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Lungu O, Toscani D, Giuliani N. Mechanistic insights into bone destruction in multiple myeloma: Cellular and molecular perspectives. J Bone Oncol 2025; 51:100668. [PMID: 40124903 PMCID: PMC11928850 DOI: 10.1016/j.jbo.2025.100668] [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: 01/28/2025] [Revised: 02/21/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy that leads to significant bone destruction, resulting in debilitating pain and skeletal-related events. The pathophysiology of osteolytic bone destruction in MM involves complex interactions between malignant plasma cells (PCs) and the bone marrow (BM) microenvironment. This review aims to provide a comprehensive synthesis of the cellular and molecular pathways underlying MM-associated bone disease. We discuss the role of osteoclast (OC), osteoblast (OB), osteocytes, along with the complex interactions between immune cells and the BM microenvironment in shaping disease progression. Additionally, we explore the molecular signaling pathways involved in bone disease as well as the influence of inflammatory cytokines, and the role of the metabolic alterations that characterize the MM BM. We also explore novel therapeutic strategies targeting these pathways to improve clinical outcomes. Understanding these mechanisms is crucial for the development of more effective treatments to prevent bone damage in MM patients.
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Affiliation(s)
- Oxana Lungu
- Laboratory of Hematology, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Denise Toscani
- Laboratory of Hematology, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Nicola Giuliani
- Laboratory of Hematology, Department of Medicine and Surgery, University of Parma, Parma, Italy
- Hematology and BMT Unit, “Azienda Ospedaliero-Universitaria di Parma”, Parma, Italy
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2
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Pilard C, Roncarati P, Ancion M, Luyckx M, Renard M, Reynders C, Lerho T, Poulain F, Bruyere D, Lebeau A, Hendrick E, Crake R, Peiffer R, Nokin MJ, Peulen O, Delvenne P, Hubert P, Herfs M. RANKL blockade inhibits cancer growth through reversing the tolerogenic profile of tumor-infiltrating (plasmacytoid) dendritic cells. J Immunother Cancer 2025; 13:e010753. [PMID: 40081943 PMCID: PMC11907081 DOI: 10.1136/jitc-2024-010753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/26/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Originally identified for its involvement in bone remodeling, accumulating data emerged in the past years indicating that receptor activator of nuclear factor κB ligand (RANKL) actually acts as a multifunctional soluble molecule that influences various physiological and pathological processes. Regarding its role in carcinogenesis, while direct effects on tumor cell behavior have been precisely characterized, the impact of the RANKL/RANK system (and its inhibition) on the intratumoral immune landscape remains unclear. METHODS After various in silico/in situ/in vitro analyses, the immunotherapeutic efficacy of RANKL blockade (alone and in combination with immune checkpoint inhibitors (anti-programmed cell death protein-1 (PD-1)) or doxorubicin/paclitaxel-based chemotherapy) was investigated using different syngeneic mouse models of triple-negative breast cancer (4T1, 67NR and E0771). Isolated from retrieved tumors, 14 immune cell (sub)populations, along with the activation status of antigen-presenting cells, were thoroughly analyzed in each condition. Finally, the impact of RANKL on the functionality of both dendritic cells (DC) and plasmacytoid dendritic cells (pDC) was determined. RESULTS A drastic tumor growth inhibition was reproductively observed following RANKL inhibition. Strikingly, this antitumor activity was not detected in immunocompromised mice, demonstrating its dependence on the adaptive immune responses and justifying the diverse enriched signatures linked to immune cell regulation/differentiation detected in RANKLhigh-expressing human neoplasms. Interestingly, neoadjuvant chemotherapy (but not PD-1 checkpoint inhibition) potentiated the anticancer effects of RANKL blockade by priming effector T cells and increasing their infiltration within the tumor microenvironment. Mechanistically, we highlighted that RANKL indirectly promotes regulatory T cell differentiation and suppressive function by inhibiting the mTOR signaling pathway on antigen-presenting cells. CONCLUSIONS Taken together, this study provides insight into the role of RANKL/RANK axis in immune tolerance, demonstrates the significant impact of RANKL-dependent impairment of T cell-DC/pDC crosstalk on tumor development and, ultimately, supports that this ligand could be an interesting actionable target for cancer immunotherapy.
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Affiliation(s)
- Charlotte Pilard
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Patrick Roncarati
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Marie Ancion
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Margaux Luyckx
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Michael Renard
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Celia Reynders
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Thomas Lerho
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Florian Poulain
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Diane Bruyere
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Alizee Lebeau
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Elodie Hendrick
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Rebekah Crake
- Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Raphael Peiffer
- Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Marie-Julie Nokin
- Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Olivier Peulen
- Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Philippe Delvenne
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
- Department of Pathology, University Hospital Center of Liege, Liege, Belgium
| | - Pascale Hubert
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
| | - Michael Herfs
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium
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Lee DK, Jin X, Choi PR, Cui Y, Che X, Lee S, Hur K, Kim HJ, Choi JY. Phospholipase C β4 promotes RANKL-dependent osteoclastogenesis by interacting with MKK3 and p38 MAPK. Exp Mol Med 2025; 57:323-334. [PMID: 39894822 PMCID: PMC11873240 DOI: 10.1038/s12276-025-01390-8] [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: 06/18/2024] [Revised: 10/30/2024] [Accepted: 11/05/2024] [Indexed: 02/04/2025] Open
Abstract
Phospholipase C β (PLCβ) is involved in diverse biological processes, including inflammatory responses and neurogenesis; however, its role in bone cell function is largely unknown. Among the PLCβ isoforms (β1-β4), we found that PLCβ4 was the most highly upregulated during osteoclastogenesis. Here we used global knockout and osteoclast lineage-specific PLCβ4 conditional knockout (LysM-PLCβ4-/-) mice as subjects and demonstrated that PLCβ4 is a crucial regulator of receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation. The deletion of PLCβ4, both globally and in the osteoclast lineage, resulted in a significant reduction in osteoclast formation and the downregulation of osteoclast marker genes. Notably, male LysM-PLCβ4-/- mice presented greater bone mass and fewer osteoclasts in vivo than their wild-type littermates, without altered osteoblast function. Mechanistically, we found that PLCβ4 forms a complex with p38 mitogen-activated protein kinase (MAPK) and MAPK kinase 3 (MKK3) in response to RANKL-induced osteoclast differentiation, thereby modulating p38 activation. An immunofluorescence assay further confirmed the colocalization of PLCβ4 with p38 after RANKL exposure. Moreover, p38 activation rescued impaired osteoclast formation and restored the reduction in p38 phosphorylation caused by PLCβ4 deficiency. Thus, our findings reveal that PLCβ4 controls osteoclastogenesis via the RANKL-dependent MKK3-p38 MAPK pathway and that PLCβ4 may be a potential therapeutic candidate for bone diseases such as osteoporosis.
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Affiliation(s)
- Dong-Kyo Lee
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Xian Jin
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Poo-Reum Choi
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Ying Cui
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Xiangguo Che
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sihoon Lee
- Department of Internal Medicine and Laboratory of Molecular Endocrinology, Gachon University School of Medicine, Incheon, Republic of Korea
| | - Keun Hur
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Hyun-Ju Kim
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
| | - Je-Yong Choi
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
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Pérez-Chacón G, Santamaría PG, Redondo-Pedraza J, González-Suárez E. RANK/RANKL Signaling Pathway in Breast Development and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:309-345. [PMID: 39821032 DOI: 10.1007/978-3-031-70875-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
RANK pathway has attracted increasing interest as a promising target in breast cancer, given the availability of denosumab, an anti-RANKL drug. RANK signaling mediates progesterone-driven regulation of mammary gland development and favors breast cancer initiation by controlling mammary cell proliferation and stem cell fate. RANK activation promotes luminal mammary epithelial cell senescence, acting as an initial barrier to tumorigenesis but ultimately facilitating tumor progression and metastasis. Comprehensive analyses have demonstrated that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and estrogen receptor-negative breast cancer patients. RANK pathway also has multiple roles in immunity and inflammation, regulating innate and adaptive responses. In the tumor microenvironment, RANK and RANKL are expressed by different immune cell populations and contribute to the regulation of tumor immune surveillance, mainly driving immunosuppressive effects.Herein, we discuss the preventive and therapeutic potential of targeting RANK signaling in breast cancer given its tumor cell intrinsic and extrinsic effects. RANKL inhibition has been shown to induce mammary tumor cell differentiation and an antitumor immune response. Moreover, loss of RANK signaling increases sensitivity of breast cancer cells to chemotherapy, targeted therapies such as HER2 and CDK4/6 inhibitors, and immunotherapy. Finally, we describe clinical trials of denosumab for breast cancer prevention, such as those ongoing in women with high risk of developing breast cancer, large phase III clinical trials where the impact of adjuvant denosumab on disease-free survival has been assessed, and window trials to evaluate the immunomodulatory effects of denosumab in breast cancer and other solid tumors.
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Affiliation(s)
- Gema Pérez-Chacón
- Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | | | | | - Eva González-Suárez
- Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
- Oncobell, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
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Freeman C, A S MD, A S P. Unraveling the Intricacies of OPG/RANKL/RANK Biology and Its Implications in Neurological Disorders-A Comprehensive Literature Review. Mol Neurobiol 2024; 61:10656-10670. [PMID: 38777981 DOI: 10.1007/s12035-024-04227-z] [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: 02/03/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024]
Abstract
The OPG/RANKL/RANK framework, along with its specific receptors, plays a crucial role in bone remodeling and the functioning of the central nervous system (CNS) and associated disorders. Recent research and investigations provide evidence that the components of osteoprotegerin (OPG), receptor activator of NF-kB ligand (RANKL), and receptor activator of NF-kB (RANK) are expressed in the CNS. The CNS structure encompasses cells involved in neuroinflammation, including local macrophages, inflammatory cells, and microglia that cross the blood-brain barrier. The OPG/RANKL/RANK trio modulates the neuroinflammatory response based on the molecular context. The levels of OPG/RANKL/RANK components can serve as biomarkers in the blood and cerebrospinal fluid. They act as neuroprotectants following brain injuries and also participate in the regulation of body weight, internal body temperature, brain ischemia, autoimmune encephalopathy, and energy metabolism. Although the OPG/RANKL/RANK system is primarily known for its role in bone remodeling, further exploring deeper into its multifunctional nature can uncover new functions and novel drug targets for diseases not previously associated with OPG/RANKL/RANK signaling.
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Affiliation(s)
- Chrisanne Freeman
- Department of Biotechnology, Bishop Heber College, Tamil Nadu, Tiruchirappalli, 620017, India.
| | - Merlyn Diana A S
- Department of Biotechnology, Bishop Heber College, Tamil Nadu, Tiruchirappalli, 620017, India
- Department of Zoology and Research Centre, Lady Doak College, Tamil Nadu, Madurai, 625002, India
| | - Priscilla A S
- Department of Zoology and Research Centre, Lady Doak College, Tamil Nadu, Madurai, 625002, India
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Song S, Yan Q, Yu J. Bidirectional two-sample Mendelian randomization analysis unveils causal association between inflammatory cytokines and the risk of diabetic nephropathy. Sci Rep 2024; 14:25425. [PMID: 39455620 PMCID: PMC11511841 DOI: 10.1038/s41598-024-73800-2] [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: 08/06/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024] Open
Abstract
OBJECTIVE Previous observational studies have indicated associations between various inflammatory cytokines and diabetic nephropathy (DN) caused by type 2 diabetes mellitus (T2DM). However, the causality remains unclear. We aimed to further evaluate the causal association between 91 inflammatory cytokines and DN using bidirectional two-sample Mendelian randomization (MR) analysis. METHOD Summary statistics for DN were obtained from a publicly available genome-wide association study (GWAS) analysis. Data pertaining to inflammatory cytokines were derived from a GWAS protein quantitative trait locus (pQTL) study. The primary analytical approach employed the inverse variance weighted (IVW) method, complemented by MR-Egger regression, weighted mode (WM), and weighted median (WME) methods to evaluate the causal association between inflammatory cytokines and DN. Sensitivity analyses were conducted to validate the robustness of the findings. RESULT Among individuals of European ancestry, the IVW method results revealed a positive causal association between the gene expression of tumor necrosis factor ligand superfamily member 14 (TNFSF14), and TNF-related activation-induced cytokine (TRANCE) with DN. Conversely, a negative causal association was observed between the gene expression of interleukin-1-alpha (IL-1α), and transforming growth factor-alpha (TGF-α) with DN. Among individuals of East Asian ancestry, the IVW method results indicated a negative causal association between the gene expression of glial cell line-derived neurotrophic factor (GDNF) and DN. Notably, these findings persisted without evidence of horizontal pleiotropy or heterogeneity, ensuring their robustness and reliability. CONCLUSION The MR analysis underscores a causal association between inflammatory cytokines and DN, providing an important reference and evidence for the study of DN.
