 22:ijms22126430. [PMID: 34208498 PMCID: PMC8234340 DOI: 10.3390/ijms22126430] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/11/2021] [Accepted: 06/12/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary CYP1B1 is a cytochrome P450 monooxygenase involved in oxidative metabolism of different endogenous lipids and drugs. The loss of function (LoF) of this gene underlies many cases of recessive primary congenital glaucoma (PCG), an infrequent disease and a common cause of infantile loss of vision in children. To the best of our knowledge, this is the first study to generate a cyp1b1 knockout zebrafish model. The zebrafish line did not exhibit glaucoma-related phenotypes; however, adult mutant zebrafish presented variable craniofacial alterations, including uni- or bilateral craniofacial alterations with incomplete penetrance and variable expressivity. Transcriptomic analyses of seven-dpf cyp1b1-KO zebrafish revealed differentially expressed genes related to extracellular matrix and cell adhesion, cell growth and proliferation, lipid metabolism and inflammation. Overall, this study provides evidence for the complexity of the phenotypes and molecular pathways associated with cyp1b1 LoF, as well as for the dysregulation of extracellular matrix gene expression as one of the mechanisms underlying cyp1b1 disruption-associated pathogenicity. Abstract CYP1B1 loss of function (LoF) is the main known genetic alteration present in recessive primary congenital glaucoma (PCG), an infrequent disease characterized by delayed embryonic development of the ocular iridocorneal angle; however, the underlying molecular mechanisms are poorly understood. To model CYP1B1 LoF underlying PCG, we developed a cyp1b1 knockout (KO) zebrafish line using CRISPR/Cas9 genome editing. This line carries the c.535_667del frameshift mutation that results in the 72% mRNA reduction with the residual mRNA predicted to produce an inactive truncated protein (p.(His179Glyfs*6)). Microphthalmia and jaw maldevelopment were observed in 23% of F0 somatic mosaic mutant larvae (144 hpf). These early phenotypes were not detected in cyp1b1-KO F3 larvae (144 hpf), but 27% of adult (four months) zebrafish exhibited uni- or bilateral craniofacial alterations, indicating the existence of incomplete penetrance and variable expressivity. These phenotypes increased to 86% in the adult offspring of inbred progenitors with craniofacial defects. No glaucoma-related phenotypes were observed in cyp1b1 mutants. Transcriptomic analyses of the offspring (seven dpf) of cyp1b1-KO progenitors with adult-onset craniofacial defects revealed functionally enriched differentially expressed genes related to extracellular matrix and cell adhesion, cell growth and proliferation, lipid metabolism (retinoids, steroids and fatty acids and oxidation–reduction processes that include several cytochrome P450 genes) and inflammation. In summary, this study shows the complexity of the phenotypes and molecular pathways associated with cyp1b1 LoF, with species dependency, and provides evidence for the dysregulation of extracellular matrix gene expression as one of the mechanisms underlying the pathogenicity associated with cyp1b1 disruption.
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Affiliation(s)
- Susana Alexandre-Moreno
- Área de Genética, Facultad de Medicina de Albacete, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, 02006 Albacete, Spain; (S.A.-M.); (J.-M.B.-F.); (R.A.-A.)
- Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality (OFTARED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Juan-Manuel Bonet-Fernández
- Área de Genética, Facultad de Medicina de Albacete, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, 02006 Albacete, Spain; (S.A.-M.); (J.-M.B.-F.); (R.A.-A.)
- Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality (OFTARED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Raquel Atienzar-Aroca
- Área de Genética, Facultad de Medicina de Albacete, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, 02006 Albacete, Spain; (S.A.-M.); (J.-M.B.-F.); (R.A.-A.)
- Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality (OFTARED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - José-Daniel Aroca-Aguilar
- Área de Genética, Facultad de Medicina de Albacete, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, 02006 Albacete, Spain; (S.A.-M.); (J.-M.B.-F.); (R.A.-A.)
- Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality (OFTARED), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (J.-D.A.-A.); (J.E.)
| | - Julio Escribano
- Área de Genética, Facultad de Medicina de Albacete, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, 02006 Albacete, Spain; (S.A.-M.); (J.-M.B.-F.); (R.A.-A.)
- Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality (OFTARED), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (J.-D.A.-A.); (J.E.)
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19
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Ansalone C, Cole J, Chilaka S, Sunzini F, Sood S, Robertson J, Siebert S, McInnes IB, Goodyear CS. TNF is a homoeostatic regulator of distinct epigenetically primed human osteoclast precursors. Ann Rheum Dis 2021; 80:748-757. [PMID: 33692019 PMCID: PMC8142443 DOI: 10.1136/annrheumdis-2020-219262] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/31/2020] [Accepted: 01/25/2021] [Indexed: 12/21/2022]
Abstract
OBJECTIVES Circulating myeloid precursors are responsible for post-natal osteoclast (OC) differentiation and skeletal health, although the exact human precursors have not been defined. Enhanced osteoclastogenesis contributes to joint destruction in rheumatoid arthritis (RA) and tumour necrosis factor (TNF) is a well-known pro-osteoclastogenic factor. Herein, we investigated the interplay between receptor activator of nuclear factor kappa-Β ligand (RANK-L), indispensable for fusion of myeloid precursors and the normal development of OCs, and TNF in directing the differentiation of diverse pre-OC populations derived from human peripheral blood. METHODS Flow cytometric cell sorting and analysis was used to assess the potential of myeloid populations to differentiate into OCs. Transcriptomic, epigenetic analysis, receptor expression and inhibitor experiments were used to unravel RANK-L and TNF signalling hierarchy. RESULTS TNF can act as a critical homoeostatic regulator of CD14+ monocyte (MO) differentiation into OCs by inhibiting osteoclastogenesis to favour macrophage development. In contrast, a distinct previously unidentified CD14-CD16-CD11c+ myeloid pre-OC population was exempt from this negative regulation. In healthy CD14+ MOs, TNF drove epigenetic modification of the RANK promoter via a TNFR1-IKKβ-dependent pathway and halted osteoclastogenesis. In a subset of patients with RA, CD14+ MOs exhibited an altered epigenetic state that resulted in dysregulated TNF-mediated OC homoeostasis. CONCLUSIONS These findings fundamentally re-define the relationship between RANK-L and TNF. Moreover, they have identified a novel pool of human circulating non-MO OC precursors that unlike MOs are epigenetically preconditioned to ignore TNF-mediated signalling. In RA, this epigenetic preconditioning occurs in the MO compartment providing a pathological consequence of failure of this pathway.
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Affiliation(s)
- Cecilia Ansalone
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - John Cole
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Sabarinadh Chilaka
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Flavia Sunzini
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Shatakshi Sood
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Jamie Robertson
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Stefan Siebert
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Iain B McInnes
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Carl S Goodyear
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
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Sun K, Zhu J, Deng Y, Xu X, Kong F, Sun X, Huan L, Ren C, Sun J, Shi J. Gamabufotalin Inhibits Osteoclastgenesis and Counteracts Estrogen-Deficient Bone Loss in Mice by Suppressing RANKL-Induced NF-κB and ERK/MAPK Pathways. Front Pharmacol 2021; 12:629968. [PMID: 33967763 PMCID: PMC8104077 DOI: 10.3389/fphar.2021.629968] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 02/04/2021] [Indexed: 11/25/2022] Open
Abstract
Osteolytic bone disease is a condition of imbalanced bone homeostasis, characterized mainly by excessive bone-resorptive activity, which could predispose these populations, such as the old and postmenopausal women, to developing high risk of skeletal fragility and fracture. The nature of bone homeostasis is the coordination between the osteoblasts (OBs) and osteoclasts (OCs). Abnormal activation of osteoclasts (OCs) could compromise the bone homeostasis, constantly followed by a clutch of osteolytic diseases, including postmenopausal osteoporosis, osteoarthritis, and rheumatoid arthritis. Thus, it is imperatively urgent to explore effective medical interventions for patients. The traditional Chinese medicine (TCM) gamabufotalin (CS-6) is a newly identified natural product from Chansu and has been utilized for oncologic therapies owing to its good clinical efficacy with less adverse events. Previous study suggested that CS-6 could be a novel anti-osteoporotic agent. Nevertheless, whether CS-6 suppresses RANK-(receptor activator of nuclear factor-κ B ligand)/TRAF6 (TNF receptor-associated factor 6)-mediated downstream signaling activation in OCs, as well as the effects of CS-6 on OC differentiation in vivo, remains elusive. Therefore, in this present study, we aimed to explore the biological effects of CS-6 on osteoclastogenesis and RANKL-induced activation of related signaling pathways, and further to examine the potential therapeutic application in estrogen-deficient bone loss in the mice model. The results of in vitro experiment showed that CS-6 can inhibit RANKL-induced OC formation and the ability of bone resorption in a dose-dependent manner at both the early and late stages of osteoclastogenesis. The gene expression of OC-related key genes such as tartrate-resistant acid phosphatase (TRAP), CTSK, DC-STAMP, MMP9, and β3 integrin was evidently reduced. In addition, CS-6 could mitigate the systemic estrogen-dependent bone loss and pro-inframammary cytokines in mice in vivo. The molecular mechanism analysis suggested that CS-6 can suppress RANKL/TRAF6-induced early activation of NF-κB and ERK/MAPK signaling pathways, which consequently suppressed the transcription activity of c-Fos and NFATc1. Taken together, this present study provided ample evidence that CS-6 has the promise to become a therapeutic candidate in treating osteolytic conditions mediated by elevated OC formation and bone resorption.
