|
1
|
Chen J, Zeng X, Wang L, Zhang W, Li G, Cheng X, Su P, Wan Y, Li X. Mutual regulation of microglia and astrocytes after Gas6 inhibits spinal cord injury. Neural Regen Res 2025; 20:557-573. [PMID: 38819067 PMCID: PMC11317951 DOI: 10.4103/nrr.nrr-d-23-01130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 12/05/2023] [Accepted: 01/17/2024] [Indexed: 06/01/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202502000-00032/figure1/v/2024-05-28T214302Z/r/image-tiff Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord injury. Microglia and astrocytes play key roles in the spinal cord injury micro-environment and share a close interaction. However, the mechanisms involved remain unclear. In this study, we found that after spinal cord injury, resting microglia (M0) were polarized into pro-inflammatory phenotypes (MG1 and MG3), while resting astrocytes were polarized into reactive and scar-forming phenotypes. The expression of growth arrest-specific 6 (Gas6) and its receptor Axl were significantly down-regulated in microglia and astrocytes after spinal cord injury. In vitro experiments showed that Gas6 had negative effects on the polarization of reactive astrocytes and pro-inflammatory microglia, and even inhibited the cross-regulation between them. We further demonstrated that Gas6 can inhibit the polarization of reactive astrocytes by suppressing the activation of the Yes-associated protein signaling pathway. This, in turn, inhibited the polarization of pro-inflammatory microglia by suppressing the activation of the nuclear factor-κB/p65 and Janus kinase/signal transducer and activator of transcription signaling pathways. In vivo experiments showed that Gas6 inhibited the polarization of pro-inflammatory microglia and reactive astrocytes in the injured spinal cord, thereby promoting tissue repair and motor function recovery. Overall, Gas6 may play a role in the treatment of spinal cord injury. It can inhibit the inflammatory pathway of microglia and polarization of astrocytes, attenuate the interaction between microglia and astrocytes in the inflammatory microenvironment, and thereby alleviate local inflammation and reduce scar formation in the spinal cord.
Collapse
Affiliation(s)
- Jiewen Chen
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Province Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong Province, China
| | - Xiaolin Zeng
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Province Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong Province, China
| | - Le Wang
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Province Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong Province, China
| | - Wenwu Zhang
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Province Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong Province, China
| | - Gang Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Province Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong Province, China
| | - Xing Cheng
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Province Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong Province, China
| | - Peiqiang Su
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Province Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong Province, China
| | - Yong Wan
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Province Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong Province, China
| | - Xiang Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Province Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong Province, China
| |
Collapse
|
|
2
|
Wei Y, Zhang S, Shao F, Sun Y. Ankylosing spondylitis: From pathogenesis to therapy. Int Immunopharmacol 2025; 145:113709. [PMID: 39644789 DOI: 10.1016/j.intimp.2024.113709] [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: 10/28/2024] [Revised: 11/22/2024] [Accepted: 11/22/2024] [Indexed: 12/09/2024]
Abstract
Ankylosing spondylitis (AS) is an autoimmune rheumatic disease that primarily affects the axial joints, with its etiology complex and still not fully understood. The unknown pathogenesis of AS limits the development of treatment strategies, so keeping up-to-date with the current research on AS can help in searching for potential therapeutic targets. In addition to the classic HLA-B27 genetic susceptibility and Th17-related inflammatory signals, increasing research is focusing on the influence of autoantigen-centered autoimmune responses and bone stromal cells on the onset of AS. Autoantigens derived from gut microbiota and preferential TCR both exacerbate the autoimmune response in patients with AS. Furthermore, dysregulated bone metabolism also promotes pathological new bone formation in AS. Current treatments approved for AS almost focus on the management of inflammation with inconsistent treatment results due to the heterogeneity of patients. In this review, we systematically summarized various pathogenesis and management of AS, meanwhile discussed the underlying risk factors and potential therapeutic targets.
Collapse
Affiliation(s)
- Yuxiao Wei
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, Jiangsu, China.
| | - Shuqiong Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, Jiangsu, China.
| | - Fenli Shao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Yang Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, Jiangsu, China.