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Affiliation(s)
- Siyuan Song
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Qianhua Yan
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China.
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China.
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Jiangyi Yu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China.
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China.
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
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Cheng X, Hu D, Wang C, Lu T, Ning Z, Li K, Ren Z, Huang Y, Zhou L, Chung SK, Liu Z, Xia Z, Meng W, Tang G, Sun J, Guo J. Plasma Inflammation Markers Linked to Complications and Outcomes after Spontaneous Intracerebral Hemorrhage. J Proteome Res 2024; 23:4369-4383. [PMID: 39225497 DOI: 10.1021/acs.jproteome.4c00311] [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] [Indexed: 09/04/2024]
Abstract
Intracerebral hemorrhage (ICH) could trigger inflammatory responses. However, the specific role of inflammatory proteins in the pathological mechanism, complications, and prognosis of ICH remains unclear. In this study, we investigated the expression of 92 plasma inflammation-related proteins in patients with ICH (n = 55) and healthy controls (n = 20) using an Olink inflammation panel and discussed the relation to the severity of stroke, clinical complications, 30-day mortality, and 90-day outcomes. Our result showed that six proteins were upregulated in ICH patients compared with healthy controls, while seventy-four proteins were downregulated. In patients with ICH, seven proteins were increased in the severe stroke group compared with the moderate stroke group. In terms of complications, two proteins were downregulated in patients with pneumonia, while nine proteins were upregulated in patients with sepsis. Compared with the survival group, three proteins were upregulated, and one protein was downregulated in the death group. Compared with the good outcome group, eight proteins were upregulated, and four proteins were downregulated in the poor outcome group. In summary, an in-depth exploration of the differential inflammatory factors in the early stages of ICH could deepen our understanding of the pathogenesis of ICH, predict patient prognosis, and explore new treatment strategies.
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Affiliation(s)
- Xiao Cheng
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
- Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
- Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou 510120, Guangdong China
- Chinese Medicine Guangdong Laboratory, Hengqin 519000, Guangdong China
| | - Dafeng Hu
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
| | - Chengyi Wang
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
| | - Ting Lu
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
| | - Zhenqiu Ning
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
| | - Kunhong Li
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
| | - Zhixuan Ren
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
| | - Yan Huang
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
- Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
- Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou 510120, Guangdong China
- Chinese Medicine Guangdong Laboratory, Hengqin 519000, Guangdong China
| | - Lihua Zhou
- Department of Anatomy, Zhong Shan School of Medicine, Sun Yat-sen University, Shenzhen 518107, Guangdong China
| | - Sookja Kim Chung
- Faculty of Medicine, Macau University of Science and Technology, Macao Special Administration Region 999078, China
| | - Zhenchuan Liu
- Department of Neurology, Linyi City People's Hospital, Linyi 276000, Shandong China
| | - Zhangyong Xia
- Department of Neurology, Liaocheng City People's Hospital, Liaocheng 252600, Shandong China
| | - Wei Meng
- Department of Neurology, Panjin City Central Hospital, Panjin 124010, Liaoning China
| | - Guanghai Tang
- Department of Neurology, Shenyang City Second Hospital of Traditional Chinese Medicine, Shenyang 110000, Liaoning China
| | - Jingbo Sun
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
- Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
- Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou 510120, Guangdong China
- Chinese Medicine Guangdong Laboratory, Hengqin 519000, Guangdong China
| | - Jianwen Guo
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
- Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong China
- Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou 510120, Guangdong China
- Chinese Medicine Guangdong Laboratory, Hengqin 519000, Guangdong China
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Long J, Dang H, Su W, Moneruzzaman M, Zhang H. Interactions between circulating inflammatory factors and autism spectrum disorder: a bidirectional Mendelian randomization study in European population. Front Immunol 2024; 15:1370276. [PMID: 38742104 PMCID: PMC11089225 DOI: 10.3389/fimmu.2024.1370276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 04/16/2024] [Indexed: 05/16/2024] Open
Abstract
Background Extensive observational studies have reported an association between inflammatory factors and autism spectrum disorder (ASD), but their causal relationships remain unclear. This study aims to offer deeper insight into causal relationships between circulating inflammatory factors and ASD. Methods Two-sample bidirectional Mendelian randomization (MR) analysis method was used in this study. The genetic variation of 91 circulating inflammatory factors was obtained from the genome-wide association study (GWAS) database of European ancestry. The germline GWAS summary data for ASD were also obtained (18,381 ASD cases and 27,969 controls). Single nucleotide polymorphisms robustly associated with the 91 inflammatory factors were used as instrumental variables. The random-effects inverse-variance weighted method was used as the primary analysis, and the Bonferroni correction for multiple comparisons was applied. Sensitivity tests were carried out to assess the validity of the causal relationship. Results The forward MR analysis results suggest that levels of sulfotransferase 1A1, natural killer cell receptor 2B4, T-cell surface glycoprotein CD5, Fms-related tyrosine kinase 3 ligand, and tumor necrosis factor-related apoptosis-inducing ligand are positively associated with the occurrence of ASD, while levels of interleukin-7, interleukin-2 receptor subunit beta, and interleukin-2 are inversely associated with the occurrence of ASD. In addition, matrix metalloproteinase-10, caspase 8, tumor necrosis factor-related activation-induced cytokine, and C-C motif chemokine 19 were considered downstream consequences of ASD. Conclusion This MR study identified additional inflammatory factors in patients with ASD relative to previous studies, and raised a possibility of ASD-caused immune abnormalities. These identified inflammatory factors may be potential biomarkers of immunologic dysfunction in ASD.
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Affiliation(s)
- Junzi Long
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Neurorehabilitation, China Rehabilitation Research Center, Beijing, China
- Division of Brain Sciences, Changping Laboratory, Beijing, China
| | - Hui Dang
- Department of Neurorehabilitation, China Rehabilitation Research Center, Beijing, China
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Wenlong Su
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Neurorehabilitation, China Rehabilitation Research Center, Beijing, China
| | - Md. Moneruzzaman
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Neurorehabilitation, China Rehabilitation Research Center, Beijing, China
| | - Hao Zhang
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Neurorehabilitation, China Rehabilitation Research Center, Beijing, China
- Division of Brain Sciences, Changping Laboratory, Beijing, China
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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9
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Pereira MVA, Galvani RG, Gonçalves-Silva T, de Vasconcelo ZFM, Bonomo A. Tissue adaptation of CD4 T lymphocytes in homeostasis and cancer. Front Immunol 2024; 15:1379376. [PMID: 38690280 PMCID: PMC11058666 DOI: 10.3389/fimmu.2024.1379376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 04/01/2024] [Indexed: 05/02/2024] Open
Abstract
The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression.
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Affiliation(s)
- Marina V. A. Pereira
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Laboratory of High Complexity, Fernandes Figueira National Institute for The Health of Mother, Child, and Adolescent, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Rômulo G. Galvani
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Triciana Gonçalves-Silva
- National Center for Structural Biology and Bioimaging - CENABIO, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Zilton Farias Meira de Vasconcelo
- Laboratory of High Complexity, Fernandes Figueira National Institute for The Health of Mother, Child, and Adolescent, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Adriana Bonomo
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
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Sakai T. Fracture risks and their mechanisms in atopic dermatitis, focusing on receptor activator of nuclear factor kappa-B ligand. Clin Exp Dermatol 2023; 48:1209-1213. [PMID: 37379576 DOI: 10.1093/ced/llad220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/14/2023] [Accepted: 06/16/2023] [Indexed: 06/30/2023]
Abstract
Recent multiple studies have shown that the long-term consequences of atopic dermatitis (AD) include an increased risk of osteoporosis and fracture, especially an increase in hip, pelvic, spinal and wrist fractures. AD is very common worldwide, and some kinds of fractures, such as hip fractures, are associated with increased mortality, which has a substantial socioeconomic impact; however, the precise mechanisms for this remain unclear. Receptor activator of nuclear factor kappa-Β (RANK) ligand (RANKL) and osteoprotegerin (OPG) are members of the tumour necrosis factor ligand and receptor family, members of which also are known as bone biomarkers. Alterations in the RANKL/RANK/OPG system and the balance among these factors (represented by the RANKL/OPG ratio) are central to the pathogenesis of bone loss from osteoporosis, and it is postulated that there is a potential association between the serum levels of RANKL and OPG, and bone density or fracture. Recently, our research group demonstrated that the serum RANKL/OPG ratio positively correlated with AD severity and suggests fracture risk in older women with AD. This review summarizes and discusses the risk and mechanisms of osteoporotic fracture in AD. RANKL may be involved in the pathogenesis of AD, regarding not only bone abnormality but also inflammation. Although further investigation will be needed to verify the hypotheses, recent findings may provide new insights into the pathogenesis of AD and therapeutic targets.
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Affiliation(s)
- Takashi Sakai
- Department of Dermatology, Faculty of Medicine, Oita University, Oita, Japan
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11
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Roato I, Pavone L, Pedraza R, Bosso I, Baima G, Erovigni F, Mussano F. Denosumab and Zoledronic Acid Differently Affect Circulating Immune Subsets: A Possible Role in the Onset of MRONJ. Cells 2023; 12:2430. [PMID: 37887274 PMCID: PMC10605172 DOI: 10.3390/cells12202430] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 09/29/2023] [Accepted: 10/08/2023] [Indexed: 10/28/2023] Open
Abstract
This work investigated whether the anti-resorptive drugs (ARDs) zoledronic acid (Zol) and denosumab (Dmab) affect differently the levels of circulating immune cell subsets, possibly predicting the risk of developing medication-related ONJ (MRONJ) during the first 18 months of treatment. Blood samples were collected from 10 bone metastatic breast cancer patients receiving cyclin inhibitors at 0, 6, 12, and 18 months from the beginning of Dmab or Zol treatment. Eight breast cancer patients already diagnosed with MRONJ and treated with cyclin inhibitors and ARDs were in the control group. PBMCs were isolated; the trend of circulating immune subsets during the ARD treatment was monitored, and 12 pro-inflammatory cytokines were analyzed in sera using flow cytometry. In Dmab-treated patients, activated T cells were stable or increased, as were the levels of IL-12, TNF-α, GM-CSF, IL-5, and IL-10, sustaining them. In Zol-treated patients, CD8+T cells decreased, and the level of IFN-γ was undetectable. γδT cells were not altered in Dmab-treated patients, while they dramatically decreased in Zol-treated patients. In the MRONJ control group, Zol-ONJ patients showed a reduction in activated T cells and γδT cells compared to Dmab-ONJ patients. Dmab was less immunosuppressive than Zol, not affecting γδT cells and increasing activated T cells.
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Affiliation(s)
- Ilaria Roato
- Bone and Dental Bioengineering Laboratory, CIR-Dental School, Department of Surgical Sciences, University of Turin, Via Nizza 230, 10126 Turin, Italy; (L.P.); (R.P.); (G.B.); (F.M.)
| | - Lorenzo Pavone
- Bone and Dental Bioengineering Laboratory, CIR-Dental School, Department of Surgical Sciences, University of Turin, Via Nizza 230, 10126 Turin, Italy; (L.P.); (R.P.); (G.B.); (F.M.)
| | - Riccardo Pedraza
- Bone and Dental Bioengineering Laboratory, CIR-Dental School, Department of Surgical Sciences, University of Turin, Via Nizza 230, 10126 Turin, Italy; (L.P.); (R.P.); (G.B.); (F.M.)
- Institute of Sciences and Technologies for Sustainable Energy and Mobility, National Council of Research, 10135 Turin, Italy
- DIMEAS, Politecnico di Torino, 10129 Turin, Italy
| | - Ilaria Bosso
- CIR-Dental School, Città della Scienza e della Salute, 10126 Turin, Italy; (I.B.); (F.E.)
| | - Giacomo Baima
- Bone and Dental Bioengineering Laboratory, CIR-Dental School, Department of Surgical Sciences, University of Turin, Via Nizza 230, 10126 Turin, Italy; (L.P.); (R.P.); (G.B.); (F.M.)