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Affiliation(s)
- Kaiqiang Sun
- Department of Spine Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jian Zhu
- Department of Spine Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yi Deng
- Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Ximing Xu
- Department of Spine Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Fanqi Kong
- Department of Spine Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiaofei Sun
- Department of Spine Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Le Huan
- Department of Spine Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Changzhen Ren
- Department of Cardiology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jingchuan Sun
- Department of Spine Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jiangang Shi
- Department of Spine Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
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21
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Liu Y, Shan H, Zong Y, Lin Y, Xia W, Wang N, Zhou L, Gao Y, Ma X, Jiang C, Yu X. IKKe in osteoclast inhibits the progression of methylprednisolone-induced osteonecrosis. Int J Biol Sci 2021; 17:1353-1360. [PMID: 33867851 PMCID: PMC8040464 DOI: 10.7150/ijbs.57962] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/14/2021] [Indexed: 11/15/2022] Open
Abstract
Previous studies have described that NF-κB signaling mediated by NFκB-inducing kinase (NIK) plays a critical role of the differentiation of osteoclasts. We aim to explore the role of IKKe in methylprednisolone -induced osteonecrosis of the femoral head (ONFH). Methylprednisolone-induced ONFH mice model was successfully established, and subjected to micro computed tomography to detect the femoral head image of the mice. Bone marrow cells from experimental mice were collected and cultured. qPCR and immunoblot were performed to examine the possible signal pathways of IKKe involvement, and osteoclast-related gene expressions in IKKe+/+ and IKKe-/- cells in vitro and in vivo were examined. It was found that the levels of IKKe decreased in ONFH patients, and IKKe interacted with NIK in the NF-κB signal pathway to suppress osteoclasts via inhibiting the transcription of NIK. Furthermore, IKKe knockout promoted the osteoclastogenesis in mice model. Finally, IKKe knockout suppressed methylprednisolone-induced ONFH and pro-inflammatory responses in mice model. Our findings show a mechanism of IKKe inhibition of the progression of methylprednisolone-induced ONFH via the NIK/NF-κB pathway.
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Affiliation(s)
- Yingjie Liu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Haojie Shan
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yang Zong
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yiwei Lin
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Wenyang Xia
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Nan Wang
- Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Lihui Zhou
- Department of Orthopaedic Surgery, Xiangshan First People's Hospital, Ningbo 315700, Zhejiang, China
| | - Youshui Gao
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Xin Ma
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Chaolai Jiang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Xiaowei Yu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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22
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Hao Y, Lu C, Zhang B, Xu Z, Guo H, Zhang G. Identifying the Potential Differentially Expressed miRNAs and mRNAs in Osteonecrosis of the Femoral Head Based on Integrated Analysis. Clin Interv Aging 2021; 16:187-202. [PMID: 33542623 PMCID: PMC7851582 DOI: 10.2147/cia.s289479] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 12/22/2020] [Indexed: 12/17/2022] Open
Abstract
Purpose Osteonecrosis of the femoral head is a common disease of the hip that leads to severe pain or joint disability. We aimed to identify potential differentially expressed miRNAs and mRNAs in osteonecrosis of the femoral head. Methods The data of miRNA and mRNA were firstly downloaded from the database. Secondly, the regulatory network of miRNAs-mRNAs was constructed, followed by function annotation of mRNAs. Thirdly, an in vitro experiment was applied to validate the expression of miRNAs and targeted mRNAs. Finally, GSE123568 dataset was used for electronic validation and diagnostic analysis of targeted mRNAs. Results Several regulatory interaction pairs between miRNA and mRNAs were identified, such as hsa-miR-378c-WNT3A/DACT1/CSF1, hsa-let-7a-5p-RCAN2/IL9R, hsa-miR-28-5p-RELA, hsa-miR-3200-5p-RELN, and hsa-miR-532-5p-CLDN18/CLDN10. Interestingly, CLDN10, CLDN18, CSF1, DACT1, IL9R, RCAN2, RELN, and WNT3A had the diagnostic value for osteonecrosis of the femoral head. Wnt signaling pathway (involved WNT3A), chemokine signaling pathway (involved RELA), focal adhesion and ECM-receptor interaction (involved RELN), cell adhesion molecules (CAMs) (involved CLDN18 and CLDN10), cytokine-cytokine receptor interaction, and hematopoietic cell lineage (involved CSF1 and IL9R) were identified. Conclusion The identified differentially expressed miRNAs and mRNAs may be involved in the pathology of osteonecrosis of the femoral head.
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Affiliation(s)
- Yangquan Hao
- Department of Osteonecrosis and Joint Reconstruction, Honghui Hospital Xian Jiao Tong University Health Science Center, Xian, Shaanxi 710068, People's Republic of China
| | - Chao Lu
- Department of Osteonecrosis and Joint Reconstruction, Honghui Hospital Xian Jiao Tong University Health Science Center, Xian, Shaanxi 710068, People's Republic of China
| | - Baogang Zhang
- Department of Osteonecrosis and Joint Reconstruction, Honghui Hospital Xian Jiao Tong University Health Science Center, Xian, Shaanxi 710068, People's Republic of China
| | - Zhaochen Xu
- Department of Osteonecrosis and Joint Reconstruction, Honghui Hospital Xian Jiao Tong University Health Science Center, Xian, Shaanxi 710068, People's Republic of China
| | - Hao Guo
- Department of Osteonecrosis and Joint Reconstruction, Honghui Hospital Xian Jiao Tong University Health Science Center, Xian, Shaanxi 710068, People's Republic of China
| | - Gaokui Zhang
- Department of Osteonecrosis and Joint Reconstruction, Honghui Hospital Xian Jiao Tong University Health Science Center, Xian, Shaanxi 710068, People's Republic of China
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23
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Jeong S, Seong JH, Kang JH, Lee DS, Yim M. Dynamin-related protein 1 positively regulates osteoclast differentiation and bone loss. FEBS Lett 2020; 595:58-67. [PMID: 33084048 DOI: 10.1002/1873-3468.13963] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 09/28/2020] [Accepted: 10/04/2020] [Indexed: 01/14/2023]
Abstract
Dynamin-related protein 1 (DRP1) is a mitochondrial membrane GTPase and regulates mitochondrial fission. In this study, we found that the cytokine RANKL increased the expression of DRP1 and its receptor proteins, Fis1, Mid49, and Mid 51, during osteoclast formation in mouse bone marrow-derived macrophages. Inactivation of the kinase GSK3β appeared to induce DRP1 expression. DRP1 knockdown or the DRP1 inhibitor Mdivi1 suppressed osteoclast differentiation via downregulation of c-Fos and NFATc1, the key transcription factor for osteoclast formation. Finally, the DRP1 inhibitor suppressed lipopolysaccharide-induced osteoclast formation in a calvarial model and ovariectomy-induced bone loss in vivo. Taken together, our data demonstrate that DRP1 positively contributes to RANKL-induced osteoclast differentiation by regulating the c-Fos-NFATc1 axis, suggesting the importance of mitochondrial DRP1 in osteoclastogenesis.
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Affiliation(s)
- Sol Jeong
- College of Pharmacy, Sookmyung Women's University, Seoul, Korea
| | - Ji Hye Seong
- College of Pharmacy, Sookmyung Women's University, Seoul, Korea
| | - Ju-Hee Kang
- College of Pharmacy, Sookmyung Women's University, Seoul, Korea
| | - Dong-Seok Lee
- College of Natural Sciences, Kyungpook National University, Daegu, Korea
| | - Mijung Yim
- College of Pharmacy, Sookmyung Women's University, Seoul, Korea
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24
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Wang J, Wang B, Lv X, Wang L. NIK inhibitor impairs chronic periodontitis via suppressing non-canonical NF-κB and osteoclastogenesis. Pathog Dis 2020; 78:ftaa045. [PMID: 32860691 DOI: 10.1093/femspd/ftaa045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 08/26/2020] [Indexed: 12/19/2022] Open
Abstract
Periodontitis is an inflammatory disease that causes damages to periodontium and alveolar bone. Overactivation and formation of osteoclasts can cause bone destruction, which contributes to periodontitis development. Receptor activator of nuclear factor κB ligand (RANKL)-mediated NF-κB signaling plays an essential role in osteoclasts differentiation. We aimed to study the effects of NIK-SMI1, an NF-κB-inducing kinase (NIK) inhibitor, on the osteoclastogenesis in vitro and periodontitis progression in vivo. A ligature-induced mice model of periodontitis was incorporated to test the potential therapeutic effect of NIK-SMI1 on periodontitis. The target protein and mRNA expression levels were determined by Western blot assay and real-time PCR assay, respectively. We found that the administration of NIK-SMI1 strongly inhibited the RANKL-stimulated non-canonical NF-κB signaling as demonstrated by decreased nuclear p52 expression and activity. Blocking NIK activity also resulted in reduced osteoclasts specific genes expression and enhanced IFN-β expression. NIK-SMI1 treatment resulted in attenuated periodontitis progression and pro-inflammatory cytokines expression in vivo. Our study suggested that NIK-SMI1 exerts beneficial effects on the mitigation of osteoclastogenesis in vitro and periodontitis progression in vivo. Application of NIK-SMI1 may serve as a potential therapeutic approach for periodontitis.