| |
Collapse
|
|
3
|
Srinath A, Nakamura A, Haroon N. Sequence of Events in the Pathogenesis of Axial Spondyloarthritis: A Current Review-2023 SPARTAN Meeting Proceedings. Curr Rheumatol Rep 2024; 26:133-143. [PMID: 38324125 DOI: 10.1007/s11926-024-01136-x] [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] [Accepted: 01/21/2024] [Indexed: 02/08/2024]
Abstract
PURPOSE OF REVIEW Over the past two decades, significant progress has been made to untangle the etiology of inflammation and new bone formation (NBF) associated with axial spondyloarthritis (axSpA). However, exact mechanisms as to how the disease initiates and develops remain elusive. RECENT FINDINGS Type 3 immunity, centered around the IL-23/IL-17 axis, has been recognized as a key player in the pathogenesis of axSpA. Multiple hypotheses associated with HLA-B*27 have been proposed to account for disease onset and progression of axSpA, potentially by driving downstream T cell responses. However, HLA-B*27 alone is not sufficient to fully explain the development of axSpA. Genome-wide association studies (GWAS) identified several genes that are potentially relevant to disease pathogenesis leading to a better understanding of the immune activation seen in axSpA. Furthermore, gut microbiome studies suggest an altered microbiome in axSpA, and animal studies suggest a pathogenic role for immune cells migrating from the gut to the joint. Recent studies focusing on the pathogenesis of new bone formation (NBF) have highlighted the importance of endochondral ossification, mechanical stress, pre-existing inflammation, and activated anabolic signaling pathways during the development of NBF. Despite the complex etiology of axSpA, recent studies have shed light on pivotal pieces that could lead to a better understanding of the pathogenic events in axSpA.
Collapse
Affiliation(s)
- Archita Srinath
- Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Akihiro Nakamura
- Department of Medicine, Division of Rheumatology, Queen's University, Kingston, ON, Canada
- School of Medicine, Translational Institute of Medicine, Queen's University, Kingston, ON, Canada
- Kingston Health Science Centre, Kingston, ON, Canada
| | - Nigil Haroon
- Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada.
- Krembil Research Institute, University Health Network, Toronto, ON, Canada.
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Division of Rheumatology, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
| |
Collapse
|
|
4
|
Zacarías-Fluck MF, Soucek L, Whitfield JR. MYC: there is more to it than cancer. Front Cell Dev Biol 2024; 12:1342872. [PMID: 38510176 PMCID: PMC10952043 DOI: 10.3389/fcell.2024.1342872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/20/2024] [Indexed: 03/22/2024] Open
Abstract
MYC is a pleiotropic transcription factor involved in multiple cellular processes. While its mechanism of action and targets are not completely elucidated, it has a fundamental role in cellular proliferation, differentiation, metabolism, ribogenesis, and bone and vascular development. Over 4 decades of research and some 10,000 publications linking it to tumorigenesis (by searching PubMed for "MYC oncogene") have led to MYC becoming a most-wanted target for the treatment of cancer, where many of MYC's physiological functions become co-opted for tumour initiation and maintenance. In this context, an abundance of reviews describes strategies for potentially targeting MYC in the oncology field. However, its multiple roles in different aspects of cellular biology suggest that it may also play a role in many additional diseases, and other publications are indeed linking MYC to pathologies beyond cancer. Here, we review these physiological functions and the current literature linking MYC to non-oncological diseases. The intense efforts towards developing MYC inhibitors as a cancer therapy will potentially have huge implications for the treatment of other diseases. In addition, with a complementary approach, we discuss some diseases and conditions where MYC appears to play a protective role and hence its increased expression or activation could be therapeutic.
Collapse
Affiliation(s)
- Mariano F. Zacarías-Fluck
- Models of Cancer Therapies Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Laura Soucek
- Models of Cancer Therapies Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Peptomyc S.L., Barcelona, Spain
| | - Jonathan R. Whitfield
- Models of Cancer Therapies Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| |
Collapse
|
|
5
|
Martini V, Silvestri Y, Ciurea A, Möller B, Danelon G, Flamigni F, Jarrossay D, Kwee I, Foglierini M, Rinaldi A, Cecchinato V, Uguccioni M. Patients with ankylosing spondylitis present a distinct CD8 T cell subset with osteogenic and cytotoxic potential. RMD Open 2024; 10:e003926. [PMID: 38395454 PMCID: PMC10895246 DOI: 10.1136/rmdopen-2023-003926] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
OBJECTIVES Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease affecting mainly the axial skeleton. Peripheral involvement (arthritis, enthesitis and dactylitis) and extra-musculoskeletal manifestations, including uveitis, psoriasis and bowel inflammation, occur in a relevant proportion of patients. AS is responsible for chronic and severe back pain caused by local inflammation that can lead to osteoproliferation and ultimately spinal fusion. The association of AS with the human leucocyte antigen-B27 gene, together with elevated levels of chemokines, CCL17 and CCL22, in the sera of patients with AS, led us to study the role of CCR4+ T cells in the disease pathogenesis. METHODS CD8+CCR4+ T cells isolated from the blood of patients with AS (n=76) or healthy donors were analysed by multiparameter flow cytometry, and gene expression was evaluated by RNA sequencing. Patients with AS were stratified according to the therapeutic regimen and current disease score. RESULTS CD8+CCR4+ T cells display a distinct effector phenotype and upregulate the inflammatory chemokine receptors CCR1, CCR5, CX3CR1 and L-selectin CD62L, indicating an altered migration ability. CD8+CCR4+ T cells expressing CX3CR1 present an enhanced cytotoxic profile, expressing both perforin and granzyme B. RNA-sequencing pathway analysis revealed that CD8+CCR4+ T cells from patients with active disease significantly upregulate genes promoting osteogenesis, a core process in AS pathogenesis. CONCLUSIONS Our results shed light on a new molecular mechanism by which T cells may selectively migrate to inflammatory loci, promote new bone formation and contribute to the pathological ossification process observed in AS.