- DIMEAS, Politecnico di Torino, 10129 Turin, Italy
| | - Francesco Erovigni
- CIR-Dental School, Città della Scienza e della Salute, 10126 Turin, Italy; (I.B.); (F.E.)
| | - Federico Mussano
- Bone and Dental Bioengineering Laboratory, CIR-Dental School, Department of Surgical Sciences, University of Turin, Via Nizza 230, 10126 Turin, Italy; (L.P.); (R.P.); (G.B.); (F.M.)
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12
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Bhattacharya G, Sengupta S, Jha R, Shaw SK, Jogdand GM, Barik PK, Padhan P, Parida JR, Devadas S. IL-21/23 axis modulates inflammatory cytokines and RANKL expression in RA CD4 + T cells via p-Akt1 signaling. Front Immunol 2023; 14:1235514. [PMID: 37809066 PMCID: PMC10551441 DOI: 10.3389/fimmu.2023.1235514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 09/04/2023] [Indexed: 10/10/2023] Open
Abstract
Introduction CD4+ T cells are critically involved in the pathogenesis of Rheumatoid Arthritis; an autoimmune disorder characterized by joint inflammation and bone degeneration. In this study, we focused on the critical role of cytokines, IL-21 and IL-23 in facilitating the aberrant status of RA Th17-like cells and report their significant contribution(s) in modulating the expression of inflammatory cytokines and RANKL. Methods Blood and synovial fluid collected from a total of 167 RA patients and 25 healthy volunteers were assessed for various inflammatory markers and RANKL expression in plasma and CD4+ T cells. Subsequent ex vivo studies examined the role of specific cytokines, IL-21 and IL-23 in mediating inflammation and RANKL upregulation by blocking their expression with neutralizing antibodies in RA CD4+ T cells and terminally differentiated human Th17 cells. Further, the role of p-Akt1 as a signalling target downstream of IL-21 and IL-23 was evinced with IL-21 and IL-23 inhibition and phospho Akt-1/2 kinase inhibitor. Results Our observations highlighted the augmented inflammatory cytokine levels in plasma and an aberrant CD4+ T cell phenotype expressing exaggerated inflammatory cytokines and membrane RANKL expression in RA as opposed to healthy controls. Neutralization of either IL-21 or IL-23 (p19 and p40) or both, resulted in downregulation of the cytokines, TNF-α, IFN-γ and IL-17 and RANKL expression in these cells, signifying the critical role of IL-21/23 axis in modulating inflammation and RANKL. Subsequent dissection of the signaling pathway found p-Akt1 as the key phosphoprotein downstream of both IL-21 and IL-23, capable of increasing inflammatory cytokines and RANKL production. Discussion Our findings unequivocally identify IL-21/23 axis in RA CD4+ T cells as a key regulator dictating two critical processes i.e. exaggerated inflammation and higher RANKL expression and provide critical targets in their downstream signalling for therapeutic approaches.
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Affiliation(s)
- Gargee Bhattacharya
- Institute of Life Sciences (ILS), Bhubaneswar, Odisha, India
- Regional Centre for Biotechnology (RCB), Faridabad-Gurgaon, Haryana, India
| | - Soumya Sengupta
- Institute of Life Sciences (ILS), Bhubaneswar, Odisha, India
- Regional Centre for Biotechnology (RCB), Faridabad-Gurgaon, Haryana, India
| | - Rohila Jha
- Institute of Life Sciences (ILS), Bhubaneswar, Odisha, India
- Regional Centre for Biotechnology (RCB), Faridabad-Gurgaon, Haryana, India
| | - Shubham K. Shaw
- Institute of Life Sciences (ILS), Bhubaneswar, Odisha, India
- Regional Centre for Biotechnology (RCB), Faridabad-Gurgaon, Haryana, India
| | | | | | - Prasanta Padhan
- Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences (KIMS), Bhubaneswar, Odisha, India
| | - Jyoti R. Parida
- Odisha Arthritis & Rheumatology Centre (OARC), Bhubaneswar, Odisha, India
| | - Satish Devadas
- Institute of Life Sciences (ILS), Bhubaneswar, Odisha, India
- Regional Centre for Biotechnology (RCB), Faridabad-Gurgaon, Haryana, India
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13
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Tufail M, Wu C. RANK pathway in cancer: underlying resistance and therapeutic approaches. J Chemother 2023; 35:369-382. [PMID: 36200617 DOI: 10.1080/1120009x.2022.2129752] [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: 04/07/2022] [Revised: 08/27/2022] [Accepted: 09/23/2022] [Indexed: 10/10/2022]
Abstract
Cancer remains one of the deadliest diseases despite advances in treatment. Metastatic cancers are the leading cause of death for advanced cancer patients. Those with advanced cancer with osteolytic-type bone metastases have a significantly lower quality of life. A novel treatment plan is needed now more than ever for breast cancer patients with bone metastases. There are shreds of evidence that cancer cells in the bloodstream interact with the bone microenvironment and that this interaction is a contributing component to breast cancer progression. Preventing any stage of this cycle can result in anti-metastasis effects. Since RANKL interacts with its receptor RANK and plays an important role in the vicious cycle, it has proven to be a successful therapeutic target in cancer treatment. As a result, we have presented a complete overview of the RANK pathway in cancer and discussed RANK signaling and tumor microenvironment, and potential therapeutic approaches in this review.
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Affiliation(s)
- Muhammad Tufail
- Institute of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Changxin Wu
- Institute of Biomedical Sciences, Shanxi University, Taiyuan, China
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14
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Frech M, Danzer H, Uchil P, Azizov V, Schmid E, Schälter F, Dürholz K, Mauro D, Rauber S, Muñoz L, Taher L, Ciccia F, Schober K, Irla M, Sarter K, Schett G, Zaiss MM. Butyrophilin 2a2 (Btn2a2) expression on thymic epithelial cells promotes central T cell tolerance and prevents autoimmune disease. J Autoimmun 2023; 139:103071. [PMID: 37356345 DOI: 10.1016/j.jaut.2023.103071] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/24/2023] [Accepted: 06/06/2023] [Indexed: 06/27/2023]
Abstract
Butyrophilins are surface receptors belonging to the immunoglobulin superfamily. While several members of the butyrophilin family have been implicated in the development of unconventional T cells, butyrophilin 2a2 (Btn2a2) has been shown to inhibit conventional T cell activation. Here, we demonstrate that in steady state, the primary source of Btn2a2 are thymic epithelial cells (TEC). Absence of Btn2a2 alters thymic T cell maturation and bypasses central tolerance mechanisms. Furthermore, Btn2a2-/- mice develop spontaneous autoimmunity resembling human primary Sjögren's Syndrome (pSS), including formation of tertiary lymphoid structures (TLS) in target organs. Ligation of Btn2a2 on developing thymocytes is associated with reduced TCR signaling and CD5 levels, while absence of Btn2a2 results in increased TCR signaling and CD5 levels. These results define a novel role for Btn2a2 in promoting central tolerance by modulating TCR signaling strength and indicate a potential mechanism of pSS development.
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Affiliation(s)
- Michael Frech
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Heike Danzer
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Pooja Uchil
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Vugar Azizov
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Eva Schmid
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Fabian Schälter
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Kerstin Dürholz
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Daniele Mauro
- Institute of Biomedical Informatics, Graz University of Technology, Graz, Austria
| | - Simon Rauber
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Luis Muñoz
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Leila Taher
- Institute of Biomedical Informatics, Graz University of Technology, Graz, Austria
| | - Francesco Ciccia
- Dipartimento di Medicina di Precisione, University Della Campania L. Vanvitelli, Naples, Italy
| | - Kilian Schober
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Magali Irla
- CNRS, INSERM, Centre D'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, Marseille, France
| | - Kerstin Sarter
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Mario M Zaiss
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universiät Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
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15
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Rudqvist NP, Charpentier M, Lhuillier C, Wennerberg E, Spada S, Sheridan C, Zhou XK, Zhang T, Formenti SC, Sims JS, Alonso A, Demaria S. Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors. Nat Commun 2023; 14:5146. [PMID: 37620372 PMCID: PMC10449830 DOI: 10.1038/s41467-023-40844-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 08/13/2023] [Indexed: 08/26/2023] Open
Abstract
Radiation therapy (RT) increases tumor response to CTLA-4 inhibition (CTLA4i) in mice and in some patients, yet deep responses are rare. To identify rational combinations of immunotherapy to improve responses we use models of triple negative breast cancer highly resistant to immunotherapy in female mice. We find that CTLA4i promotes the expansion of CD4+ T helper cells, whereas RT enhances T cell clonality and enriches for CD8+ T cells with an exhausted phenotype. Combination therapy decreases regulatory CD4+ T cells and increases effector memory, early activation and precursor exhausted CD8+ T cells. A combined gene signature comprising these three CD8+ T cell clusters is associated with survival in patients. Here we show that targeting additional immune checkpoints expressed by intratumoral T cells, including PD1, is not effective, whereas CD40 agonist therapy recruits resistant tumors into responding to the combination of RT and CTLA4i, indicating the need to target different immune compartments.
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Affiliation(s)
- Nils-Petter Rudqvist
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson, Houston, TX, 77030, USA
- Department of Immunology, University of Texas MD Anderson, Houston, TX, 77030, USA
| | - Maud Charpentier
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Claire Lhuillier
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Immuno-Oncology, Sanofi, 94403, Vitry-sur-Seine, France
| | - Erik Wennerberg
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, 10065, USA
- Division of Radiotherapy and Imaging, Institute of Cancer Research, London, SM2 5NG, UK
| | - Sheila Spada
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Caroline Sheridan
- Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Xi Kathy Zhou
- Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Tuo Zhang
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Silvia C Formenti
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Jennifer S Sims
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Alicia Alonso
- Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Sandra Demaria
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, 10065, USA.
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
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16
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Yao YM, Zhang H, Wu Y. [Novel strategy of sepsis immunomodulation targeting dendritic cells]. ZHONGHUA SHAO SHANG YU CHUANG MIAN XIU FU ZA ZHI 2023; 39:606-611. [PMID: 37805688 DOI: 10.3760/cma.j.cn501225-20230321-00087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 10/09/2023]
Abstract
Dendritic cells (DCs) are the major antigen-presenting cells that play critical roles in regulating both innate and acquire immune responses. In the state of sepsis, the number of DCs is obviously decreased with inhibited antigen presenting ability as well as abnormal cytokine secretion, thereby resulting in an impairment of T lymphocyte activation. Previous studies have demonstrated that the depletion and dysfunction of DCs appear to be the main causes associated with the development of sepsis-induced immunosuppression. Based on the characteristic changes of DCs in sepsis and analysis of recent research progress, the authors propose a novel strategy of immunomodulation targeting the apoptosis, differentiation, and dysfunction of DCs, in order to provide new ideas for the prevention and treatment of severe burns and trauma complicated with sepsis.
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Affiliation(s)
- Y M Yao
- Translational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of PLA General Hospital, Beijing 100853, China
| | - H Zhang
- Translational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of PLA General Hospital, Beijing 100853, China
| | - Y Wu
- Translational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of PLA General Hospital, Beijing 100853, China
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17
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Arroyo Hornero R, Idoyaga J. Plasmacytoid dendritic cells: A dendritic cell in disguise. Mol Immunol 2023; 159:38-45. [PMID: 37269733 PMCID: PMC10625168 DOI: 10.1016/j.molimm.2023.05.007] [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: 03/14/2023] [Accepted: 05/20/2023] [Indexed: 06/05/2023]
Abstract
Since their discovery, the identity of plasmacytoid dendritic cells (pDCs) has been at the center of a continuous dispute in the field, and their classification as dendritic cells (DCs) has been recently re-challenged. pDCs are different enough from the rest of the DC family members to be considered a lineage of cells on their own. Unlike the exclusive myeloid ontogeny of cDCs, pDCs may have dual origin developing from myeloid and lymphoid progenitors. Moreover, pDCs have the unique ability to quickly secrete abundant levels of type I interferon (IFN-I) in response to viral infections. In addition, pDCs undergo a differentiation process after pathogen recognition that allows them to activate T cells, a feature that has been shown to be independent of presumed contaminating cells. Here, we aim to provide an overview of the historic and current understanding of pDCs and argue that their classification as either lymphoid or myeloid may be an oversimplification. Instead, we propose that the capacity of pDCs to link the innate and adaptive immune response by directly sensing pathogens and activating adaptive immune responses justify their inclusion within the DC network.