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Affiliation(s)
- Jiang Wang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of General Dentistry and Emergency, The Hospital of Stomatology, The Fourth Military Medical University, Shaanxi 710000, China
| | - Bo Wang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Digital Center, The Hospital of Stomatology, The Fourth Military Medical University, Shaanxi 710000, China
| | - Xin Lv
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of General Dentistry and Emergency, The Hospital of Stomatology, The Fourth Military Medical University, Shaanxi 710000, China
| | - Lei Wang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, The Hospital of Stomatology, The Fourth Military Medical University, Shaanxi 710000, China
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25
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Eluard B, Thieblemont C, Baud V. NF-κB in the New Era of Cancer Therapy. Trends Cancer 2020; 6:677-687. [DOI: 10.1016/j.trecan.2020.04.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/13/2020] [Accepted: 04/16/2020] [Indexed: 01/06/2023]
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26
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Ballard A, Zeng R, Zarei A, Shao C, Cox L, Yan H, Franco A, Dorn GW, Faccio R, Veis DJ. The tethering function of mitofusin2 controls osteoclast differentiation by modulating the Ca 2+-NFATc1 axis. J Biol Chem 2020; 295:6629-6640. [PMID: 32165499 DOI: 10.1074/jbc.ra119.012023] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 03/06/2020] [Indexed: 12/16/2022] Open
Abstract
Dynamic regulation of the mitochondrial network by mitofusins (MFNs) modulates energy production, cell survival, and many intracellular signaling events, including calcium handling. However, the relative importance of specific mitochondrial functions and their dependence on MFNs vary greatly among cell types. Osteoclasts have many mitochondria, and increased mitochondrial biogenesis and oxidative phosphorylation enhance bone resorption, but little is known about the mitochondrial network or MFNs in osteoclasts. Because expression of each MFN isoform increases with osteoclastogenesis, we conditionally deleted MFN1 and MFN2 (double conditional KO (dcKO)) in murine osteoclast precursors, finding that this increased bone mass in young female mice and abolished osteoclast precursor differentiation into mature osteoclasts in vitro Defective osteoclastogenesis was reversed by overexpression of MFN2 but not MFN1; therefore, we generated mice lacking only MFN2 in osteoclasts. MFN2-deficient female mice had increased bone mass at 1 year and resistance to Receptor Activator of NF-κB Ligand (RANKL)-induced osteolysis at 8 weeks. To explore whether MFN-mediated tethering or mitophagy is important for osteoclastogenesis, we overexpressed MFN2 variants defective in either function in dcKO precursors and found that, although mitophagy was dispensable for differentiation, tethering was required. Because the master osteoclastogenic transcriptional regulator nuclear factor of activated T cells 1 (NFATc1) is calcium-regulated, we assessed calcium release from the endoplasmic reticulum and store-operated calcium entry and found that the latter was blunted in dcKO cells. Restored osteoclast differentiation by expression of intact MFN2 or the mitophagy-defective variant was associated with normalization of store-operated calcium entry and NFATc1 levels, indicating that MFN2 controls mitochondrion-endoplasmic reticulum tethering in osteoclasts.
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Affiliation(s)
- Anna Ballard
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.,Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Rong Zeng
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.,Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Allahdad Zarei
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.,Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Christine Shao
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.,Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Linda Cox
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.,Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Hui Yan
- Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri 63110.,Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110.,Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China
| | - Antonietta Franco
- Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Gerald W Dorn
- Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Roberta Faccio
- Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri 63110.,Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110.,Shriners Hospitals for Children, St. Louis, Missouri 63110
| | - Deborah J Veis
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 .,Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri 63110.,Shriners Hospitals for Children, St. Louis, Missouri 63110.,Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110
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27
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NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium. Sci Rep 2020; 10:4316. [PMID: 32152480 PMCID: PMC7062729 DOI: 10.1038/s41598-020-61331-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 02/07/2020] [Indexed: 12/07/2022] Open
Abstract
This study sought to evaluate the association of 28 single nucleotide polymorphisms (SNPs) within NFKB and inflammasome pathway genes with the risk of rheumatoid arthritis (RA) and response to TNF inhibitors (TNFi). We conducted a case-control study in a European population of 1194 RA patients and 1328 healthy controls. The association of potentially interesting markers was validated with data from the DANBIO (695 RA patients and 978 healthy controls) and DREAM (882 RA patients) registries. The meta-analysis of our data with those from the DANBIO registry confirmed that anti-citrullinated protein antibodies (ACPA)-positive subjects carrying the NFKB2rs11574851T allele had a significantly increased risk of developing RA (PMeta_ACPA + = 0.0006) whereas no significant effect was found in ACPA-negative individuals (PMeta_ACPA- = 0.35). An ACPA-stratified haplotype analysis including both cohorts (n = 4210) confirmed that ACPA-positive subjects carrying the NFKB2TT haplotype had an increased risk of RA (OR = 1.39, P = 0.0042) whereas no effect was found in ACPA-negative subjects (OR = 1.04, P = 0.82). The meta-analysis of our data with those from the DANBIO and DREAM registries also revealed a suggestive association of the NFKB2rs1056890 SNP with larger changes in DAS28 (OR = 1.18, P = 0.007). Functional experiments showed that peripheral blood mononuclear cells from carriers of the NFKB2rs1005044C allele (in LD with the rs1056890, r2 = 1.00) showed increased production of IL10 after stimulation with LPS (P = 0.0026). These results provide first evidence of a role of the NFKB2 locus in modulating the risk of RA in an ACPA-dependent manner and suggest its implication in determining the response to TNFi. Additional studies are now warranted to further validate these findings.
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28
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Zhao B. Intrinsic Restriction of TNF-Mediated Inflammatory Osteoclastogenesis and Bone Resorption. Front Endocrinol (Lausanne) 2020; 11:583561. [PMID: 33133025 PMCID: PMC7578415 DOI: 10.3389/fendo.2020.583561] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/24/2020] [Indexed: 11/13/2022] Open
Abstract
TNF (Tumor necrosis factor) is a pleiotropic cytokine that plays an important role in immunity and inflammatory bone destruction. Homeostatic osteoclastogenesis is effectively induced by RANKL (Receptor activator of nuclear factor kappa-B ligand). In contrast, TNF often acts on cell types other than osteoclasts, or synergically with RANKL to indirectly promote osteoclastogenesis and bone resorption. TNF and RANKL are members of the TNF superfamily. However, the direct osteoclastogenic capacity of TNF is much weaker than that of RANKL. Recent studies have uncovered key intrinsic mechanisms by which TNF acts on osteoclast precursors to restrain osteoclastogenesis, including the mechanisms mediated by RBP-J signaling, RBP-J and ITAM (Immunoreceptor tyrosine-based activation motif) crosstalk, RBP-J mediated regulatory network, NF-κB p100, IRF8, and Def6. Some of these mechanisms, such as RBP-J and its mediated regulatory network, uniquely and predominantly limit osteoclastogenesis mediated by TNF but not by RANKL. As a consequence, targeting RBP-J activities suppresses inflammatory bone destruction but does not significantly impact normal bone remodeling or inflammation. Hence, discovery of these intrinsic inhibitory mechanisms addresses why TNF has a weak osteoclastogenic potential, explains a significant difference between RANKL and TNF signaling, and provides potentially new or complementary therapeutic strategies to selectively treat inflammatory bone resorption, without undesirable effects on normal bone remodeling or immune response in disease settings.