Collapse
Affiliation(s)
- Veronica Martini
- Institute for Research in Biomedicine, Universitá della Svizzera italiana, Bellinzona, Switzerland
| | - Ylenia Silvestri
- Institute for Research in Biomedicine, Universitá della Svizzera italiana, Bellinzona, Switzerland
| | - Adrian Ciurea
- Department of Rheumatology, University of Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Burkhard Möller
- Department of Rheumatology and Immunology, Inselspital-University Hospital Bern, University of Bern, Bern, Switzerland
| | - Gabriela Danelon
- Institute for Research in Biomedicine, Universitá della Svizzera italiana, Bellinzona, Switzerland
| | - Flavio Flamigni
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - David Jarrossay
- Institute for Research in Biomedicine, Universitá della Svizzera italiana, Bellinzona, Switzerland
| | - Ivo Kwee
- Institute for Research in Biomedicine, Universitá della Svizzera italiana, Bellinzona, Switzerland
| | - Mathilde Foglierini
- Institute for Research in Biomedicine, Universitá della Svizzera italiana, Bellinzona, Switzerland
| | - Andrea Rinaldi
- Institute of Oncology Research, Universitá della Svizzera italiana, Bellinzona, Switzerland
| | - Valentina Cecchinato
- Institute for Research in Biomedicine, Universitá della Svizzera italiana, Bellinzona, Switzerland
| | - Mariagrazia Uguccioni
- Institute for Research in Biomedicine, Universitá della Svizzera italiana, Bellinzona, Switzerland
| |
Collapse
|
|
6
|
Feng X, Wang C, Ji B, Qiao J, Xu Y, Zhu S, Ji Z, Zhou B, Tong W, Xu W. CD_99 G1 neutrophils modulate osteogenic differentiation of mesenchymal stem cells in the pathological process of ankylosing spondylitis. Ann Rheum Dis 2024; 83:324-334. [PMID: 37977819 PMCID: PMC10894850 DOI: 10.1136/ard-2023-224107] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 10/28/2023] [Indexed: 11/19/2023]
Abstract
OBJECTIVES This study aimed to identify the types and heterogeneity of cells within the spinal enthesis and investigate the underlying mechanisms of osteogenesis. METHODS Single-cell RNA sequencing was used to identify cell populations and their gene signatures in the spinal enthesis of five patients with ankylosing spondylitis (AS) and three healthy individuals. The transcriptomes of 40 065 single cells were profiled and divided into 7 clusters: neutrophils, monocytic cells, granulomonocytic progenitor_erythroblasts, T cells, B cells, plasma cells and stromal cells. Real-time quantitative PCR, immunofluorescence, flow cytometry, osteogenesis induction, alizarin red staining, immunohistochemistry, short hairpin RNA and H&E staining were applied to validate the bioinformatics analysis. RESULTS Pseudo-time analysis showed two differentiation directions of stromal cells from the mesenchymal stem cell subpopulation MSC-C2 to two Cxcl12-abundant-reticular (CAR) cell subsets, Osteo-CAR and Adipo-CAR, within which three transcription factors, C-JUN, C-FOS and CAVIN1, were highly expressed in AS and regulated the osteogenesis of mesenchymal stem cells. A novel subcluster of early-stage neutrophils, CD99_G1, was elevated in AS. The proinflammatory characteristics of monocyte dendritic cell progenitor-recombinant adiponectin receptor 2 monocytic cells were explored. Interactions between Adipo-CAR cells, CD99_G1 neutrophils and other cell types were mapped by identifying ligand-receptor pairs, revealing the recruitment characteristics of CD99_G1 neutrophils by Adipo-CAR cells and the pathogenesis of osteogenesis induced in AS. CONCLUSIONS Our results revealed the dynamics of cell subpopulations, gene expression and intercellular interactions during AS pathogenesis. These findings provide new insights into the cellular and molecular mechanisms of osteogenesis and will benefit the development of novel therapeutic strategies.