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Affiliation(s)
- Rebeca Arroyo Hornero
- Microbiology & Immunology Department, and Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Juliana Idoyaga
- Microbiology & Immunology Department, and Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
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18
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Lyu Z, Hu Y, Guo Y, Liu D. Modulation of bone remodeling by the gut microbiota: a new therapy for osteoporosis. Bone Res 2023; 11:31. [PMID: 37296111 PMCID: PMC10256815 DOI: 10.1038/s41413-023-00264-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 04/01/2023] [Accepted: 04/18/2023] [Indexed: 06/12/2023] Open
Abstract
The gut microbiota (GM) plays a crucial role in maintaining the overall health and well-being of the host. Recent studies have demonstrated that the GM may significantly influence bone metabolism and degenerative skeletal diseases, such as osteoporosis (OP). Interventions targeting GM modification, including probiotics or antibiotics, have been found to affect bone remodeling. This review provides a comprehensive summary of recent research on the role of GM in regulating bone remodeling and seeks to elucidate the regulatory mechanism from various perspectives, such as the interaction with the immune system, interplay with estrogen or parathyroid hormone (PTH), the impact of GM metabolites, and the effect of extracellular vesicles (EVs). Moreover, this review explores the potential of probiotics as a therapeutic approach for OP. The insights presented may contribute to the development of innovative GM-targeted therapies for OP.
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Affiliation(s)
- Zhengtian Lyu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yongfei Hu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yuming Guo
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Dan Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
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19
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Fischer V, Bülow JM, Krüger BT, Ragipoglu D, Vikman A, Haffner-Luntzer M, Katsoulis-Dimitriou K, Dudeck A, Ignatius A. Role of Mast-Cell-Derived RANKL in Ovariectomy-Induced Bone Loss in Mice. Int J Mol Sci 2023; 24:ijms24119135. [PMID: 37298085 DOI: 10.3390/ijms24119135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/17/2023] [Accepted: 05/20/2023] [Indexed: 06/12/2023] Open
Abstract
Mast cells may contribute to osteoporosis development, because patients with age-related or post-menopausal osteoporosis exhibit more mast cells in the bone marrow, and mastocytosis patients frequently suffer from osteopenia. We previously showed that mast cells crucially regulated osteoclastogenesis and bone loss in ovariectomized, estrogen-depleted mice in a preclinical model for post-menopausal osteoporosis and found that granular mast cell mediators were responsible for these estrogen-dependent effects. However, the role of the key regulator of osteoclastogenesis, namely, receptor activator of NFκB ligand (RANKL), which is secreted by mast cells, in osteoporosis development has, to date, not been defined. Here, we investigated whether mast-cell-derived RANKL participates in ovariectomy (OVX)-induced bone loss by using female mice with a conditional Rankl deletion. We found that this deletion in mast cells did not influence physiological bone turnover and failed to protect against OVX-induced bone resorption in vivo, although we demonstrated that RANKL secretion was significantly reduced in estrogen-treated mast cell cultures. Furthermore, Rankl deletion in mast cells did not influence the immune phenotype in non-ovariectomized or ovariectomized mice. Therefore, other osteoclastogenic factors released by mast cells might be responsible for the onset of OVX-induced bone loss.
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Affiliation(s)
- Verena Fischer
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
| | - Jasmin Maria Bülow
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
| | - Benjamin Thilo Krüger
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
| | - Deniz Ragipoglu
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
| | - Anna Vikman
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
| | - Melanie Haffner-Luntzer
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
| | - Konstantinos Katsoulis-Dimitriou
- Institute for Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Anne Dudeck
- Institute for Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
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20
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Huang ST, Chiu TF, Chiu CW, Kao YN, Wang IK, Chang CT, Li CY, Sun CS, Lin CL, Yu TM, Kao CH. Denosumab treatment and infection risks in patients with osteoporosis: propensity score matching analysis of a national-wide population-based cohort study. Front Endocrinol (Lausanne) 2023; 14:1182753. [PMID: 37274347 PMCID: PMC10235685 DOI: 10.3389/fendo.2023.1182753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 05/04/2023] [Indexed: 06/06/2023] Open
Abstract
Introduction Denosumab demonstrates efficacy in reducing the incidence of hip, vertebral, and nonvertebral fractures in postmenopausal women with osteoporosis. We present a population-based national cohort study to evaluate the infection risks in patients with osteoporosis after long-term denosumab therapy. Methods We used the Taiwan National Health Insurance Research Database (NHIRD) to identify patients with osteoporosis. The case cohort comprised patients treated with denosumab. Propensity score (PS) matching was used to select denosumab nonusers for the control cohort. The study period was between August 2011 and December 2017. Our study comprised 30,106 pairs of case and control patients. Results Patients receiving denosumab therapy had high risks of the following infections: pneumonia and influenza (adjusted hazard ratio [aHR]: 1.33; 95% confidence interval [CI]: 1.27 -1.39), urinary tract infection (aHR: 1.36; 95% CI:1.32 -1.40), tuberculosis (aHR: 1.60; 95% CI: 1.36 -1.87), fungal infection (aHR: 1.67; 95% CI:1.46 -1.90), candidiasis (aHR: 1.68; 95% CI: 1.47 -1.93), herpes zoster infection (aHR: 1.27; 95% CI: 1.19 -1.35), sepsis (aHR: 1.54; 95% CI:1.43 -1.66), and death (aHR: 1.26; 95% CI: 1.20 -1.32). However, the longer the duration of denosumab treatment, the lower the risk patients had of developing infections. Discussion Denosumab therapy is associated with a higher infection risk at the early periods of treatment. Nevertheless, the risk attenuates significantly after the 2nd year of therapy. Clinicians should closely monitor infection status in patients with osteoporosis during the initial stages of denosumab therapy.
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Affiliation(s)
- Shih-Ting Huang
- Division of Nephrology, Taichung Veterans General Hospital, Taichung, Taiwan
- Graduate Institute of Public Health, China Medical University, Taichung, Taiwan
- Department of Internal Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Ting-Fang Chiu
- Department of Pediatrics, Taipei City Hospital Zhongxiao Branch, Taipei, Taiwan
- Department of Health and Welfare, University of Taipei, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Graduate Institute of Business Administration, Fu Jen Catholic University, New Taipei, Taiwan
| | - Chih-Wei Chiu
- Department of Nephrology, Kaohsiung Medical University Baccalaureate Medicine, Kaohsiung, Taiwan
| | - Yu-Nong Kao
- Division of Nephrology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Internal Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - I-Kang Wang
- Department of Internal Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Chi-Tzung Chang
- Department of Internal Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Chi-Yuan Li
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Chung-Shu Sun
- Department of Pediatrics, Taipei City Hospital Zhongxiao Branch, Taipei, Taiwan
| | - Cheng-Li Lin
- Department of Internal Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Tung-Min Yu
- Division of Nephrology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Internal Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
- Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
- Artificial Intelligence Center, China Medical University Hospital, Taichung, Taiwan
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21
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Hu N, Wang J, Ju B, Li Y, Fan P, Jin X, Kang X, Wu S. Recent advances of osteoimmunology research in rheumatoid arthritis: From single-cell omics approach. Chin Med J (Engl) 2023:00029330-990000000-00608. [PMID: 37166215 DOI: 10.1097/cm9.0000000000002678] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Indexed: 05/12/2023] Open
Abstract
ABSTRACT Cellular immune responses as well as generalized and periarticular bone loss are the key pathogenic features of rheumatoid arthritis (RA). Under the pathological conditions of RA, dysregulated inflammation and immune processes tightly interact with skeletal system, resulting in pathological bone damage via inhibition of bone formation or induction of bone resorption. Single-cell omics technologies are revolutionary tools in the field of modern biological research.They enable the display of the state and function of cells in various environments from a single-cell resolution, thus making it conducive to identify the dysregulated molecular mechanisms of bone destruction in RA as well as the discovery of potential therapeutic targets and biomarkers. Here, we summarize the latest findings of single-cell omics technologies in osteoimmunology research in RA. These results suggest that single-cell omics have made significant contributions to transcriptomics and dynamics of specific cells involved in bone remodeling, providing a new direction for our understanding of cellular heterogeneity in the study of osteoimmunology in RA.
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Affiliation(s)
- Nan Hu
- Department of Rheumatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Jing Wang
- Department of Rheumatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Bomiao Ju
- Department of Rheumatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yuanyuan Li
- Department of Rheumatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Ping Fan
- Department of Rheumatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Xinxin Jin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China
| | - Xiaomin Kang
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Shufang Wu
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
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22
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Onji M, Penninger JM. RANKL and RANK in Cancer Therapy. Physiology (Bethesda) 2023; 38:0. [PMID: 36473204 DOI: 10.1152/physiol.00020.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Receptor activator of nuclear factor-κB (RANK) and its ligand (RANKL) are key regulators of mammalian physiology such as bone metabolism, immune tolerance and antitumor immunity, and mammary gland biology. Here, we explore the multiple functions of RANKL/RANK in physiology and pathophysiology and discuss underlying principles and strategies to modulate the RANKL/RANK pathway as a therapeutic target in immune-mediated cancer treatment.
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Affiliation(s)
- Masahiro Onji
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, VBC-Vienna BioCenter, Vienna, Austria
| | - Josef M Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, VBC-Vienna BioCenter, Vienna, Austria.,Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
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23
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Kim HJ, Lee DK, Choi JY. Functional Role of Phospholipase D in Bone Metabolism. J Bone Metab 2023; 30:117-125. [PMID: 37449345 PMCID: PMC10346002 DOI: 10.11005/jbm.2023.30.2.117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/14/2023] [Accepted: 05/27/2023] [Indexed: 07/18/2023] Open
Abstract
Phospholipase D (PLD) proteins are major enzymes that regulate various cellular functions, such as cell growth, cell migration, membrane trafficking, and cytoskeletal dynamics. As they are responsible for such important biological functions, PLD proteins have been considered promising therapeutic targets for various diseases, including cancer and vascular and neurological diseases. Intriguingly, emerging evidence indicates that PLD1 and PLD2, 2 major mammalian PLD isoenzymes, are the key regulators of bone remodeling; this suggests that these isozymes could be used as potential therapeutic targets for bone diseases, such as osteoporosis and rheumatoid arthritis. PLD1 or PLD2 deficiency in mice can lead to decreased bone mass and dysregulated bone homeostasis. Although both mutant mice exhibit similar skeletal phenotypes, PLD1 and PLD2 play distinct and nonredundant roles in bone cell function. This review summarizes the physiological roles of PLD1 and PLD2 in bone metabolism, focusing on recent findings of the biological functions and action mechanisms of PLD1 and PLD2 in bone cells.
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24
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Lai ZZ, Zhou WJ, Shi JW, Meng YH, Wu JN, Ye JF, Peng T, Xu CE, Li MQ. RANKL up-regulated by progesterone aggravates lipopolysaccharide-induced acute lung injury during pregnancy. J Reprod Immunol 2023; 155:103788. [PMID: 36580846 DOI: 10.1016/j.jri.2022.103788] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 11/21/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Acute lung injury (ALI) is a common acute respiratory disease with high morbidity and mortality rate in pregnant women. Receptor activator of NF-κB ligand (TNFSF11, also known as RANKL) exerts either pro-inflammatory or anti-inflammatory effects on the immune response. LPS administration reduced the survival time (n = 10, p < 0.01), increased wet/dry ratio (n = 10, p < 0.001) and lung injury score (n = 10, p < 0.001), the elevated proportions of plasmacytoid dendritic cells (pDCs) (n = 10, p < 0.0001), tissue-resident DCs (resDCs) (n = 10, p < 0.0001), macrophages (n = 10, p < 0.0001), and neutrophils (n = 10, p < 0.0001), and the expressions of costimulatory molecules and inflammation cytokines (n = 10, p < 0.05) in lungs of pregnant mice, compared with non-pregnant mice. In vitro, progesterone up-regulated the expression of RANKL (n > 6, p < 0.05) on pulmonary fibroblasts. The results of cytokine arrays showed that the cytokines associated with inflammatory response and leukocyte differentiation were decreased in pulmonary fibroblasts after treatment with anti-RANKL neutralizing antibody, compared with control pulmonary fibroblasts. More notably, we found that Tnfsf11-/- pregnant mice had longer survival durations (n = 10, p < 0.01), lower lung injury scores (n = 10, p < 0.05), and lower immune cell infiltration (n = 10, p < 0.05). These data imply that the RANKL/RANK axis plays an essential role in LPS-induced ALI during pregnancy possibly through a variety of pathways.