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Affiliation(s)
- Baohong Zhao
- Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, United States
- Graduate Program in Biochemistry, Cell and Molecular Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
- *Correspondence: Baohong Zhao,
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29
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Jimi E, Takakura N, Hiura F, Nakamura I, Hirata-Tsuchiya S. The Role of NF-κB in Physiological Bone Development and Inflammatory Bone Diseases: Is NF-κB Inhibition "Killing Two Birds with One Stone"? Cells 2019; 8:cells8121636. [PMID: 31847314 PMCID: PMC6952937 DOI: 10.3390/cells8121636] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/11/2019] [Accepted: 12/11/2019] [Indexed: 12/14/2022] Open
Abstract
Nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of various genes involved in inflammation and the immune response. The activation of NF-κB occurs via two pathways: inflammatory cytokines, such as TNF-α and IL-1β, activate the "classical pathway", and cytokines involved in lymph node formation, such as CD40L, activate the "alternative pathway". NF-κB1 (p50) and NF-κB2 (p52) double-knockout mice exhibited severe osteopetrosis due to the total lack of osteoclasts, suggesting that NF-κB activation is required for osteoclast differentiation. These results indicate that NF-κB may be a therapeutic target for inflammatory bone diseases, such as rheumatoid arthritis and periodontal disease. On the other hand, mice that express the dominant negative form of IκB kinase (IKK)-β specifically in osteoblasts exhibited increased bone mass, but there was no change in osteoclast numbers. Therefore, inhibition of NF-κB is thought to promote bone formation. Taken together, the inhibition of NF-κB leads to "killing two birds with one stone": it suppresses bone resorption and promotes bone formation. This review describes the role of NF-κB in physiological bone metabolism, pathologic bone destruction, and bone regeneration.
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Affiliation(s)
- Eijiro Jimi
- Oral Health/Brain Health/Total Health Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; (N.T.); (F.H.)
- Correspondence: ; Tel.: 81-92-642-6332
| | - Nana Takakura
- Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; (N.T.); (F.H.)
| | - Fumitaka Hiura
- Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; (N.T.); (F.H.)
| | - Ichiro Nakamura
- Faculty of Health and Medical Science, Teikyo Heisei University, 2-51-4 Higashi-Ikebukuro, Toshima, Tokyo 170-8445, Japan;
| | - Shizu Hirata-Tsuchiya
- Department of Biological Endodontics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan;
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30
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The endocannabinoid system: Novel targets for treating cancer induced bone pain. Biomed Pharmacother 2019; 120:109504. [PMID: 31627091 DOI: 10.1016/j.biopha.2019.109504] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/16/2019] [Accepted: 09/26/2019] [Indexed: 02/08/2023] Open
Abstract
Treating Cancer-induced bone pain (CIBP) continues to be a major clinical challenge and underlying mechanisms of CIBP remain unclear. Recently, emerging body of evidence suggested the endocannabinoid system (ECS) may play essential roles in CIBP. Here, we summarized the current understanding of the antinociceptive mechanisms of endocannabinoids in CIBP and discussed the beneficial effects of endocannabinoid for CIBP treatment. Targeting non-selective cannabinoid 1 receptors or selective cannabinoid 2 receptors, and modulation of peripheral AEA and 2-AG, as well as the inhibition the function of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have produced analgesic effects in animal models of CIBP. Management of ECS therefore appears to be a promising way for the treatment of CIBP in terms of efficacy and safety. Further clinical studies are encouraged to confirm the possible translation to humans of the very promising results already obtained in the preclinical studies.
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Abstract
The inflammation of bone tissue is called osteomyelitis, and most cases are caused by an infection with the bacterium Staphylococcus aureus. To date, the bone-building cells, osteoblasts, have been implicated in the progression of these infections, but not much is known about how the bone-resorbing cells, osteoclasts, participate. In this study, we show that S. aureus can infect osteoclasts and proliferate inside these cells, whereas bone-residing macrophages, immune cells related to osteoclasts, destroy the bacteria. These findings elucidate a unique role for osteoclasts to harbor bacteria during infection, providing a possible mechanism by which bacteria could evade destruction by the immune system. Osteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. OM is predominantly caused by Staphylococcus aureus, and even with proper treatment, OM has a high rate of recurrence and chronicity. While S. aureus has been shown to infect osteoblasts, it remains unclear whether osteoclasts (OCs) are also a target of intracellular infection. Here, we demonstrate the ability of S. aureus to intracellularly infect and divide within OCs. OCs were differentiated from bone marrow macrophages (BMMs) by exposure to receptor activator of nuclear factor kappa-B ligand (RANKL). By utilizing an intracellular survival assay and flow cytometry, we found that at 18 h postinfection the intracellular burden of S. aureus increased dramatically in cells with at least 2 days of RANKL exposure, while the bacterial burden decreased in BMMs. To further explore the signals downstream of RANKL, we manipulated factors controlling OC differentiation, NFATc1 and alternative NF-κB, and found that intracellular bacterial growth correlates with NFATc1 levels in RANKL-treated cells. Confocal and time-lapse microscopy in mature OCs showed a range of intracellular infection that correlated inversely with S. aureus-phagolysosome colocalization. The propensity of OCs to become infected, paired with their diminished bactericidal capacity compared to BMMs, could promote OM progression by allowing S. aureus to evade initial immune regulation and proliferate at the periphery of lesions where OCs are most abundant.
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Abstract
Chronic inflammation is one of the most evident and common pathological conditions leading to deregulated osteoclastogenesis and bone remodeling. Tumor necrosis factor (TNF) as a pleiotropic cytokine plays a key role, not only in inflammation, but also in bone erosion in diseases associated with bone loss. TNF can stimulate the proliferation of osteoclast precursors and, in most conditions, act together with other cytokines and growth factors such as receptor activator of nuclear factor (NF)-[kappa]B ligand (RANKL), interleukin-6, and transforming growth factor beta to synergistically promote osteoclast formation and bone resorption in vivo. A longstanding enigma in the field is why TNF alone is not able to induce osteoclast differentiation as effectively as the same superfamily member RANKL, a physiological master osteoclastogenic cytokine. Recent studies have highlighted several lines of evidence showing the intrinsic mechanisms through RBP-J, NF-[kappa]B p100/TNF receptor-associated factor 3, or interferon regulatory factor-8 that restrain TNF-induced osteoclast differentiation and bone resorption. These feedback inhibitory mechanisms driven by TNF shed light into the current paradigm of osteoclastogenesis and would provide novel therapeutic implications on controlling inflammatory bone resorption.
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Affiliation(s)
- Baohong Zhao
- Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, Graduate Program in Biochemistry, Cell and Molecular Biology, Weill Cornell Graduate School of Medical Sciences, and Department of Medicine, Weill Cornell Medical College, 535 E. 70th Street New York, New York 10021
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33
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Gupta AS, Biswas DD, Brown LSN, Mockenhaupt K, Marone M, Hoskins A, Siebenlist U, Kordula T. A detrimental role of RelB in mature oligodendrocytes during experimental acute encephalomyelitis. J Neuroinflammation 2019; 16:161. [PMID: 31362762 PMCID: PMC6664766 DOI: 10.1186/s12974-019-1548-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 07/17/2019] [Indexed: 12/31/2022] Open
Abstract
Background Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). It is firmly established that overactivation of the p65 (RelA) nuclear factor kappa B (NF-κB) transcription factor upregulates expression of inflammatory mediators in both immune and non-immune resident CNS cells and promotes inflammation during MS. In contrast to p65, NF-κB family member RelB regulates immune cell development and can limit inflammation. Although RelB expression is induced during inflammation in the CNS, its role in MS remains unknown. Methods To examine the role of RelB in non-immune CNS cells, we generated mice with RelB specifically deleted in astrocytes (RelBΔAST), oligodendrocytes (RelBΔOLIGO), or neural progenitor-derived cells (RelBΔNP). We used experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS, to assess the effect of RelB deletion on disease outcomes and performed analysis on the histological, cellular, and molecular level. Results Despite being a negative regulator of inflammation, conditional knockout of RelB in non-immune resident CNS cells surprisingly decreased the severity of EAE. This protective effect was recapitulated by conditional deletion of RelB in oligodendrocytes but not astrocytes. Deletion of RelB in oligodendrocytes reduced disease severity, promoted survival of mature oligodendrocytes, and correlated with increased activation of p65 NF-κB. Conclusions These findings suggest that RelB fine tunes inflammation and cell death/survival during EAE. Importantly, our data points out the detrimental role RelB plays in controlling survival of mature oligodendrocytes, which could be explored as a viable option to treat MS in the future. Electronic supplementary material The online version of this article (10.1186/s12974-019-1548-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Angela S Gupta
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, VA, 23298, USA
| | - Debolina D Biswas
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, VA, 23298, USA
| | - La Shardai N Brown
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, VA, 23298, USA
| | - Karli Mockenhaupt
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, VA, 23298, USA
| | - Michael Marone
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, VA, 23298, USA
| | - Andrew Hoskins
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, VA, 23298, USA
| | - Ulrich Siebenlist
- Laboratory of Molecular Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tomasz Kordula
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, VA, 23298, USA.