Collapse
Affiliation(s)
- Xinzhe Feng
- Department of Joint Bone Disease Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Chen Wang
- Department of Joint Bone Disease Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Boyao Ji
- Department of Joint Bone Disease Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Junjie Qiao
- Department of Joint Bone Disease Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yihong Xu
- Department of Joint Bone Disease Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Shanbang Zhu
- Department of Joint Bone Disease Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhou Ji
- Department of Joint Bone Disease Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Bole Zhou
- Department of Joint Bone Disease Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Wenwen Tong
- Department of Joint Bone Disease Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Weidong Xu
- Department of Joint Bone Disease Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| |
Collapse
|
|
7
|
Mathew A, Bhagavaldas MC, Biswas R, Biswas L. Genetic risk factors in ankylosing spondylitis: Insights into etiology and disease pathogenesis. Int J Rheum Dis 2024; 27:e15023. [PMID: 38151980 DOI: 10.1111/1756-185x.15023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 11/07/2023] [Accepted: 12/18/2023] [Indexed: 12/29/2023]
Affiliation(s)
- Ashlin Mathew
- Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, India
| | | | - Raja Biswas
- Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, India
| | - Lalitha Biswas
- Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, India
| |
Collapse
|
|
8
|
Purine metabolites promote ectopic new bone formation in ankylosing spondylitis. Int Immunopharmacol 2023; 116:109810. [PMID: 36774858 DOI: 10.1016/j.intimp.2023.109810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 02/12/2023]
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that mainly affects the axial skeleton, whose typical features are inflammatory back pain, bone structural damage and pathological new bone formation. The pathology of ectopic new bone formation is still little known. In this study, we found increased purine metabolites in plasma of patients with AS. Similarly, metabolome analysis indicated increased purine metabolites in both serum of CD4-Cre; Ptpn11fl/fl and SHP2-deficient chondrocytes. SHP2-deficient chondrocytes promoted the growth of wild type chondrocytes and differentiation of osteoblasts in CD4-Cre; Ptpn11fl/fl mice, which spontaneously developed AS-like bone disease. Purine metabolites, along with PTHrP derived from SHP2-deficient chondrocytes, accelerated the growth of chondrocytes and ectopic new bone formation through PKA/CREB signaling. Moreover, Suramin, a purinergic receptor antagonist, suppressed pathological new bone formation in AS-like bone disease. Overall, these results highlight the potential role of targeting purinergic signaling in retarding ectopic new bone formation in AS.
Collapse
|
|
9
|
Jin Q, Liu Y, Zhang Z, Wen X, Chen Z, Tian H, Kang Z, Wu X, Xu H. MYC promotes fibroblast osteogenesis by regulating ALP and BMP2 to participate in ectopic ossification of ankylosing spondylitis. Arthritis Res Ther 2023; 25:28. [PMID: 36803548 PMCID: PMC9942334 DOI: 10.1186/s13075-023-03011-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 02/09/2023] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND Ectopic ossification is an important cause of disability in patients with ankylosing spondylitis (AS). Whether fibroblasts can transdifferentiate into osteoblasts and contribute to ossification remains unknown. This study aims to investigate the role of stem cell transcription factors (POU5F1, SOX2, KLF4, MYC, etc.) of fibroblasts in ectopic ossification in patients with AS. METHODS Primary fibroblasts were isolated from the ligaments of patients with AS or osteoarthritis (OA). In an in vitro study, primary fibroblasts were cultured in osteogenic differentiation medium (ODM) to induce ossification. The level of mineralization was assessed by mineralization assay. The mRNA and protein levels of stem cell transcription factors were measured by real-time quantitative PCR (q-PCR) and western blotting. MYC was knocked down by infecting primary fibroblasts with lentivirus. The interactions between stem cell transcription factors and osteogenic genes were analysed by chromatin immunoprecipitation (ChIP). Recombinant human cytokines were added to the osteogenic model in vitro to evaluate their role in ossification. RESULTS We found that MYC was elevated significantly in the process of inducing primary fibroblasts to differentiate into osteoblasts. In addition, the level of MYC was remarkably higher in AS ligaments than in OA ligaments. When MYC was knocked down, the expression of the osteogenic genes alkaline phosphatase (ALP) and bone morphogenic protein 2 (BMP2) was decreased, and the level of mineralization was reduced significantly. In addition, the ALP and BMP2 were confirmed to be the direct target genes of MYC. Furthermore, interferon-γ (IFN-γ), which showed high expression in AS ligaments, was found to promote the expression of MYC in fibroblasts in the process of ossification in vitro. CONCLUSIONS This study demonstrates the role of MYC in ectopic ossification. MYC may act as the critical bridge that links inflammation with ossification in AS, thus providing new insights into the molecular mechanisms of ectopic ossification in AS.
Collapse
Affiliation(s)
- Qianmei Jin
- Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Yaoyang Liu
- Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Zhiguo Zhang
- Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Xingzhu Wen
- Department of General Surgery, 72nd Group Army Hospital, Huzhou University, Huzhou, 313000, Zhejiang, China
| | - Ziqiang Chen
- Department of Orthopaedics, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Haijun Tian
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zijian Kang
- Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Xin Wu
- Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Huji Xu
- Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
- School of Medicine, Tsinghua University, Beijing, 100084, China.
- Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
| |
Collapse
|
|
10
|
Yang Q, Zhao Z, Zhao W, Chen Y, Chen Y, Shi J, Ni Q, Cao Y, Sun X, Wang H, Yuan H, Wang R, Sun W. A rescue diet raises the plasma calcium concentration and ameliorates rheumatoid arthritis in mice: Role of CaSR-mediated inhibition of osteoclastogenesis. FASEB J 2023; 37:e22673. [PMID: 36468692 DOI: 10.1096/fj.202200761rrr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 11/09/2022] [Accepted: 11/15/2022] [Indexed: 12/12/2022]
Abstract
Calcium modulates bone cell recruitment, differentiation, and function by binding to the calcium-sensing receptor (CaSR). However, the function of CaSR induced by high extracellular calcium (Ca2+ e ) in the regulation of osteoclast formation in rheumatoid arthritis (RA) remains unknown. Here, we used TNFα-transgenic (TNFTG ) RA mice and their wildtype (WT) littermates fed a normal or a rescue diet (high calcium, high phosphorus, and high lactose diet, termed rescue diet) to compare their joint bone phenotypes. In comparison to TNFTG mice fed the normal diet, articular bone volume and cartilage area are increased, whereas inflamed area, eroded surface, TRAP+ surface, and osteoclast-related genes expression are decreased in TNFTG mice fed the rescue diet. Besides, TNFTG mice fed the rescue diet were found to exhibit more CaSR+ area and less NFATc1+ /TRAP+ area. Furthermore, at normal Ca2+ e concentrations, osteoclast precursors (OCPs) from TNFTG mice formed more osteoclasts than OCPs from WT mice, but the number of osteoclasts gradually decreased when the Ca2+ e concentration increased. Meanwhile, the expression of CaSR increased responding to a high level of Ca2+ e , whereas the expression of NF-κB/NFATc1 signaling molecules decreased. At last, the knockdown of CaSR blocked the inhibition of osteoclast differentiation attributed to high Ca2+ e . Taken together, our findings indicate that high Ca2+ e inhibits osteoclast differentiation in RA mice partially through the CaSR/NF-κB/NFATc1 pathway.
Collapse
Affiliation(s)
- Qiudong Yang
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.,Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Ziwei Zhao
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.,Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Wenhua Zhao
- Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Yue Chen
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yuyi Chen
- Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Jiali Shi
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Qiaoqi Ni
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yanan Cao
- Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Xu Sun
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.,Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Hua Wang
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Hua Yuan
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Ruixia Wang
- Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Wen Sun
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| |
Collapse
|
|
11
|
Iamartino L, Brandi ML. The calcium-sensing receptor in inflammation: Recent updates. Front Physiol 2022; 13:1059369. [PMID: 36467702 PMCID: PMC9716066 DOI: 10.3389/fphys.2022.1059369] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 11/07/2022] [Indexed: 07/30/2023] Open
Abstract
The Calcium-Sensing Receptor (CaSR) is a member of the class C of G-proteins coupled receptors (GPCRs), it plays a pivotal role in calcium homeostasis by directly controlling calcium excretion in the kidneys and indirectly by regulating parathyroid hormone (PTH) release from the parathyroid glands. The CaSR is found to be ubiquitously expressed in the body, playing a plethora of additional functions spanning from fluid secretion, insulin release, neuronal development, vessel tone to cell proliferation and apoptosis, to name but a few. The present review aims to elucidate and clarify the emerging regulatory effects that the CaSR plays in inflammation in several tissues, where it mostly promotes pro-inflammatory responses, with the exception of the large intestine, where contradictory roles have been recently reported. The CaSR has been found to be expressed even in immune cells, where it stimulates immune response and chemokinesis. On the other hand, CaSR expression seems to be boosted under inflammatory stimulus, in particular, by pro-inflammatory cytokines. Because of this, the CaSR has been addressed as a key factor responsible for hypocalcemia and low levels of PTH that are commonly found in critically ill patients under sepsis or after burn injury. Moreover, the CaSR has been found to be implicated in autoimmune-hypoparathyroidism, recently found also in patients treated with immune-checkpoint inhibitors. Given the tight bound between the CaSR, calcium and vitamin D metabolism, we also speculate about their roles in the pathogenesis of severe acute respiratory syndrome coronavirus-19 (SARS-COVID-19) infection and their impact on patients' prognosis. We will further explore the therapeutic potential of pharmacological targeting of the CaSR for the treatment and management of aberrant inflammatory responses.