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Affiliation(s)
- Zhen-Zhen Lai
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200080, People's Republic of China; NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 201203, People's Republic of China
| | - Wen-Jie Zhou
- Center of Reproductive Medicine of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Jia-Wei Shi
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200080, People's Republic of China
| | - Yu-Han Meng
- Center of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang 261035, People's Republic of China
| | - Jiang-Nan Wu
- Clinical Epidemiology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, People's Republic of China
| | - Jiang-Feng Ye
- Institute for Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138632, Singapore
| | - Ting Peng
- Department of Obstetrics, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, People's Republic of China.
| | - Chang-En Xu
- Department of Obstetrics, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, People's Republic of China.
| | - Ming-Qing Li
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200080, People's Republic of China; NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 201203, People's Republic of China; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China.
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25
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Wu Y, Yang Y, Wang L, Chen Y, Han X, Sun L, Chen H, Chen Q. Effect of Bifidobacterium on osteoclasts: TNF-α/NF-κB inflammatory signal pathway-mediated mechanism. Front Endocrinol (Lausanne) 2023; 14:1109296. [PMID: 36967748 PMCID: PMC10034056 DOI: 10.3389/fendo.2023.1109296] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 02/14/2023] [Indexed: 03/11/2023] Open
Abstract
Osteoporosis is a systemic multifactorial bone disease characterized by low bone quality and density and bone microstructure damage, increasing bone fragility and fracture vulnerability. Increased osteoclast differentiation and activity are important factors contributing to bone loss, which is a common pathological manifestation of bone diseases such as osteoporosis. TNF-a/NF-κB is an inflammatory signaling pathway with a key regulatory role in regulating osteoclast formation, and the classical pathway RANKL/RANK/OPG assists osteoclast formation. Activation of this inflammatory pathway promotes the formation of osteoclasts and accelerates the process of osteoporosis. Recent studies and emerging evidence have consistently demonstrated the potential of probiotics to modulate bone health. Secretions of Bifidobacterium, a genus of probiotic bacteria in the phylum Actinobacteria, such as short-chain fatty acids, equol, and exopolysaccharides, have indicated beneficial effects on bone health. This review discusses the molecular mechanisms of the TNF-a/NF-κB inflammatory pathway in regulating osteoclast formation and describes the secretions produced by Bifidobacterium and their potential effects on bone health through this pathway, opening up new directions for future research.
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Affiliation(s)
- Yue Wu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yunjiao Yang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lan Wang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yiding Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xuke Han
- College of Acupuncture & Tuina, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Lisha Sun
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Huizhen Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Qiu Chen,
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26
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Zhang R, Peng S, Zhu G. The role of secreted osteoclastogenic factor of activated T cells in bone remodeling. JAPANESE DENTAL SCIENCE REVIEW 2022; 58:227-232. [PMID: 35898473 PMCID: PMC9309401 DOI: 10.1016/j.jdsr.2022.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 06/05/2022] [Accepted: 07/10/2022] [Indexed: 12/23/2022] Open
Abstract
The process of bone remodeling is connected with the regulated balance between bone cell populations (including bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte). And the mechanism of bone remodeling activity is related to the major pathway, receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) signaling axis. Recently, researchers have found a novel cytokine secreted by activated T cells, which is related to osteoclastogenesis in the absence of osteoblasts or RANKL, leading to bone destruction. They name it the secreted osteoclastogenic factor of activated T cells (SOFAT). SOFAT has been proven to play an essential role in bone remodeling, like mediating the bone resorption in rheumatoid arthritis (RA) and periodontitis. In this review, we outline the latest research concerning SOFAT and discuss the characteristics, location, and regulation of SOFAT. We also summarize the clinical progress of SOFAT and assume the future therapeutic target in some diseases related to bone remodeling.
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Affiliation(s)
- Ruonan Zhang
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuang Peng
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guangxun Zhu
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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27
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Kim HJ, Lee DK, Jin X, Che X, Ryu SH, Choi JY. Phospholipase D2 controls bone homeostasis by modulating M-CSF-dependent osteoclastic cell migration and microtubule stability. EXPERIMENTAL & MOLECULAR MEDICINE 2022; 54:1146-1155. [PMID: 35945449 PMCID: PMC9440116 DOI: 10.1038/s12276-022-00820-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/17/2022] [Accepted: 06/13/2022] [Indexed: 11/09/2022]
Abstract
Phospholipase D2 (PLD2), a signaling protein, plays a central role in cellular communication and various biological processes. Here, we show that PLD2 contributes to bone homeostasis by regulating bone resorption through osteoclastic cell migration and microtubule-dependent cytoskeletal organization. Pld2-deficient mice exhibited a low bone mass attributed to increased osteoclast function without altered osteoblast activity. While Pld2 deficiency did not affect osteoclast differentiation, its absence promoted the migration of osteoclast lineage cells through a mechanism involving M-CSF-induced activation of the PI3K–Akt–GSK3β signaling pathway. The absence of Pld2 also boosted osteoclast spreading and actin ring formation, resulting in elevated bone resorption. Furthermore, Pld2 deletion increased microtubule acetylation and stability, which were later restored by treatment with a specific inhibitor of Akt, an essential molecule for microtubule stabilization and osteoclast bone resorption activity. Interestingly, PLD2 interacted with the M-CSF receptor (c-Fms) and PI3K, and the association between PLD2 and c-Fms was reduced in response to M-CSF. Altogether, our findings indicate that PLD2 regulates bone homeostasis by modulating osteoclastic cell migration and microtubule stability via the M-CSF-dependent PI3K–Akt–GSK3β axis. A signaling protein that regulates bone resorption may prove a useful target in treating skeletal conditions such as osteoporosis and rheumatoid arthritis. Bone is synthesized by cells called osteoblasts, while osteoclasts trigger bone resorption, keeping the skeleton healthy. Imbalances in this recycling process are common in bone disorders. Je-Young Choi and Hyun-Ju Kim at Kyungpook National University in Daegu, South Korea, and co-workers demonstrated that phospholipase D2 (PLD2), a membrane protein, directly regulates bone resorption in mice. Mice without the Pld2 gene had increased osteoclast activity, resulting in low bone mass. The absence of PLD2 promotes the migration of osteoclasts via a particular signaling pathway. This increased the organization of microtubules, polymers that help form the cytoskeleton. The results suggest that regulating PLD2 activity could form the basis of a future treatment method.
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Affiliation(s)
- Hyun-Ju Kim
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Korea Mouse Phenotyping Center, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
| | - Dong-Kyo Lee
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Korea Mouse Phenotyping Center, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Xian Jin
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Korea Mouse Phenotyping Center, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Xiangguo Che
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Korea Mouse Phenotyping Center, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Sung Ho Ryu
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Je-Yong Choi
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Korea Mouse Phenotyping Center, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
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28
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Uresti-Rivera EE, García-Hernández MH. AIM2-inflammasome role in systemic lupus erythematous and rheumatoid arthritis. Autoimmunity 2022; 55:443-454. [PMID: 35880661 DOI: 10.1080/08916934.2022.2103802] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The inflammasome AIM2 regulates multiple aspects of innate immune functions and serves as a critical mediator of inflammatory responses. AIM2 inflammasome activation leads to the production of pro-inflammatory cytokines, IL-1β and IL-18 and participates triggering a pyroptosis response needed to counteract excessive cell proliferation. In addition, AIM2 expression and activation is wide regulated since alteration in its activity may derived in pathological consequences. Consequently, deregulated AIM2 activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of AIM2 inflammasome, as well as its contribution in rheumatoid arthritis and systemic lupus erythematous pathology. Finally, we highlight the participation of the AIM2-inflammasome at the level of joint in rheumatoid arthritis and at kidney in systemic lupus erythematous. The development of therapeutic strategies based on modulation of AIM2-inflammasome activity should have a tissue-specific focus.
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Affiliation(s)
- E E Uresti-Rivera
- Research Center for Health Sciences and Biomedicine, UASLP, San Luis Potosi, Mexico.,Laboratory of Immunology and Cellular and Molecular Biology, Faculty of Chemical Sciences, Autonomous University of San Luis Potosí, UASLP, San Luis Potosí, Mexico
| | - M H García-Hernández
- Instituto Mexicano del Seguro Social, IMSS, Unidad de Investigación Biomédica, Delegación Zacatecas, Zacatecas, México
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29
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Han Y, Colditz GA, Toriola AT. Changes in adiposity over the life course and gene expression in postmenopausal women. Cancer Med 2022; 11:2699-2710. [PMID: 35304837 PMCID: PMC9249983 DOI: 10.1002/cam4.4649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/19/2022] [Accepted: 01/23/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Early life adiposity and changes in adiposity over the life course are associated with mammographic breast density among postmenopausal women. However, the underlying mechanisms are unknown; therefore, we comprehensively examined the associations of early life body mass index (BMI) and changes in BMI from ages 10, 18 to age at mammogram with growth factor, RANK pathway, and sex hormone gene expression in 372 postmenopausal women. METHODS We estimated early life BMI at age 10 using the validated 9-level Stunkard pictogram. We calculated BMI at other ages (18, 30, and current age at mammogram) by dividing weight in kilograms at these ages with height in meters squared. Sequencing for gene expression was performed using the NanoString nCounter system. After adjusting for confounders, we estimated associations using multivariable linear regressions. RESULTS A 10 kg/m2 increase in early life BMI at age 10 was associated with a 17.2% decrease in RANKL gene expression (95% confidence interval [CI] = -30.8, -0.9) but was not associated with changes in other markers. BMI changes from ages 10, 18 to age at mammogram were associated with an increase in BMP2 and decreases in RANK, RANKL, and TNFRSF13B gene expression but were not associated with gene expression of other markers. A 10 kg/m2 increase in early life BMI from age 10 to current age was associated with a 7.8% increase in BMP2 (95% CI = -1.4, 17.8), an 8.5% decrease in RANK (95% CI = -13.9, -2.8), a 10.4% decrease in RANKL (95% CI = -16.9, -3.3), and an 8.5% decrease in TNFRSF13B gene expression (95% CI = -13.8, -2.8). CONCLUSION The results provide new insights into the biological mechanisms underlying the associations of adiposity changes from early life to adulthood and early life adiposity with mammographic breast density in postmenopausal women.
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Affiliation(s)
- Yunan Han
- Division of Public Health Sciences, Department of SurgeryWashington University School of MedicineSaint LouisMissouriUSA
| | - Graham A. Colditz
- Division of Public Health Sciences, Department of SurgeryWashington University School of MedicineSaint LouisMissouriUSA
- Alvin J. Siteman Cancer CenterBarnes‐Jewish Hospital and Washington University School of MedicineSaint LouisMissouriUSA
| | - Adetunji T. Toriola
- Division of Public Health Sciences, Department of SurgeryWashington University School of MedicineSaint LouisMissouriUSA
- Alvin J. Siteman Cancer CenterBarnes‐Jewish Hospital and Washington University School of MedicineSaint LouisMissouriUSA
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30
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Abstract
Since the receptor activator of nuclear factor-kappa B ligand (RANKL), its cognate receptor activator of nuclear factor-kappa B (RANK), and the decoy receptor osteoprotegerin (OPG) were discovered, a number of studies have uncovered the crucial role of the RANKL-RANK-OPG pathway in controlling the key aspect of bone homeostasis, the immune system, inflammation, cancer, and other systems under pathophysiological condition. These findings have expanded the understanding of the multifunctional biology of the RANKL-RANK-OPG pathway and led to the development of therapeutic potential targeting this pathway. The successful development and application of anti-RANKL antibody in treating diseases causing bone loss validates the utility of therapeutic approaches based on the modulation of this pathway. Moreover, recent studies have demonstrated the involvement of the RANKL-RANK pathway in osteoblast differentiation and bone formation, shedding light on the RANKL-RANK dual signaling in coupling bone resorption and bone formation. In this review, we will summarize the current understanding of the RANKL-RANK-OPG system in the context of the bone and the immune system as well as the impact of this pathway in disease conditions, including cancer development and metastasis.