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Chatterjee B, Roy P, Sarkar UA, Zhao M, Ratra Y, Singh A, Chawla M, De S, Gomes J, Sen R, Basak S. Immune Differentiation Regulator p100 Tunes NF-κB Responses to TNF. Front Immunol 2019; 10:997. [PMID: 31134075 PMCID: PMC6514058 DOI: 10.3389/fimmu.2019.00997] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/18/2019] [Indexed: 11/14/2022] Open
Abstract
Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating inflammatory and adaptive immune responses. However, uncontrolled TNF signaling causes aberrant inflammation and has been implicated in several human ailments. Therefore, an understanding of the molecular mechanisms underlying dynamical and gene controls of TNF signaling bear significance for human health. As such, TNF engages the canonical nuclear factor kappa B (NF-κB) pathway to activate RelA:p50 heterodimers, which induce expression of specific immune response genes. Brief and chronic TNF stimulation produces transient and long-lasting NF-κB activities, respectively. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to short-lived TNF signals. The non-canonical NF-κB pathway mediates RelB activity during immune differentiation involving p100. We uncovered an unexpected role of p100 in TNF signaling. Brief TNF stimulation of p100-deficient cells triggered an additional late NF-κB activity consisting of RelB:p50 heterodimers, which modified the TNF-induced gene-expression program. In p100-deficient cells subjected to brief TNF stimulation, RelB:p50 not only sustained the expression of a subset of RelA-target immune response genes but also activated additional genes that were not normally induced by TNF in WT mouse embryonic fibroblasts (MEFs) and were related to immune differentiation and metabolic processes. Despite this RelB-mediated distinct gene control, however, RelA and RelB bound to mostly overlapping chromatin sites in p100-deficient cells. Repeated TNF pulses strengthened this RelB:p50 activity, which was supported by NF-κB-driven RelB synthesis. Finally, brief TNF stimulation elicited late-acting expressions of NF-κB target pro-survival genes in p100-deficient myeloma cells. In sum, our study suggests that the immune-differentiation regulator p100 enforces specificity of TNF signaling and that varied p100 levels may provide for modifying TNF responses in diverse physiological and pathological settings.
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Affiliation(s)
- Budhaditya Chatterjee
- Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.,Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India
| | - Payel Roy
- Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India
| | - Uday Aditya Sarkar
- Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India
| | - Mingming Zhao
- Gene Regulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD, United States
| | - Yashika Ratra
- Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India
| | - Amit Singh
- Gene Regulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD, United States
| | - Meenakshi Chawla
- Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India
| | - Supriyo De
- Laboratory of Genetics and Genomics, National Institute on Aging, Baltimore, MD, United States
| | - James Gomes
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India
| | - Ranjan Sen
- Gene Regulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD, United States
| | - Soumen Basak
- Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India
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Nakatomi C, Nakatomi M, Matsubara T, Komori T, Doi-Inoue T, Ishimaru N, Weih F, Iwamoto T, Matsuda M, Kokabu S, Jimi E. Constitutive activation of the alternative NF-κB pathway disturbs endochondral ossification. Bone 2019; 121:29-41. [PMID: 30611922 DOI: 10.1016/j.bone.2019.01.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/28/2018] [Accepted: 01/02/2019] [Indexed: 01/29/2023]
Abstract
Endochondral ossification is important for skeletal development. Recent findings indicate that the p65 (RelA) subunit, a main subunit of the classical nuclear factor-κB (NF-κB) pathway, plays essential roles in chondrocyte differentiation. Although several groups have reported that the alternative NF-κB pathway also regulates bone homeostasis, the role of the alternative NF-κB pathway in chondrocyte development is still unclear. Here, we analyzed the in vivo function of the alternative pathway on endochondral ossification using p100-deficient (p100-/-) mice, which carry a homozygous deletion of the COOH-terminal ankyrin repeats of p100 but still express functional p52 protein. The alternative pathway was activated during the periarticular stage in wild-type mice. p100-/- mice exhibited dwarfism, and histological analysis of the growth plate revealed abnormal arrangement of chondrocyte columns and a narrowed hypertrophic zone. Consistent with these observations, the expression of hypertrophic chondrocyte markers, type X collagen (ColX) or matrix metalloproteinase 13, but not early chondrogenic markers, such as Col II or aggrecan, was suppressed in p100-/- mice. An in vivo BrdU tracing assay clearly demonstrated less proliferative activity in chondrocytes in p100-/- mice. These defects were partly rescued when the RelB gene was deleted in p100-/- mice. Taken together, the alternative NF-κB pathway may regulate chondrocyte proliferation and differentiation to maintain endochondral ossification.
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Affiliation(s)
- Chihiro Nakatomi
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-kux, Kitakyushu 803-8580, Japan
| | - Mitsushiro Nakatomi
- Division of Anatomy, Department of Health Improvement, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580, Japan
| | - Takuma Matsubara
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-kux, Kitakyushu 803-8580, Japan
| | - Toshihisa Komori
- Department of Cell Biology, Unit of Basic Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan
| | | | - Naozumi Ishimaru
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima 770-8504, Japan
| | - Falk Weih
- Research Group Immunology, Leibniz-Institute on Aging - Fritz Lipmann Institute, Beutenbergstrasse 11, Jena 07745, Germany
| | - Tsutomu Iwamoto
- Department of Pediatric Dentistry, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima 770-8504, Japan
| | - Miho Matsuda
- Laboratory of Molecular and Cellular Biochemistry, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Shoichiro Kokabu
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-kux, Kitakyushu 803-8580, Japan
| | - Eijiro Jimi
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-kux, Kitakyushu 803-8580, Japan; Laboratory of Molecular and Cellular Biochemistry, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Oral Health/Brain Health/Total Health Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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36
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Meloni L, Verstrepen L, Kreike M, Staal J, Driege Y, Afonina IS, Beyaert R. Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function. Molecules 2018; 23:molecules23123144. [PMID: 30513612 PMCID: PMC6320945 DOI: 10.3390/molecules23123144] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 11/23/2018] [Accepted: 11/27/2018] [Indexed: 12/26/2022] Open
Abstract
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular cysteine protease (paracaspase) that plays an integral role in innate and adaptive immunity. The phenothiazine mepazine has been shown to inhibit the proteolytic activity of MALT1 and is frequently used to study its biological role. MALT1 has recently been suggested as a therapeutic target in rheumatoid arthritis. Here, we analyzed the effect of mepazine on the receptor activator of nuclear factor κ-B (RANK)-induced osteoclastogenesis. The treatment of mouse bone marrow precursor cells with mepazine strongly inhibited the RANK ligand (RANKL)-induced formation of osteoclasts, as well as the expression of several osteoclast markers, such as TRAP, cathepsin K, and calcitonin. However, RANKL induced osteoclastogenesis equally well in bone marrow cells derived from wild-type and Malt1 knock-out mice. Furthermore, the protective effect of mepazine was not affected by MALT1 deficiency. Additionally, the absence of MALT1 did not affect RANK-induced nuclear factor κB (NF-κB) and activator protein 1 (AP-1) activation. Overall, these studies demonstrate that MALT1 is not essential for RANK-induced osteoclastogenesis, and implicate a MALT1-independent mechanism of action of mepazine that should be taken into account in future studies using this compound.
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Affiliation(s)
- Laura Meloni
- Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
| | - Lynn Verstrepen
- Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
| | - Marja Kreike
- Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
| | - Jens Staal
- Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
| | - Yasmine Driege
- Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
| | - Inna S Afonina
- Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
| | - Rudi Beyaert
- Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
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He YQ, Zhang Q, Shen Y, Han T, Zhang QL, Zhang JH, Lin B, Song HT, Hsu HY, Qin LP, Xin HL, Zhang QY. Rubiadin-1-methyl ether from Morinda officinalis How. Inhibits osteoclastogenesis through blocking RANKL-induced NF-κB pathway. Biochem Biophys Res Commun 2018; 506:927-931. [PMID: 30392907 DOI: 10.1016/j.bbrc.2018.10.100] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 10/16/2018] [Indexed: 12/14/2022]
Abstract
Rubiadin-1-methyl ether (RBM) is a natural anthraquinone compound isolated from the root of Morinda officinalis How. In our previous study, RBM was found to have inhibitory effects on the TRAP activity of osteoclasts, which means that RBM may be a candidate for therapy of bone diseases characterized by enhanced bone resorption. However, the further effect of RBM on osteoclasts and the underlying mechanism remain unclear. In the present study, we investigated the effects of RBM isolated from Morinda officinalis How. on osteoclasts derived from bone marrow macrophages (BMMs) and the underlying mechanism in vitro. RBM at the dose that did not affect the viability of cells significantly inhibited RANKL-induced osteoclastogenesis and actin ring formation of osteoclast, while RBM performed a stronger effect at the early stage. In addition, RBM downregulated the expression of osteoclast-related proteins, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), cellular oncogene Fos (c-Fos), matrix metallopeptidase 9 (MMP-9) and cathepsin K (CtsK) as shown by Western blot. Furthermore, RBM inhibited the phosphorylation of NF-κB p65 and the degradation of IκBα as well as decreased the nuclear translocation of p65. Collectively, the results suggest that RBM inhibit osteoclastic bone resorption through blocking NF-κB pathway and may be a promising agent for the prevention and treatment of bone diseases characterized by excessive bone resorption.