Collapse
Affiliation(s)
- Luca Iamartino
- Department of Experimental Clinical and Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Maria Luisa Brandi
- F.I.R.M.O. (Italian Foundation for the Research on Bone Diseases), Florence, Italy
| |
Collapse
|
|
12
|
Ren WH, Xin S, Yang K, Yu YB, Li SM, Zheng JJ, Huang K, Zeng RC, Yang XX, Gao L, Li SQ, Zhi K. Strontium‐Doped Hydroxyapatite Promotes Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in Osteoporotic Rats through the CaSR‐JAK2/STAT3 Signaling Pathway. ADVANCED NANOBIOMED RESEARCH 2022. [DOI: 10.1002/anbr.202200018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Affiliation(s)
- Wen-Hao Ren
- Department of Oral and Maxillofacial Surgery The Affiliated Hospital of Qingdao University No.1677 Wutaishan Road Qingdao 266003 China
| | - Shanshan Xin
- Department of Oral and Maxillofacial Surgery The Affiliated Hospital of Qingdao University No.1677 Wutaishan Road Qingdao 266003 China
- School of Stomatology of Qingdao University Qingdao University Qingdao 266003 China
| | - Kai Yang
- School of Materials Science and Engineering Shandong University of Science and Technology Qingdao Shandong 266590 China
| | - Yan-Bin Yu
- State Key Laboratory of Mining Disaster Prevention and Control Co-founded by Shandong Province and the Ministry of Science and Technology Shandong University of Science and Technology Qingdao 266590 China
| | - Shao-Ming Li
- Department of Oral and Maxillofacial Surgery The Affiliated Hospital of Qingdao University No.1677 Wutaishan Road Qingdao 266003 China
- School of Stomatology of Qingdao University Qingdao University Qingdao 266003 China
| | - Jing-Jing Zheng
- Department of Endodontics The Affiliated Hospital of Qingdao University Qingdao 266003 China
| | - Kai Huang
- Department of Radiology The Affiliated Hospital of Qingdao University Qingdao China
| | - Rong-Chang Zeng
- School of Materials Science and Engineering Shandong University of Science and Technology Qingdao Shandong 266590 China
| | - Xiao-Xia Yang
- Department of Oral and Maxillofacial Surgery The Affiliated Hospital of Qingdao University No.1677 Wutaishan Road Qingdao 266003 China
- School of Stomatology of Qingdao University Qingdao University Qingdao 266003 China
| | - Ling Gao
- Department of Oral and Maxillofacial Surgery The Affiliated Hospital of Qingdao University No.1677 Wutaishan Road Qingdao 266003 China
- Key Lab of Oral Clinical Medicine The Affiliated Hospital of Qingdao University Qingdao 266003 China
| | - Shuo-Qi Li
- School of Materials Science and Engineering Shandong University of Science and Technology Qingdao Shandong 266590 China
| | - Keqian Zhi
- Department of Oral and Maxillofacial Surgery The Affiliated Hospital of Qingdao University No.1677 Wutaishan Road Qingdao 266003 China
- School of Stomatology of Qingdao University Qingdao University Qingdao 266003 China
- Key Lab of Oral Clinical Medicine The Affiliated Hospital of Qingdao University Qingdao 266003 China
| |
Collapse
|
|
13
|
Cui H, Li Z, Chen S, Li X, Chen D, Wang J, Li Z, Hao W, Zhong F, Zhang K, Zheng Z, Zhan Z, Liu H. CXCL12/CXCR4-Rac1-mediated migration of osteogenic precursor cells contributes to pathological new bone formation in ankylosing spondylitis. SCIENCE ADVANCES 2022; 8:eabl8054. [PMID: 35385310 PMCID: PMC8986111 DOI: 10.1126/sciadv.abl8054] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 02/15/2022] [Indexed: 05/29/2023]
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by inflammatory back pain and spinal ankylosis due to pathological new bone formation. Here, we identified CXCL12 as a critical contributor to pathological new bone formation through recruitment of osteogenic precursor cells (OPCs). CXCL12 was found highly expressed in the regions that would potentially develop pathological new bone. OPCs were recruited to the regions where CXCL12 was up-regulated. Inhibition of CXCL12/CXCR4 axis with AMD3100 or conditional knockout of CXCR4 attenuated OPCs migration and subsequent pathological new bone formation in animal models of AS. By contrast, a genetically engineered animal model with CXCL12 overexpression developed a joint ankylosis phenotype. Furthermore, Rac1 was found essential for OPCs migration and pathological new bone formation. These findings ravel the novel role of CXCL12 in AS and indicate a potential strategy for targeting the CXCL12/CXCR4-Rac1 axis to prevent progression of axial skeleton ankylosis.