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Affiliation(s)
- Noriko Takegahara
- Departments of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Hyunsoo Kim
- Departments of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Yongwon Choi
- Departments of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
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Improved Characteristics of RANKL Immuno-PET Imaging Using Radiolabeled Antibody Fab Fragments. Pharmaceutics 2022; 14:pharmaceutics14050939. [PMID: 35631525 PMCID: PMC9147590 DOI: 10.3390/pharmaceutics14050939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/15/2022] [Accepted: 04/20/2022] [Indexed: 01/25/2023] Open
Abstract
Purpose: RANKL expression in the tumor microenvironment has been identified as a biomarker of immune suppression, negating the effect of some cancer immunotherapies. Previously we had developed a radiotracer based on the FDA-approved RANKL-specific antibody denosumab, [89Zr]Zr-DFO-denosumab, enabling successful immuno-PET imaging. Radiolabeled denosumab, however, showed long blood circulation and delayed tumor uptake, potentially limiting its applications. Here we aimed to develop a smaller radiolabeled denosumab fragment, [64Cu]Cu-NOTA-denos-Fab, that would ideally show faster tumor accumulation and better diffusion into the tumor for the visualization of RANKL. Experimental design: Fab fragments were prepared from denosumab using papain and conjugated to a NOTA chelator for radiolabeling with 64Cu. The bioconjugates were characterized in vitro using SDS-PAGE analysis, and the binding affinity was assessed using a radiotracer cell binding assay. Small animal PET imaging evaluated tumor targeting and biodistribution in transduced RANKL-ME-180 xenografts. Results: The radiolabeling yield of [64Cu]Cu-NOTA-denos-Fab was 58 ± 9.2%, with a specific activity of 0.79 ± 0.11 MBq/µg (n = 3). A radiotracer binding assay proved specific targeting of RANKL in vitro. PET imaging showed fast blood clearance and high tumor accumulation as early as 1 h p.i. (2.14 ± 0.21% ID/mL), which peaked at 5 h p.i. (2.72 ± 0.61% ID/mL). In contrast, [64Cu]Cu-NOTA-denosumab reached its highest tumor uptake at 24 h p.i. (6.88 ± 1.12% ID/mL). [64Cu]Cu-NOTA-denos-Fab specifically targeted human RANKL in transduced ME-180 xenografts compared with the blocking group and negative ME-180 xenograft model. Histological analysis confirmed RANKL expression in RANKL-ME-180 xenografts. Conclusions: Here, we report on a novel RANKL PET imaging agent, [64Cu]Cu-NOTA-denos-Fab, that allows for fast tumor imaging with improved imaging contrast when compared with its antibody counterpart, showing promise as a potential PET RANKL imaging tool for future clinical applications.
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Li B, Wang P, Jiao J, Wei H, Xu W, Zhou P. Roles of the RANKL-RANK Axis in Immunity-Implications for Pathogenesis and Treatment of Bone Metastasis. Front Immunol 2022; 13:824117. [PMID: 35386705 PMCID: PMC8977491 DOI: 10.3389/fimmu.2022.824117] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 02/16/2022] [Indexed: 12/13/2022] Open
Abstract
A substantial amount patients with cancer will develop bone metastases, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis. Despite advancements in systemic therapies for advanced cancer, survival remains poor for those with bone metastases. The interaction between bone cells and the immune system contributes to a better understanding of the role that the immune system plays in the bone metastasis of cancer. The immune and bone systems share various molecules, including transcription factors, signaling molecules, and membrane receptors, which can stimulate the differentiation and activation of bone-resorbing osteoclasts. The process of cancer metastasis to bone, which deregulates bone turnover and results in bone loss and skeletal-related events (SREs), is also controlled by primary cancer-related factors that modulate the intratumoral microenvironment as well as cellular immune process. The nuclear factor kappa B ligand (RANKL) and the receptor activator of nuclear factor kappa B (RANK) are key regulators of osteoclast development, bone metabolism, lymph node development, and T-cell/dendritic cell communication. RANKL is an osteoclastogenic cytokine that links the bone and the immune system. In this review, we highlight the role of RANKL and RANK in the immune microenvironment and bone metastases and review data on the role of the regulatory mechanism of immunity in bone metastases, which could be verified through clinical efficacy of RANKL inhibitors for cancer patients with bone metastases. With the discovery of the specific role of RANK signaling in osteoclastogenesis, the humanized monoclonal antibody against RANKL, such as denosumab, was available to prevent bone loss, SREs, and bone metastases, providing a unique opportunity to target RANKL/RANK as a future strategy to prevent bone metastases.
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Affiliation(s)
- Bo Li
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Pengru Wang
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jian Jiao
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Haifeng Wei
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wei Xu
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Pingting Zhou
- Department of Radiation Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Pro-Calcific Environment Impairs Ischaemia-Driven Angiogenesis. Int J Mol Sci 2022; 23:ijms23063363. [PMID: 35328786 PMCID: PMC8954938 DOI: 10.3390/ijms23063363] [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: 01/31/2022] [Revised: 03/14/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023] Open
Abstract
Peripheral arterial disease (PAD) is characterised by accelerated arterial calcification and impairment in angiogenesis. Studies implicate vascular calcification as a contributor to PAD, but the mechanisms remain unclear. We aimed to determine the effect of calcification on ischaemia-driven angiogenesis. Human coronary artery endothelial cells (ECs) were treated with calcification medium (CM: CaCl2 2.7 mM, Na2PO4 2.0 mM) for 24 h and exposed to normoxia (5% CO2) or hypoxia (1.2% O2; 5% CO2 balanced with N2). In normoxia, CM significantly inhibited tubule formation and migration and upregulated calcification markers of ALP, BMP2, and Runx2. CM elevated levels of calcification-protective gene OPG, demonstrating a compensatory mechanism by ECs. CM failed to induce pro-angiogenic regulators VEGFA and HIF-1α in hypoxia and further suppressed the phosphorylation of endothelial nitric oxide synthase (eNOS) that is essential for vascular function. In vivo, osteoprotegerin-deficient mice (OPG−/−), a calcification model, were subjected to hind-limb ischaemia (HLI) surgery. OPG−/− mice displayed elevated serum alkaline phosphatase (ALP) activity compared to wild-type controls. OPG−/− mice experienced striking reductions in blood-flow reperfusion in both 8-week-old and 6-month-old mice post-HLI. This coincided with significant impairment in tissue ischaemia and reduced limb function as assessed by clinical scoring (Tarlov). This study demonstrated for the first time that a pro-calcific environment is detrimental to ischaemia-driven angiogenesis. The degree of calcification in patients with PAD can often be a limiting factor with the use of standard therapies. These highly novel findings require further studies for full elucidation of the mechanisms involved and have implications for the development of therapies to suppress calcification in PAD.
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Lee S, Kim M, Hong S, Kim EJ, Kim JH, Sohn Y, Jung HS. Effects of Sparganii Rhizoma on Osteoclast Formation and Osteoblast Differentiation and on an OVX-Induced Bone Loss Model. Front Pharmacol 2022; 12:797892. [PMID: 35058781 PMCID: PMC8764242 DOI: 10.3389/fphar.2021.797892] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/06/2021] [Indexed: 12/31/2022] Open
Abstract
Postmenopausal osteoporosis is caused by an imbalance between osteoclasts and osteoblasts and causes severe bone loss. Osteoporotic medicines are classified into bone resorption inhibitors and bone formation promoters according to the mechanism of action. Long-term use of bisphosphonate and selective estrogen receptor modulators (SERMs) can cause severe side effects in postmenopausal osteoporosis patients. Therefore, it is important to find alternative natural products that reduce osteoclast activity and increase osteoblast formation. Sparganii Rhizoma (SR) is the dried tuberous rhizome of Sparganium stoloniferum Buchanan-Hamilton and is called “samreung” in Korea. However, to date, the effect of SR on osteoclast differentiation and the ovariectomized (OVX)-induced bone loss model has not been reported. In vitro, tartrate-resistant acid phosphatase (TRAP) staining, western blots, RT-PCR and other methods were used to examine the effect of SR on osteoclast differentiation and osteoblasts. In vivo, we confirmed the effect of SR in a model of OVX-induced postmenopausal osteoporosis. SR inhibited osteoclast differentiation and decreased the expression of TNF receptor-associated factor 6 (TRAF6), nuclear factor of activated T cells 1 (NFATc1) and c-Fos pathway. In addition, SR stimulates osteoblast differentiation and increased protein expression of the bone morphogenetic protein 2 (BMP-2)/SMAD signaling pathway. Moreover, SR protected against bone loss in OVX-induced rats. Our results appear to advance our knowledge of SR and successfully demonstrate its potential role as a osteoclastogenesis-inhibiting and osteogenesis-promoting herbal medicine for the treatment of postmenopausal osteoporosis.
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Affiliation(s)
- Sungyub Lee
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Minsun Kim
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Sooyeon Hong
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Eom Ji Kim
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Jae-Hyun Kim
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Youngjoo Sohn
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Hyuk-Sang Jung
- Department of Anatomy, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
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35
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CD40 stimulation as a molecular adjuvant for cancer vaccines and other immunotherapies. Cell Mol Immunol 2022; 19:14-22. [PMID: 34282297 PMCID: PMC8752810 DOI: 10.1038/s41423-021-00734-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/31/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023] Open
Abstract
The substantial advances attained by checkpoint blockade immunotherapies have driven an expansion in the approaches used to promote T cell access to the tumor microenvironment to provide targets for checkpoint immunotherapy. Inherent in any T cell response to a tumor antigen is the capacity of dendritic cells to initiate and support such responses. Here, the rationale and early immunobiology of CD40 as a master regulator of dendritic cell activation is reviewed, with further contextualization and appreciation for the role of CD40 stimulation not only in cancer vaccines but also in other contemporary immune-oncology approaches.
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36
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The Roadmap of RANKL/RANK Pathway in Cancer. Cells 2021; 10:cells10081978. [PMID: 34440747 PMCID: PMC8393235 DOI: 10.3390/cells10081978] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 01/02/2023] Open
Abstract
The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.
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37
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Hasegawa T, Kikuta J, Ishii M. Imaging of bone and joints in vivo: pathological osteoclastogenesis in arthritis. Int Immunol 2021; 33:679-686. [PMID: 34324641 DOI: 10.1093/intimm/dxab047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 07/28/2021] [Indexed: 11/12/2022] Open
Abstract
Osteoimmunology highlights the reciprocal interactions between the skeletal and immune systems. Over the past two decades, many molecules that link the two have been identified, including cytokines, receptors and transcription factors, leading to successful translation of research into therapeutic approaches to autoimmune diseases such as rheumatoid arthritis. The development of an intravital imaging system using multi-photon microscopy, combined with a variety of fluorescent probes and reporter mouse strains, has provided valuable insights into the real-time dynamics of osteoclasts and immune cells in the bone marrow. This technique is now applied to the synovial tissue of arthritic mice to investigate the pathogenesis of osteoimmune diseases and enables direct observation of complex biological phenomena in vivo. In addition, rapid progress in the next-generation sequencing technologies has provided important insights into the field of osteoimmunology through characterizing individual cells in the synovial microenvironment. Single-cell RNA sequencing (scRNA-seq) dissects cellular heterogeneity within a biological system and enables the identification of specific cells differentiating into mature osteoclasts within the previously defined "osteoclast precursor (OP)-containing population". In this review, we will explain the cellular interactions and cytokine milieu involved in inflammatory bone destruction and update how the novel technologies, such as scRNA-seq and intravital imaging, have contributed to better understand the pathogenesis of bone destruction in arthritis.