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Affiliation(s)
- Yu-Qiong He
- Department of Pharmacognosy, Second Military Medical University School of Pharmacy, Shanghai, 200433, China; College of Pharmaceutical science, Zhejiang Chinese Medical University, Hangzhou, 311402, China
| | - Qi Zhang
- School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China
| | - Yi Shen
- School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China
| | - Ting Han
- Department of Pharmacognosy, Second Military Medical University School of Pharmacy, Shanghai, 200433, China
| | - Quan-Long Zhang
- College of Pharmaceutical science, Zhejiang Chinese Medical University, Hangzhou, 311402, China
| | - Jian-Hua Zhang
- Department of Pharmacognosy, Second Military Medical University School of Pharmacy, Shanghai, 200433, China
| | - Bing Lin
- Fuzhou General Hospital of Nanjing Military Region, Fuzhou, 350025, China
| | - Hong-Tao Song
- Fuzhou General Hospital of Nanjing Military Region, Fuzhou, 350025, China
| | - Hsien-Yeh Hsu
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Lu-Ping Qin
- Department of Pharmacognosy, Second Military Medical University School of Pharmacy, Shanghai, 200433, China; College of Pharmaceutical science, Zhejiang Chinese Medical University, Hangzhou, 311402, China.
| | - Hai-Liang Xin
- Department of Pharmacognosy, Second Military Medical University School of Pharmacy, Shanghai, 200433, China.
| | - Qiao-Yan Zhang
- Department of Pharmacognosy, Second Military Medical University School of Pharmacy, Shanghai, 200433, China; College of Pharmaceutical science, Zhejiang Chinese Medical University, Hangzhou, 311402, China.
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38
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Zarei A, Yang C, Gibbs J, Davis JL, Ballard A, Zeng R, Cox L, Veis DJ. Manipulation of the Alternative NF-κB Pathway in Mice Has Sexually Dimorphic Effects on Bone. JBMR Plus 2018; 3:14-22. [PMID: 30680359 PMCID: PMC6339559 DOI: 10.1002/jbm4.10066] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 05/21/2018] [Accepted: 06/08/2018] [Indexed: 12/26/2022] Open
Abstract
Alternative NF‐κB signaling promotes osteoclastogenesis and pathological bone loss, but the effect of sex on phenotype has not been explored. We disrupted alternative NF‐κB signaling by deletion of upstream kinase NF‐κB‐inducing kinase (NIK) or NF‐κB subunit RelB and found that both NIK‐deficient and RelB‐deficient female mice possessed more than twofold higher trabecular bone mass compared to controls, whereas no differences were observed in males. In vitro, RelB‐deficient precursors from female mice showed a more severe osteoclast (OC) differentiation defect than male, while WT had no sex bias. Next, we asked whether pharmacologic activation of alternative NF‐κB by inhibitor of apoptosis (IAP) antagonist BV6 has sex‐dependent effects on bone. Unlike male mice that lost bone, female mice on BV6 for 4 weeks showed no changes in either trabecular bone mass or OC number. Because estrogen generally suppresses NF‐κB, we hypothesized that estrogen protects bone from BV6 effects in vivo. Thus, we performed ovariectomy or sham surgery in female mice, then treated with BV6 or vehicle for 4 weeks. Although ovariectomy caused bone loss, BV6 did not have any additional impact, suggesting that direct estrogen effects do not cause resistance to BV6 in vivo. The osteopenic effects of IAP antagonists in males may have implications for their use in cancer therapy. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Allahdad Zarei
- Musculoskeletal Research Center Division of Bone and Mineral Diseases Department of Medicine Washington University School of Medicine St. Louis MO USA
| | - Chang Yang
- Musculoskeletal Research Center Division of Bone and Mineral Diseases Department of Medicine Washington University School of Medicine St. Louis MO USA
| | - Jesse Gibbs
- Musculoskeletal Research Center Division of Bone and Mineral Diseases Department of Medicine Washington University School of Medicine St. Louis MO USA
| | - Jennifer L Davis
- Musculoskeletal Research Center Division of Bone and Mineral Diseases Department of Medicine Washington University School of Medicine St. Louis MO USA
| | - Anna Ballard
- Musculoskeletal Research Center Division of Bone and Mineral Diseases Department of Medicine Washington University School of Medicine St. Louis MO USA
| | - Rong Zeng
- Musculoskeletal Research Center Division of Bone and Mineral Diseases Department of Medicine Washington University School of Medicine St. Louis MO USA
| | - Linda Cox
- Musculoskeletal Research Center Division of Bone and Mineral Diseases Department of Medicine Washington University School of Medicine St. Louis MO USA
| | - Deborah J Veis
- Musculoskeletal Research Center Division of Bone and Mineral Diseases Department of Medicine Washington University School of Medicine St. Louis MO USA.,Department of Pathology and Immunology Washington University School of Medicine St. Louis MO USA
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39
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Kanaya T, Sakakibara S, Jinnohara T, Hachisuka M, Tachibana N, Hidano S, Kobayashi T, Kimura S, Iwanaga T, Nakagawa T, Katsuno T, Kato N, Akiyama T, Sato T, Williams IR, Ohno H. Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-κB signaling. J Exp Med 2018; 215:501-519. [PMID: 29339448 PMCID: PMC5789402 DOI: 10.1084/jem.20160659] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 11/05/2017] [Accepted: 12/13/2017] [Indexed: 12/31/2022] Open
Abstract
TRAF6 is essential for RANK-mediated NF-κB activation and is involved in the development of several types of cells. Kanaya et al. demonstrate that RANK–TRAF6-mediated NF-κB is essential for the development of M cells and FAE. M cells are located in the follicle-associated epithelium (FAE) that covers Peyer’s patches (PPs) and are responsible for the uptake of intestinal antigens. The differentiation of M cells is initiated by receptor activator of NF-κB. However, the intracellular pathways involved in M cell differentiation are still elusive. In this study, we demonstrate that the NF-κB pathway activated by RANK is essential for M cell differentiation using in vitro organoid culture. Overexpression of NF-κB transcription factors enhances the expression of M cell–associated molecules but is not sufficient to complete M cell differentiation. Furthermore, we evaluated the requirement for tumor necrosis factor receptor–associated factor 6 (TRAF6). Conditional deletion of TRAF6 in the intestinal epithelium causes a complete loss of M cells in PPs, resulting in impaired antigen uptake into PPs. In addition, the expression of FAE-associated genes is almost silenced in TRAF6-deficient mice. This study thus demonstrates the crucial role of TRAF6-mediated NF-κB signaling in the development of M cells and FAE.
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Affiliation(s)
- Takashi Kanaya
- Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.,Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
| | - Sayuri Sakakibara
- Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Toshi Jinnohara
- Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.,Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
| | - Masami Hachisuka
- Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.,Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
| | - Naoko Tachibana
- Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Shinya Hidano
- Department of Infectious Diseases Control, Faculty of Medicine, Oita University, Oita, Japan
| | - Takashi Kobayashi
- Department of Infectious Diseases Control, Faculty of Medicine, Oita University, Oita, Japan
| | - Shunsuke Kimura
- Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Toshihiko Iwanaga
- Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Tomoo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tatsuro Katsuno
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Taishin Akiyama
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Toshiro Sato
- Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan
| | - Ifor R Williams
- Department of Pathology, Emory University School of Medicine, Atlanta, GA
| | - Hiroshi Ohno
- Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan .,Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
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Wang Q, Liu F, Zhang M, Zhou P, Xu C, Li Y, Bian L, Liu Y, Yao Y, Wang F, Fang Y, Li D. NLRP12 Promotes Mouse Neutrophil Differentiation through Regulation of Non-canonical NF-κB and MAPK ERK1/2 Signaling. Int J Biol Sci 2018; 14:147-155. [PMID: 29483833 PMCID: PMC5821036 DOI: 10.7150/ijbs.23231] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 12/09/2017] [Indexed: 01/21/2023] Open
Abstract
Neutrophils are the most important component of the innate immune system. Mechanistic understanding of the mechanism underlying neutrophil differentiation remains elusive. Using genome-wide RNA-seq, we identified genes whose expression is dramatically up-regulated during neutrophil differentiation. Among them is nucleotide-binding leucine-rich repeat and pyrindomain-containing receptor 12 (NLRP12), which plays a role in immune inflammatory responses. Genetic ablation of NLRP12 suppresses NF-κB inducing kinase (NIK) stabilization, RelB nuclear translocation and neutrophil differentiation in vitro. At a mechanistic level, NLRP12 inhibits the activity of mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK1/2), relieves ERK1/2 suppression of NIK protein levels. Thus, NLRP12 enhances noncanonical NF-κB signaling through inhibition of ERK1/2 signaling, thereby promoting neutrophil differentiation.