Collapse
Affiliation(s)
- Haowen Cui
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China
| | - Zihao Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China
| | - Siwen Chen
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China
| | - Xiang Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China
| | - Dongying Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
| | - Jianru Wang
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China
| | - Zemin Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China
| | - Wenjun Hao
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China
| | - Fangling Zhong
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China
| | - Kuibo Zhang
- Department of Spine Surgery, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
| | - Zhaomin Zheng
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China
| | - Zhongping Zhan
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
| | - Hui Liu
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China
| |
Collapse
|
|
14
|
Jo S, Lee JS, Nam B, Lee YL, Kim H, Lee EY, Park YS, Kim TH. SOX9 + enthesis cells are associated with spinal ankylosis in ankylosing spondylitis. Osteoarthritis Cartilage 2022; 30:280-290. [PMID: 34826571 DOI: 10.1016/j.joca.2021.11.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 11/09/2021] [Accepted: 11/17/2021] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Although cartilage degeneration and invasion of the subchondral bone plate in entheseal lesion has been considered to consequently lead bony ankylosis in ankylosing spondylitis (AS), no evident mechanisms are known. DESIGN To identify histopathological and physiological changes in enthesitis-related ankylosis in AS, we performed molecular characterization of transcription factors and surface markers, and transcriptome analysis with human tissues. Entheseal tissue containing subchondral bone was obtained from the facet joints of 9 patients with AS and 10 disease controls, and assessed by using differential staining techniques. Enthesis cells were isolated, characterized, stimulated with TNF and/or IL-17A, and analysed by cell-based experimental tools. RESULTS We found diffusely distributed granular tissue and cartilage in the subchondral bone in AS. Co-expression of SOX9, a specific transcription factor in cartilage, and matrix metalloproteinase 13 (MMP13) was found in the granular tissues within the subchondral bone from AS patients. Intriguingly, SOX9 expression was significantly higher in AS enthesis cells than controls and correlated with TNFR1 and IL-17RA expressions, which is important for high reactivity to TNF and IL-17A cytokines. Co-stimulation by TNF and IL-17A resulted in accelerated mineralization/calcification features, and increased OCN expression in AS enthesis cells. Furthermore, SOX9 overexpression in enthesis leads to promoting mineralization feature by TNF and IL-17A stimuli. Finally, OCN expression is elevated in the destructive enthesis of advanced AS. CONCLUSION These findings provide insight into the links between inflammation and the mineralization of entheseal tissue as the initiation of spinal ankylosis, emphasizing the importance of SOX9+ enthesis cells.
Collapse
Affiliation(s)
- S Jo
- Hanyang University Institute for Rheumatology Research, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Republic of Korea
| | - J S Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; GENOME INSIGHT Inc., Daejeon 34141, Republic of Korea
| | - B Nam
- Hanyang University Institute for Rheumatology Research, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Republic of Korea
| | - Y L Lee
- Hanyang University Institute for Rheumatology Research, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Republic of Korea
| | - H Kim
- Department of Pathology, Hanyang University Seoul Hospital, Seoul 04763, Republic of Korea
| | - E Y Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Y-S Park
- Department of Orthopedic Surgery, Guri Hospital, Hanyang University College of Medicine, Guri 11923, Republic of Korea
| | - T-H Kim
- Hanyang University Institute for Rheumatology Research, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Republic of Korea; Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Republic of Korea.
| |
Collapse
|
|
15
|
Xu J, Cao K, Liu X, Zhao L, Feng Z, Liu J. Punicalagin Regulates Signaling Pathways in Inflammation-Associated Chronic Diseases. Antioxidants (Basel) 2021; 11:29. [PMID: 35052533 PMCID: PMC8773334 DOI: 10.3390/antiox11010029] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/19/2021] [Accepted: 12/22/2021] [Indexed: 01/04/2023] Open
Abstract
Inflammation is a complex biological defense system associated with a series of chronic diseases such as cancer, arthritis, diabetes, cardiovascular and neurodegenerative diseases. The extracts of pomegranate fruit and peel have been reported to possess health-beneficial properties in inflammation-associated chronic diseases. Punicalagin is considered to be the major active component of pomegranate extracts. In this review we have focused on recent studies into the therapeutic effects of punicalagin on inflammation-associated chronic diseases and the regulatory roles in NF-κB, MAPK, IL-6/JAK/STAT3 and PI3K/Akt/mTOR signaling pathways. We have concluded that punicalagin may be a promising therapeutic compound in preventing and treating inflammation-associated chronic diseases, although further clinical studies are required.
Collapse
Affiliation(s)
- Jie Xu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (J.X.); (K.C.); (X.L.); (L.Z.)
| | - Ke Cao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (J.X.); (K.C.); (X.L.); (L.Z.)
| | - Xuyun Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (J.X.); (K.C.); (X.L.); (L.Z.)
| | - Lin Zhao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (J.X.); (K.C.); (X.L.); (L.Z.)
| | - Zhihui Feng
- Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China;
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (J.X.); (K.C.); (X.L.); (L.Z.)