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Affiliation(s)
- Tetsuo Hasegawa
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Yamada-oka, Suita, Osaka, Japan
| | - Junichi Kikuta
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Yamada-oka, Suita, Osaka, Japan.,WPI-Immunology Frontier Research Center, Osaka University, Yamada-oka, Suita, Osaka, Japan.,Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Masaru Ishii
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Yamada-oka, Suita, Osaka, Japan.,WPI-Immunology Frontier Research Center, Osaka University, Yamada-oka, Suita, Osaka, Japan.,Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
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38
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Vellozo NS, Rigoni TS, Lopes MF. New Therapeutic Tools to Shape Monocyte Functional Phenotypes in Leishmaniasis. Front Immunol 2021; 12:704429. [PMID: 34249011 PMCID: PMC8267810 DOI: 10.3389/fimmu.2021.704429] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/14/2021] [Indexed: 01/25/2023] Open
Abstract
In the innate immunity to Leishmania infection tissue-resident macrophages and inflammatory monocytes accumulate host-cell, effector, and efferocytosis functions. In addition, neutrophils, as host, effector, and apoptotic cells, as well as tissue-resident and monocyte-derived dendritic cells (DCs) imprint innate and adaptive immunity to Leishmania parasites. Macrophages develop phenotypes ranging from antimicrobial M1 to parasite-permissive M2, depending on mouse strain, Leishmania species, and T-cell cytokines. The Th1 (IFN-γ) and Th2 (IL-4) cytokines, which induce classically-activated (M1) or alternatively-activated (M2) macrophages, underlie resistance versus susceptibility to leishmaniasis. While macrophage phenotypes have been well discussed, new developments addressed the monocyte functional phenotypes in Leishmania infection. Here, we will emphasize the role of inflammatory monocytes to access how potential host-directed therapies for leishmaniasis, such as all-trans-retinoic acid (ATRA) and the ligand of Receptor Activator of Nuclear Factor-Kappa B (RANKL) might modulate immunity to Leishmania infection, by directly targeting monocytes to develop M1 or M2 phenotypes.
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Affiliation(s)
- Natália S Vellozo
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Thaís S Rigoni
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcela F Lopes
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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39
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Keeton R, du Toit JP, Hsu NJ, Dube F, Jacobs M. Immune control of Mycobacterium tuberculosis is dependent on both soluble TNFRp55 and soluble TNFRp75. Immunology 2021; 164:524-540. [PMID: 34129695 DOI: 10.1111/imm.13385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/30/2021] [Accepted: 05/22/2021] [Indexed: 12/12/2022] Open
Abstract
Tuberculosis presents a global health challenge, and tumour necrosis factor (TNF) signalling is required for host immunity against Mycobacterium tuberculosis (Mtb). TNF receptor shedding, however, compromises effective immunity by reducing bioactive TNF through the formation of inactive complexes. In this study, we first compared the effect of total soluble TNF receptors using a transgenic p55ΔNS /p75-/- murine strain on host protection during a low-dose aerosol Mtb H37Rv challenge. We report that the presence of membrane-bound TNFRp55 alone in the absence of TNFRp75 results in superior control of a primary Mtb infection where p55ΔNS /p75-/- hyperactive dendritic cells displayed an increased capacity to induce a hyperactive Mtb-specific CD4+ T-cell response. p55ΔNS /p75-/- dendritic cells expressed a higher frequency of MHCII and increased MFIs for both CD86 and MHCII, while CD4+ T cells had higher expression of CD44 and IFN-γ. Next, the relative contributions of soluble TNFRp55 and soluble TNFRp75 to host protection against either primary Mtb infection or during reactivation of latent tuberculosis were delineated by comparing the experimental outcomes of control C57BL/6 mice to transgenic p55ΔNS /p75-/- , p55ΔNS and p75-/- mouse strains. We found that soluble TNFRp55 is redundant for immune regulation during the chronic stages of a primary Mtb infection. However, TNFRp55 together with soluble TNFRp75 has a crucial role in immune regulation of reactivation of latent tuberculosis.
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Affiliation(s)
- Roanne Keeton
- Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa
| | - Jan Pierre du Toit
- Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa
| | - Nai-Jen Hsu
- Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa
| | - Felix Dube
- Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa
| | - Muazzam Jacobs
- Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa.,National Health Laboratory Service, Johannesburg, South Africa.,Immunology of Infectious Disease Research Unit, University of Cape Town, Cape Town, South Africa
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40
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RANKL immunisation inhibits prostate cancer metastasis by modulating EMT through a RANKL-dependent pathway. Sci Rep 2021; 11:12186. [PMID: 34108600 PMCID: PMC8190078 DOI: 10.1038/s41598-021-91721-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 05/31/2021] [Indexed: 12/17/2022] Open
Abstract
Prostate cancer (PCa) morbidity in the majority of patients is due to metastatic events, which are a clinical obstacle. Therefore, a better understanding of the mechanism underlying metastasis is imperative if we are to develop novel therapeutic strategies. Receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) regulates bone remodelling. Thus, agents that suppress RANKL signalling may be useful pharmacological treatments. Here, we used preclinical experimental models to investigate whether an inactive form of RANKL affects bone metastasis in RANKL-induced PCa. RANKL was associated with epithelial–mesenchymal transition (EMT) and expression of metastasis-related genes in PC3 cells. Therefore, we proposed a strategy to induce anti-cytokine antibodies using mutant RANKL as an immunogen. RANKL promoted migration and invasion of PC3 cells through EMT, and induced a significant increase in binding of β-catenin to TCF-4, an EMT-induced transcription factor in PCa cells, via mitogen-activated protein kinase and β-catenin/TCF-4 signalling. Thus, RANKL increased EMT and the metastatic properties of PC3 cells, suggesting a role as a therapeutic target to prevent PCa metastasis. Treatment with mutant RANKL reduced EMT and metastasis of PC3 PCa cells in an experimental metastasis model. Thus, mutant RANKL could serve as a potential vaccine to prevent and treat metastatic PCa.
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41
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Systems genetics in diversity outbred mice inform BMD GWAS and identify determinants of bone strength. Nat Commun 2021; 12:3408. [PMID: 34099702 PMCID: PMC8184749 DOI: 10.1038/s41467-021-23649-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 05/10/2021] [Indexed: 12/14/2022] Open
Abstract
Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; however, their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Here, we use Diversity Outbred (DO) mice to directly address these limitations by performing a systems genetics analysis of 55 complex skeletal phenotypes. We apply a network approach to cortical bone RNA-seq data to discover 66 genes likely to be causal for human BMD GWAS associations, including the genes SERTAD4 and GLT8D2. We also perform GWAS in the DO for a wide-range of bone traits and identify Qsox1 as a gene influencing cortical bone accrual and bone strength. In this work, we advance our understanding of the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics. Osteoporosis GWAS faces two challenges, causal gene discovery and a lack of phenotypic diversity. Here, the authors use the Diversity Outbred mouse population to inform human GWAS using networks and map genetic loci for 55 bone traits, identifying new potential bone strength genes.
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42
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Elango J, Bao B, Wu W. The hidden secrets of soluble RANKL in bone biology. Cytokine 2021; 144:155559. [PMID: 33994070 DOI: 10.1016/j.cyto.2021.155559] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 12/25/2022]
Abstract
The discovery of cytokine tumor necrosis factor (TNF) in the 20th century revealed numerous secrets about organ development. In particular, the functions identified for the receptor activator of nuclear factor kappa-β (NF-κβ) ligand (also known as the RANKL/osteoprotegerin ligand (OPGL) or RANK ligand/TNFSF11) in the homeostasis of skeletal structure, function and regulation were not anticipated. Empirical evidence established the receptor-ligand interaction of RANKL with RANK in osteoclast formation. Reverse signaling of RANKL triggers NF-κβ for the degradation of β-catenin to inhibit bone formation. There is also evidence that RANKL modifies the behavior of other cells in the bone microenvironment, including osteoblasts, chondrocytes, endothelial cells and lymphocytes during normal (homeostatic) and diseased (osteoimmune) states. Two forms of RANKL, i.e., soluble and membrane-bound RANKL, are produced by bone cells. Even though soluble RANKL (sRANKL) and membrane-bound RANKL (mRANKL) both stimulate osteoclast formation in vitro, their biological roles are different. mRANKL triggers osteoclastogenesis by binding to RANK through cell-cell interaction; however, sRANKL released from osteogenic cells binds to RANK without cell-cell interaction. This review attempts to hypothesize how sRANKL functions biologically in bone and explore how this hypothesis might influence future research.
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Affiliation(s)
- Jeevithan Elango
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
| | - Bin Bao
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Wenhui Wu
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
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Dewulf J, Vangestel C, Verhoeven Y, De Waele J, Zwaenepoel K, van Dam PA, Elvas F, Van den Wyngaert T. Immuno-PET Molecular Imaging of RANKL in Cancer. Cancers (Basel) 2021; 13:cancers13092166. [PMID: 33946410 PMCID: PMC8124205 DOI: 10.3390/cancers13092166] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/26/2021] [Accepted: 04/27/2021] [Indexed: 12/15/2022] Open
Abstract
PURPOSE The involvement of RANK/RANKL signaling in the tumor microenvironment (TME) in driving response or resistance to immunotherapy has only very recently been recognized. Current quantification methods of RANKL expression suffer from issues such as sensitivity, variability, and uncertainty on the spatial heterogeneity within the TME, resulting in conflicting reports on its reliability and limited use in clinical practice. Non-invasive molecular imaging using immuno-PET is a promising approach combining superior targeting specificity of monoclonal antibodies (mAb) and spatial, temporal and functional information of PET. Here, we evaluated radiolabeled anti-RANKL mAbs as a non-invasive biomarker of RANKL expression in the TME. EXPERIMENTAL DESIGN Anti-human RANKL mAbs (AMG161 and AMG162) were radiolabeled with 89Zr using the bifunctional chelator DFO in high yield, purity and with intact binding affinity. After assessing the biodistribution in healthy CD-1 nude mice, [89Zr]Zr-DFO-AMG162 was selected for further evaluation in ME-180 (RANKL-transduced), UM-SCC-22B (RANKL-positive) and HCT-116 (RANKL-negative) human cancer xenografts to assess the feasibility of in vivo immuno-PET imaging of RANKL. RESULTS [89Zr]Zr-DFO-AMG162 was selected as the most promising tracer for further validation based on biodistribution experiments. We demonstrated specific accumulation of [89Zr]Zr-DFO-AMG162 in RANKL transduced ME-180 xenografts. In UM-SCC-22B xenograft models expressing physiological RANKL levels, [89Zr]Zr-DFO-AMG162 imaging detected significantly higher signal compared to control [89Zr]Zr-DFO-IgG2 and to RANKL negative HCT-116 xenografts. There was good visual agreement with tumor autoradiography and immunohistochemistry on adjacent slides, confirming these findings. CONCLUSIONS [89Zr]Zr-DFO-AMG162 can detect heterogeneous RANKL expression in the TME of human cancer xenografts, supporting further translation of RANKL immuno-PET to evaluate tumor RANKL distribution in patients.
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Affiliation(s)
- Jonatan Dewulf
- Molecular Imaging Center Antwerp (MICA), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium; (J.D.); (C.V.); (F.E.)
| | - Christel Vangestel
- Molecular Imaging Center Antwerp (MICA), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium; (J.D.); (C.V.); (F.E.)
- Nuclear Medicine, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium
| | - Yannick Verhoeven
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium; (Y.V.); (J.D.W.); (K.Z.); (P.A.v.D.)
| | - Jorrit De Waele
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium; (Y.V.); (J.D.W.); (K.Z.); (P.A.v.D.)
| | - Karen Zwaenepoel
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium; (Y.V.); (J.D.W.); (K.Z.); (P.A.v.D.)
- Laboratory of Pathological Anatomy, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium
| | - Peter A. van Dam
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium; (Y.V.); (J.D.W.); (K.Z.); (P.A.v.D.)
- Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium
| | - Filipe Elvas
- Molecular Imaging Center Antwerp (MICA), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium; (J.D.); (C.V.); (F.E.)
| | - Tim Van den Wyngaert
- Molecular Imaging Center Antwerp (MICA), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium; (J.D.); (C.V.); (F.E.)