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Affiliation(s)
- Qian Wang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Furao Liu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Meichao Zhang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Pingting Zhou
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ci Xu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yanyan Li
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Lei Bian
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuanhua Liu
- Department of Chemotherapy, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China
| | - Yuan Yao
- Department of Radiation Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Fei Wang
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Yong Fang
- Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Dong Li
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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41
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Wang J, Fu B, Lu F, Hu X, Tang J, Huang L. Inhibitory activity of linarin on osteoclastogenesis through receptor activator of nuclear factor κB ligand-induced NF-κB pathway. Biochem Biophys Res Commun 2017; 495:2133-2138. [PMID: 29269297 DOI: 10.1016/j.bbrc.2017.12.091] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 12/16/2017] [Indexed: 12/17/2022]
Abstract
Linarin, a natural flavonoid glycoside widely found in plants, has been reported to possess anti-inflammation, neuroprotection and osteogenic properties. However, its impact on osteoclast remains unclear. In the present study, the effects of linarin on osteoclastogenesis and its underlying molecular mechanisms of action were investigated. Using the culture systems of osteoclasts derived from bone marrow macrophages (BMMs), we found that linarin dose-dependently inhibited osteoclasts formation and bone resorptive activity. The Cell Counting Kit-8 test displayed that the viability of cells was not influenced by linarin at doses up to 10 μg/mL. In addition, linarin downregulated osteoclast-related genes expression, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAP), osteoclast-associated receptor (OSCAR) and c-Fos, as shown by quantitative real time polymerase chain reaction (RT-qPCR). Western blot analysis further showed that linarin inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced nuclear factor kappa B (NF-κB) p65 and NFATc1 activity. The present findings show that linarin exerted a potent inhibitory effect on osteoclastogenesis through RANKL-induced NF-κB signaling pathway. In conclusion, the results suggest that linarin has anti-osteoclastic effects and may serve as potential modulatory agents for the prevention and treatment of bone loss-associated diseases.
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Affiliation(s)
- Junsheng Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China; Department of Orthopaedic Surgery, Huai'an Second People's Hospital, The Affiliated Huaian Hospital of Xuzhou Medical University, Huai'an 223000, China
| | - Bin Fu
- Department of Orthopaedic Surgery, Changzhou Wujin People's Hospital, Changzhou 213100, China
| | - Fuchun Lu
- Department of Orthopaedic Surgery, Huai'an Second People's Hospital, The Affiliated Huaian Hospital of Xuzhou Medical University, Huai'an 223000, China
| | - Xiaowu Hu
- Department of Orthopaedic Surgery, Huai'an Second People's Hospital, The Affiliated Huaian Hospital of Xuzhou Medical University, Huai'an 223000, China
| | - Jinshan Tang
- Department of Orthopaedic Surgery, Huai'an Second People's Hospital, The Affiliated Huaian Hospital of Xuzhou Medical University, Huai'an 223000, China
| | - Lixin Huang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
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42
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Pang T, Gong M, Han J, Liu D. Relationship between osteoporosis and expression of Bcl-2 and CXCL12. Exp Ther Med 2017; 15:1293-1297. [PMID: 29434715 PMCID: PMC5774382 DOI: 10.3892/etm.2017.5513] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 11/02/2017] [Indexed: 01/23/2023] Open
Abstract
The changes of expression of anti-apoptotic factor B-cell lymphoma 2 (Bcl-2) and chemokine C-X-C motif ligand 12 (CXCL12) in the pathological process of osteoporosis (OP) were investigated, to provide new ideas for the diagnosis and treatment of OP. A total of 60 postmenopausal women who needed to undergo hip replacement surgery were enrolled and divided into osteoporosis group (OP, n=32) and control group (CK, n=28) according to the results of dual-energy X-ray bone density measure; after operation, cancellousbone from the femoral head or femoral neck was removed, and osteoblasts and osteoclasts were isolated and cultured in vitro. The proliferation and apoptosis in the two groups of osteoblasts and osteoclasts were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetry and Annexin V/PI double staining method, respectively. The expression levels of Bcl-2 and CXCL12 mRNA and protein in the two groups of osteoblasts and osteoclasts were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The analysis of cell proliferation and apoptosis showed that compared with the CK group, osteoblast proliferation was significantly inhibited and apoptosis rate was distinctly increased in the OP group, compared with the CK group, osteoclast proliferation was distinctly enhanced and apoptosis rate was remarkably reduced in the OP group. The results of RT-qPCR and western blot analysis displayed that Bcl-2 and CXCL12 mRNA and protein levels in osteoblasts of the OP group were significantly lower than those of the CK group, while mRNA and protein levels of Bcl-2 and CXCL12 in osteoclast of the OP group were distinctly increased compared to those in the CK group. The incidence of OP is closely associated with the bone balance maintained by osteoblasts and osteoclasts, and this mechanism may be achieved by inhibiting osteoblast proliferation and osteoclast apoptosis via regulating Bcl-2 and CXCL12 gene expression changes.
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Affiliation(s)
- Tongtao Pang
- Department of Trauma and Orthopedics, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Mingzhi Gong
- Department of Trauma and Orthopedics, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Jiangtao Han
- Department of Trauma and Orthopedics, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Dan Liu
- Department of Trauma and Orthopedics, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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Bae S, Lee MJ, Mun SH, Giannopoulou EG, Yong-Gonzalez V, Cross JR, Murata K, Giguère V, van der Meulen M, Park-Min KH. MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα. J Clin Invest 2017; 127:2555-2568. [PMID: 28530645 PMCID: PMC5490751 DOI: 10.1172/jci89935] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 03/23/2017] [Indexed: 11/17/2022] Open
Abstract
Osteoporosis is a metabolic bone disorder associated with compromised bone strength and an increased risk of fracture. Inhibition of the differentiation of bone-resorbing osteoclasts is an effective strategy for the treatment of osteoporosis. Prior work by our laboratory and others has shown that MYC promotes osteoclastogenesis in vitro, but the underlying mechanisms are not well understood. In addition, the in vivo importance of osteoclast-expressed MYC in physiological and pathological bone loss is not known. Here, we have demonstrated that deletion of Myc in osteoclasts increases bone mass and protects mice from ovariectomy-induced (OVX-induced) osteoporosis. Transcriptomic analysis revealed that MYC drives metabolic reprogramming during osteoclast differentiation and functions as a metabolic switch to an oxidative state. We identified a role for MYC action in the transcriptional induction of estrogen receptor-related receptor α (ERRα), a nuclear receptor that cooperates with the transcription factor nuclear factor of activated T cells, c1 (NFATc1) to drive osteoclastogenesis. Accordingly, pharmacological inhibition of ERRα attenuated OVX-induced bone loss in mice. Our findings highlight a MYC/ERRα pathway that contributes to physiological and pathological bone loss by integrating the MYC/ERRα axis to drive metabolic reprogramming during osteoclast differentiation.
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Affiliation(s)
- Seyeon Bae
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Min Joon Lee
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Se Hwan Mun
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Eugenia G. Giannopoulou
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
- Biological Sciences Department, New York City College of Technology, City University of New York, Brooklyn, New York, USA
| | - Vladimir Yong-Gonzalez
- Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Justin R. Cross
- Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Koichi Murata
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Vincent Giguère
- Goodman Cancer Research Centre, McGill University, Montréal, Canada; Departments of Biochemistry, Medicine and Oncology, McGill University, Montréal, Canada
| | - Marjolein van der Meulen
- Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York, USA
- Musculoskeletal Integrity Program, Hospital for Special Surgery, New York, New York, USA
| | - Kyung-Hyun Park-Min
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
- Department of Medicine, Weill Cornell Medical College, New York, New York, USA
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44
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Geraniol attenuates osteoclast differentiation by suppressingNF-kB activity and expression of osteoclastogenic genes. Med Chem Res 2017. [DOI: 10.1007/s00044-016-1715-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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45
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Lin TH, Pajarinen J, Lu L, Nabeshima A, Cordova LA, Yao Z, Goodman SB. NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2016; 107:117-154. [PMID: 28215222 DOI: 10.1016/bs.apcsb.2016.11.002] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bone-healing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system.
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Affiliation(s)
- T-H Lin
- Stanford University, Stanford, CA, United States
| | - J Pajarinen
- Stanford University, Stanford, CA, United States
| | - L Lu
- Stanford University, Stanford, CA, United States
| | - A Nabeshima
- Stanford University, Stanford, CA, United States
| | - L A Cordova
- Stanford University, Stanford, CA, United States; Faculty of Dentistry, University of Chile, Santiago, Chile
| | - Z Yao
- Stanford University, Stanford, CA, United States
| | - S B Goodman
- Stanford University, Stanford, CA, United States.
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46
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Vazquez-Santillan K, Melendez-Zajgla J, Jimenez-Hernandez LE, Gaytan-Cervantes J, Muñoz-Galindo L, Piña-Sanchez P, Martinez-Ruiz G, Torres J, Garcia-Lopez P, Gonzalez-Torres C, Ruiz V, Avila-Moreno F, Velasco-Velazquez M, Perez-Tapia M, Maldonado V. NF-kappaΒ-inducing kinase regulates stem cell phenotype in breast cancer. Sci Rep 2016; 6:37340. [PMID: 27876836 PMCID: PMC5120353 DOI: 10.1038/srep37340] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 10/18/2016] [Indexed: 02/07/2023] Open
Abstract
Breast cancer stem cells (BCSCs) overexpress components of the Nuclear factor-kappa B (NF-κB) signaling cascade and consequently display high NF-κB activity levels. Breast cancer cell lines with high proportion of CSCs exhibit high NF-κB-inducing kinase (NIK) expression. The role of NIK in the phenotype of cancer stem cell regulation is poorly understood. Expression of NIK was analyzed by quantitative RT-PCR in BCSCs. NIK levels were manipulated through transfection of specific shRNAs or an expression vector. The effect of NIK in the cancer stem cell properties was assessed by mammosphere formation, mice xenografts and stem markers expression. BCSCs expressed higher levels of NIK and its inhibition through small hairpin (shRNA), reduced the expression of CSC markers and impaired clonogenicity and tumorigenesis. Genome-wide expression analyses suggested that NIK acts on ERK1/2 pathway to exert its activity. In addition, forced expression of NIK increased the BCSC population and enhanced breast cancer cell tumorigenicity. The in vivo relevance of these results is further supported by a tissue microarray of breast cancer samples in which we observed correlated expression of Aldehyde dehydrogenase (ALDH) and NIK protein. Our results support the essential involvement of NIK in BCSC phenotypic regulation via ERK1/2 and NF-κB.
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Affiliation(s)
| | | | | | | | | | - Patricia Piña-Sanchez
- Unidad de Investigación Médica en Enfermedades Oncológicas (UIMEO), Hospital de Oncología IMSS, México
| | | | - Javier Torres
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UMAE), Hospital de Pediatría, IMSS, México
| | | | | | - Victor Ruiz
- Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas” (INER), México
| | | | | | - Mayra Perez-Tapia
- Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI) y Departamento de Inmunología, IPN, México
| | - Vilma Maldonado
- Instituto Nacional de Medicina Genómica (INMEGEN), México, 14610, México
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47
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Novack DV, Mbalaviele G. Osteoclasts-Key Players in Skeletal Health and Disease. Microbiol Spectr 2016; 4:10.1128/microbiolspec.MCHD-0011-2015. [PMID: 27337470 PMCID: PMC4920143 DOI: 10.1128/microbiolspec.mchd-0011-2015] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Indexed: 12/12/2022] Open
Abstract
The differentiation of osteoclasts (OCs) from early myeloid progenitors is a tightly regulated process that is modulated by a variety of mediators present in the bone microenvironment. Once generated, the function of mature OCs depends on cytoskeletal features controlled by an αvβ3-containing complex at the bone-apposed membrane and the secretion of protons and acid-protease cathepsin K. OCs also have important interactions with other cells in the bone microenvironment, including osteoblasts and immune cells. Dysregulation of OC differentiation and/or function can cause bone pathology. In fact, many components of OC differentiation and activation have been targeted therapeutically with great success. However, questions remain about the identity and plasticity of OC precursors and the interplay between essential networks that control OC fate. In this review, we summarize the key principles of OC biology and highlight recently uncovered mechanisms regulating OC development and function in homeostatic and disease states.
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Affiliation(s)
- Deborah Veis Novack
- Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Department of Medicine
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Gabriel Mbalaviele
- Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Department of Medicine
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48
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Baud V, Collares D. Post-Translational Modifications of RelB NF-κB Subunit and Associated Functions. Cells 2016; 5:cells5020022. [PMID: 27153093 PMCID: PMC4931671 DOI: 10.3390/cells5020022] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 04/19/2016] [Accepted: 04/26/2016] [Indexed: 01/02/2023] Open
Abstract
The family of NF-κB transcription factors plays a key role in diverse biological processes, such as inflammatory and immune responses, cell survival and tumor development. Beyond the classical NF-κB activation pathway, a second NF-κB pathway has more recently been uncovered, the so-called alternative NF-κB activation pathway. It has been shown that this pathway mainly controls the activity of RelB, a member of the NF-κB family. Post-translational modifications, such as phosphorylation, acetylation, methylation, ubiquitination and SUMOylation, have recently emerged as a strategy for the fine-tuned regulation of NF-κB. Our review discusses recent progress in the understanding of RelB regulation by post-translational modifications and the associated functions in normal and pathological conditions.
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Affiliation(s)
- Véronique Baud
- NF-κB, Differentiation and Cancer, Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France.
| | - Davi Collares
- NF-κB, Differentiation and Cancer, Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France
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49
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The Alternative Faces of Macrophage Generate Osteoclasts. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9089610. [PMID: 26977415 PMCID: PMC4761668 DOI: 10.1155/2016/9089610] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 01/14/2016] [Accepted: 01/18/2016] [Indexed: 01/08/2023]
Abstract
The understanding of how osteoclasts are generated and whether they can be altered by inflammatory stimuli is a topic of particular interest for osteoclastogenesis. It is known that the monocyte/macrophage lineage gives rise to osteoclasts (OCs) by the action of macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kB ligand (RANKL), which induce cell differentiation through their receptors, c-fms and RANK, respectively. The multinucleated giant cells (MGCs) generated by the engagement of RANK/RANKL are typical OCs. Nevertheless, very few studies have addressed the question of which subset of macrophages generates OCs. Indeed, two main subsets of macrophages are postulated, the inflammatory or classically activated type (M1) and the anti-inflammatory or alternatively activated type (M2). It has been proposed that macrophages can be polarized in vitro towards a predominantly M1 or M2 phenotype with the addition of granulocyte macrophage- (GM-) CSF or M-CSF, respectively. Various inflammatory stimuli known to induce macrophage polarization, such as LPS or TNF-α, can alter the type of MGC obtained from RANKL-induced differentiation. This review aims to highlight the role of immune-related stimuli and factors in inducing macrophages towards the osteoclastogenesis choice.
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50
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Frederiksen AL, Larsen MJ, Brusgaard K, Novack DV, Knudsen PJT, Schrøder HD, Qiu W, Eckhardt C, McAlister WH, Kassem M, Mumm S, Frost M, Whyte MP. Neonatal High Bone Mass With First Mutation of the NF-κB Complex: Heterozygous De Novo Missense (p.Asp512Ser) RELA (Rela/p65). J Bone Miner Res 2016; 31:163-72. [PMID: 26178921 PMCID: PMC5310715 DOI: 10.1002/jbmr.2590] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Revised: 07/02/2015] [Accepted: 07/06/2015] [Indexed: 12/13/2022]
Abstract
Heritable disorders that feature high bone mass (HBM) are rare. The etiology is typically a mutation(s) within a gene that regulates the differentiation and function of osteoblasts (OBs) or osteoclasts (OCs). Nevertheless, the molecular basis is unknown for approximately one-fifth of such entities. NF-κB signaling is a key regulator of bone remodeling and acts by enhancing OC survival while impairing OB maturation and function. The NF-κB transcription complex comprises five subunits. In mice, deletion of the p50 and p52 subunits together causes osteopetrosis (OPT). In humans, however, mutations within the genes that encode the NF-κB complex, including the Rela/p65 subunit, have not been reported. We describe a neonate who died suddenly and unexpectedly and was found at postmortem to have HBM documented radiographically and by skeletal histopathology. Serum was not available for study. Radiographic changes resembled malignant OPT, but histopathological investigation showed morphologically normal OCs and evidence of intact bone resorption excluding OPT. Furthermore, mutation analysis was negative for eight genes associated with OPT or HBM. Instead, accelerated bone formation appeared to account for the HBM. Subsequently, trio-based whole exome sequencing revealed a heterozygous de novo missense mutation (c.1534_1535delinsAG, p.Asp512Ser) in exon 11 of RELA encoding Rela/p65. The mutation was then verified using bidirectional Sanger sequencing. Lipopolysaccharide stimulation of patient fibroblasts elicited impaired NF-κB responses compared with healthy control fibroblasts. Five unrelated patients with unexplained HBM did not show a RELA defect. Ours is apparently the first report of a mutation within the NF-κB complex in humans. The missense change is associated with neonatal osteosclerosis from in utero increased OB function rather than failed OC action. These findings demonstrate the importance of the Rela/p65 subunit within the NF-κB pathway for human skeletal homeostasis and represent a new genetic cause of HBM.
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Affiliation(s)
- Anja L Frederiksen
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.,Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Martin J Larsen
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.,Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Klaus Brusgaard
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.,Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Deborah V Novack
- Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA
| | | | | | - Weimin Qiu
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital and University of Southern Denmark, Odense, Denmark
| | | | - William H McAlister
- Department of Pediatric Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine at St. Louis Children's Hospital, St. Louis, MO, USA
| | - Moustapha Kassem
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital and University of Southern Denmark, Odense, Denmark
| | - Steven Mumm
- Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.,Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA
| | - Morten Frost
- Endocrine Research Unit, Odense University Hospital, Odense, Denmark
| | - Michael P Whyte
- Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.,Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA
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