- Nuclear Medicine, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium
- Correspondence:
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44
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Xiong J, Zhou L, Tian J, Yang X, Li Y, Jin R, Le Y, Rao Y, Sun Y. Cigarette Smoke-Induced Lymphoid Neogenesis in COPD Involves IL-17/RANKL Pathway. Front Immunol 2021; 11:588522. [PMID: 33613513 PMCID: PMC7892459 DOI: 10.3389/fimmu.2020.588522] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 12/14/2020] [Indexed: 12/24/2022] Open
Abstract
IL-17 is critical in lung lymphoid neogenesis in COPD, but the cellular and molecular mechanisms remain to be elucidated. Receptor activator of nuclear factor-κB ligand (RANKL) functions in lymphoid follicle formation in other organs, whether it is involved in IL-17A-dependent lymphoid neogenesis in COPD is unknown. To elucidate the expression and functional role of IL-17A/RANKL pathway in COPD. We first quantified and localized RANKL, its receptor RANK and IL-17A in lungs of patients with COPD, smokers and non-smokers. Next, IL-17A-/- and wild-type (WT) mice were exposed to air or cigarette smoke (CS) for 24 weeks, and lung lymphoid follicles and RANKL-RANK expression were measured. Lastly, we studied the in vitro biological function of RANKL pertaining to lymphoid neogenesis. We found that the expressions of RANKL-RANK and IL-17A, together with lymphoid follicles, were increased in lung tissues from patients with COPD. In WT mice exposed to CS, RANKL-RANK expressions were prominent in lung lymphoid follicles, which were absent in IL-17A-/- mice exposed to CS. In the lymphoid follicles, RANKL+ cells were identified mostly as B cells and RANK was localized in dendritic cells (DCs). In vitro IL-17A increased the expressions of RANKL in B cells and RANK in DCs, which in turn responded to RANKL stimulation by upregulation of CXCL13. Altogether, these results suggest that B lymphocyte RANKL pathway is involved in IL-17A-dependent lymphoid neogenesis in COPD.
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Affiliation(s)
- Jing Xiong
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Lu Zhou
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Jieyu Tian
- Department of Respiratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Xia Yang
- Department of Respiratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yunsong Li
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Rong Jin
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yanqing Le
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Yafei Rao
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Yongchang Sun
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China
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45
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Monteiro AC, Bonomo A. Dendritic cells development into osteoclast-type APCs by 4T1 breast tumor T cells milieu boost bone consumption. Bone 2021; 143:115755. [PMID: 33217627 DOI: 10.1016/j.bone.2020.115755] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/09/2020] [Accepted: 11/11/2020] [Indexed: 12/23/2022]
Abstract
Bone metastases occur in 70% of patients with advanced breast cancer, causing severe morbidity and increased mortality due to osteolytic lesions driven by osteoclasts (OCs) inside the bone marrow (BM) microenvironment. A reciprocal vicious cycle between bone remodeling system and the tumor itself is established by the release of growth factors stored in the mineralized matrix, which in turn feed the tumor, changing tumor behavior and growth. However, BM is not a passive host microenvironment for circulating tumor cells, but instead can be actively modified by the primary tumor before metastatic spread occurs. Indeed, we have shown that T cells specific for the 4T1 mammary carcinoma cell line, are characteristically RANKL+ IL-17F+ CD4+ T cells. Those cells arrive in the BM before metastatic cells and set the pre-metastatic niche. In the absence of T cell derived RANKL, there is no pre-metastatic osteolytic disease and bone metastases do not take place. Recently, dendritic cells (DCs), the main T cell partner at the beginning of the immune response, came into the spotlight as a potential source of OCs progenitors under inflammatory conditions. Regarding bone metastasis, nothing is currently known about DCs plasticity or even its partnership with tumor induced T cells for BM pre-metastatic niche formation. Here, we show that splenic CD11c+ DCs stimulated with 4T1 conditioned media (CM) efficiently differentiated into mature and activated multinucleated giant cells (DC-OC) expressing TRAP and IL-23 cytokine. More important, 4T1 CM derived DC-OCs build a positive loop which amplifies the osteolytic phenomena by maintaining the RANKL+ Th17 T cells and by its own osteoclastic activity. In conclusion, our results indicate that differentiation of OCs from DCs may be achievable in the bone pre osteolytic disease context representing an alternative OC differentiation pathway. Besides being induced by high levels of T cells pro osteoclastogenic cytokines, especially by RANKL, DC-OC keep a positive feedback loop towards osteolysis, maintaining the pro-osteoclastogenic T cell phenotype in the BM.
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Affiliation(s)
- Ana Carolina Monteiro
- Laboratory of Osteo and Tumor Immunology, Department of Immunobiology, Fluminense Federal University, Rio de Janeiro, Brazil; Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
| | - Adriana Bonomo
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; Research Network on Neuroinflammation (RENEURIN), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
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Walsh MC, Choi Y. Regulation of T cell-associated tissues and T cell activation by RANKL-RANK-OPG. J Bone Miner Metab 2021; 39:54-63. [PMID: 33438173 PMCID: PMC8670018 DOI: 10.1007/s00774-020-01178-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/28/2020] [Indexed: 10/22/2022]
Abstract
The receptor activator of nuclear factor kappa-B ligand (RANKL)-RANK-osteoprotegerin (OPG) system is critical to bone homeostasis, but genetically deficient mouse models have revealed important roles in the immune system as well. RANKL-RANK-OPG is particularly important to T cell biology because of its organogenic control of thymic development and secondary lymphoid tissues influence central T cell tolerance and peripheral T cell function. RANKL-RANK-OPG cytokine-receptor interactions are often controlled by regulation of expression of RANKL on developing T cells, which interacts with RANK expressed on some lymphoid tissue cells to stimulate key downstream signaling pathways that affect critical tuning functions of the T cell compartment, like cell survival and antigen presentation. Activation of peripheral T cells is regulated by RANKL-enhanced dendritic cell survival, and dysregulation of the RANKL-RANK-OPG system in this context is associated with loss of T cell tolerance and autoimmune disease. Given its broader implications for immune homeostasis and osteoimmunology, it is critical to further understand how the RANKL-RANK-OPG system operates in T cell biology.
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Affiliation(s)
- Matthew C Walsh
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Yongwon Choi
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
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Rheumatoid Arthritis in the View of Osteoimmunology. Biomolecules 2020; 11:biom11010048. [PMID: 33396412 PMCID: PMC7823493 DOI: 10.3390/biom11010048] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/23/2020] [Accepted: 12/26/2020] [Indexed: 12/12/2022] Open
Abstract
Rheumatoid arthritis is characterized by synovial inflammation and irreversible bone erosions, both highlighting the immense reciprocal relationship between the immune and bone systems, designed osteoimmunology two decades ago. Osteoclast-mediated resorption at the interface between synovium and bone is responsible for the articular bone erosions. The main triggers of this local bone resorption are autoantibodies directed against citrullinated proteins, as well as pro-inflammatory cytokines and the receptor activator of nuclear factor-κB ligand, that regulate both the formation and activity of the osteoclast, as well as immune cell functions. In addition, local bone loss is due to the suppression of osteoblast-mediated bone formation and repair by inflammatory cytokines. Similarly, inflammation affects systemic bone remodeling in rheumatoid arthritis with the net increase in bone resorption, leading to systemic osteoporosis. This review summarizes the substantial progress that has been made in understanding the pathophysiology of systemic and local bone loss in rheumatoid arthritis.
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Deligiorgi MV, Trafalis DT. The safety profile of denosumab in oncology beyond the safety of denosumab as an anti-osteoporotic agent: still more to learn. Expert Opin Drug Saf 2020; 20:191-213. [PMID: 33287586 DOI: 10.1080/14740338.2021.1861246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Initially endorsed as an antiosteoporotic agent, denosumab ‒ human monoclonal antibody inhibiting the receptor activator of nuclear factor kappa-B ligand (RANKL)‒ has currently shown an anticancer potential, rationalizing its exploitation in oncology. A prerequisite for leveraging denosumab in oncology is a favorable safety profile. AREAS COVERED The present review provides an overview of the adverse events of denosumab in oncology, with a focus on hypocalcemia, medication-related osteonecrosis of the jaw, atypical femoral fracture(s), post-denosumab vertebral fractures, increased risk of infections, and excess of second primary cancer. Representative studies addressing the safety and efficacy of denosumab compared to bisphosphonates in oncology are summarized. Critical gaps in the literature concerning the safety of denosumab in oncology are highlighted as opposed to plenty of available safety data on denosumab as an antiosteoporotic agent. EXPERT OPINION Despite the generally acceptable safety profile of denosumab in oncology, many issues remain unresolved. Further research is mandatory to counteract current challenges, namely: (i) validation of risk factors for adverse events; (ii) elucidation of the pathophysiology of the adverse events in search of actionable molecular pathways; (iii) illumination of the association of denosumab with increased risk of infections and/or second primary cancer; (iv) establishment of optimal diagnostic, and therapeutic protocols.
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Affiliation(s)
- Maria V Deligiorgi
- Department of Pharmacology - Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine , Athens, Greece
| | - Dimitrios T Trafalis
- Department of Pharmacology - Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine , Athens, Greece
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Morgan D, Garg M, Tergaonkar V, Tan SY, Sethi G. Pharmacological significance of the non-canonical NF-κB pathway in tumorigenesis. Biochim Biophys Acta Rev Cancer 2020; 1874:188449. [PMID: 33058996 DOI: 10.1016/j.bbcan.2020.188449] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/04/2020] [Accepted: 10/05/2020] [Indexed: 02/06/2023]
Abstract
The understanding of the impact of the non-canonical NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway in several human diseases including autoimmune, inflammatory and cancers has been on the rise. This pathway induces the expression of several important genes involved in diverse biological processes. Though progress has been made in understanding the activation, regulation and biological functions of the non-canonical NF-κB signaling mechanism, no specific drug has been approved to target NF-κB inducing kinase (NIK), the key signaling molecule in this pathway. The inhibition of NIK can serve as a potential therapeutic strategy for various ailments, especially for the treatment of different types of human cancers. There are other targetable downstream molecules in this pathway as well. This review highlights the possible role of the non-canonical NF-κB pathway in normal physiology as well as in different cancers and discusses about various pharmacological strategies to modulate the activation of this pathway.
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Affiliation(s)
- Dhakshayini Morgan
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119 074, Singapore
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Uttar Pradesh, Noida 201313, India
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119 074, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
| | - Soo Yong Tan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119 074, Singapore; Advanced Molecular Pathology Laboratory, Institute of Molecular and Cell Biology, 61 Biopolis Dr, 138673, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 600, Singapore.
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Glasnović A, O'Mara N, Kovačić N, Grčević D, Gajović S. RANK/RANKL/OPG Signaling in the Brain: A Systematic Review of the Literature. Front Neurol 2020; 11:590480. [PMID: 33329338 PMCID: PMC7710989 DOI: 10.3389/fneur.2020.590480] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 10/22/2020] [Indexed: 12/16/2022] Open
Abstract
Together with its dominant immunological and bone remodeling involvement, RRO axis, comprising of receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) signaling, is as well-implicated in CNS functioning and corresponding pathologies. The CNS aspects of RANKL/RANK/OPG (RRO) axis were systematically reviewed. With search 10 databases, and 7 additional resources from first article publication to July 2019, resulted in total 2,222 hits, from which 33 relevant articles were selected. The elements of RRO axis in CNS include cells involved in neuroinflammation, predominantly in microglia, but as well in resident macrophages and inflammatory cells migrating across the blood-brain barrier. The expression in neurons and oligodendrocytes is mainly confined to processes of differentiation and cell death. RRO axis tunes the neuroinflammatory response, depending on the molecular, cellular and pathological context. RANK/RANKL signaling is neuroprotective in TLR-mediated inflammation, while OPG seems detrimental in stroke, but beneficial in multiple sclerosis. The levels of RRO axis elements can serve as biomarkers in the blood and cerebrospinal fluid. They act as neuroprotectant after brain damage even being implicated in body weight- and thermo-regulation. As derivatives of RRO axis already exist as therapeutic agents in bone remodeling, it would be intriquing to see if these or new RRO-based pharmaceuticals would appear effective in CNS therapies.
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Affiliation(s)
- Anton Glasnović
- Department of Histology and Embryology, Zagreb University School of Medicine, Zagreb, Croatia.,Croatian Institute for Brain Research, Zagreb University School of Medicine, Zagreb, Croatia
| | - Niall O'Mara
- Department of Medicine, Cork University Hospital, Cork, Ireland
| | - Nataša Kovačić
- Croatian Institute for Brain Research, Zagreb University School of Medicine, Zagreb, Croatia.,Department of Anatomy, Zagreb University School of Medicine, Zagreb, Croatia
| | - Danka Grčević
- Croatian Institute for Brain Research, Zagreb University School of Medicine, Zagreb, Croatia.,Department of Physiology and Immunology, Zagreb University School of Medicine, Zagreb, Croatia
| | - Srećko Gajović
- Department of Histology and Embryology, Zagreb University School of Medicine, Zagreb, Croatia.,Croatian Institute for Brain Research, Zagreb University School of Medicine, Zagreb, Croatia
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