- University of Health and Rehabilitation Sciences, Qingdao 266071, China
| |
Collapse
|
|
16
|
Harjacek M. Immunopathophysiology of Juvenile Spondyloarthritis (jSpA): The "Out of the Box" View on Epigenetics, Neuroendocrine Pathways and Role of the Macrophage Migration Inhibitory Factor (MIF). Front Med (Lausanne) 2021; 8:700982. [PMID: 34692718 PMCID: PMC8526544 DOI: 10.3389/fmed.2021.700982] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 09/06/2021] [Indexed: 12/11/2022] Open
Abstract
Juvenile spondyloarthritis (jSpA) is a an umbrella term for heterogeneous group of related seronegative inflammatory disorders sharing common symptoms. Although it mainly affects children and adolescents, it often remains active during adulthood. Genetic and environmental factors are involved in its occurrence, although the exact underlying immunopathophysiology remains incompletely elucidated. Accumulated evidence suggests that, in affected patients, subclinical gut inflammation caused by intestinal dysbiosis, is pivotal to the future development of synovial-entheseal complex inflammation. While the predominant role of IL17/23 axis, TNF-α, and IL-7 in the pathophysiology of SpA, including jSpA, is firmly established, the role of the cytokine macrophage migration inhibitory factor (MIF) is generally overlooked. The purpose of this review is to discuss and emphasize the role of epigenetics, neuroendocrine pathways and the hypothalamic-pituitary (HPA) axis, and to propose a novel hypothesis of the role of decreased NLRP3 gene expression and possibly MIF in the early phases of jSpA development. The decreased NLRP3 gene expression in the latter, due to hypomethylation of promotor site, is (one of) the cause for inflammasome malfunction leading to gut dysbiosis observed in patients with early jSpA. In addition, we highlight the role of MIF in the complex innate, adaptive cellular and main effector cytokine network, Finally, since treatment of advanced bone pathology in SpA remains an unmet clinical need, I suggest possible new drug targets with the aim to ultimately improve treatment efficacy and long-term outcome of jSpA patients.
Collapse
Affiliation(s)
- Miroslav Harjacek
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| |
Collapse
|
|
17
|
Tay SH, Yeo JG, Leong JY, Albani S, Arkachaisri T. Juvenile Spondyloarthritis: What More Do We Know About HLA-B27, Enthesitis, and New Bone Formation? Front Med (Lausanne) 2021; 8:666772. [PMID: 34095174 PMCID: PMC8174582 DOI: 10.3389/fmed.2021.666772] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/20/2021] [Indexed: 12/13/2022] Open
Abstract
Juvenile spondyloarthritis (JSpA) refers to a diverse spectrum of immune-mediated inflammatory arthritides whose onset occurs in late childhood and adolescence. Like its adult counterpart, JSpA is typified by a strong association with human leukocyte antigen-B27 (HLA-B27) and potential axial involvement, while lacking rheumatoid factor (RF) and distinguishing autoantibodies. A characteristic manifestation of JSpA is enthesitis (inflammation of insertion sites of tendons, ligaments, joint capsules or fascia to bone), which is commonly accompanied by bone resorption and new bone formation at affected sites. In this Review, advances in the role of HLA-B27, enthesitis and its associated osteoproliferation in JSpA pathophysiology and treatment options will be discussed. A deeper appreciation of how these elements contribute to the JSpA disease mechanism will better inform diagnosis, prognosis and therapy, which in turn translates to an improved quality of life for patients.
Collapse
Affiliation(s)
- Shi Huan Tay
- SingHealth Duke-National University of Singapore Academic Medical Centre, Translational Immunology Institute, Singapore, Singapore.,Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Joo Guan Yeo
- SingHealth Duke-National University of Singapore Academic Medical Centre, Translational Immunology Institute, Singapore, Singapore.,Duke-National University of Singapore Medical School, Singapore, Singapore.,Rheumatology and Immunology Service, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore
| | - Jing Yao Leong
- SingHealth Duke-National University of Singapore Academic Medical Centre, Translational Immunology Institute, Singapore, Singapore.,Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Salvatore Albani
- SingHealth Duke-National University of Singapore Academic Medical Centre, Translational Immunology Institute, Singapore, Singapore.,Duke-National University of Singapore Medical School, Singapore, Singapore.,Rheumatology and Immunology Service, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore
| | - Thaschawee Arkachaisri
- Duke-National University of Singapore Medical School, Singapore, Singapore.,Rheumatology and Immunology Service, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore
| |
Collapse
|
|
18
|
Cho H, Lee J, Jang S, Lee J, Oh TI, Son Y, Lee E. CaSR-Mediated hBMSCs Activity Modulation: Additional Coupling Mechanism in Bone Remodeling Compartment. Int J Mol Sci 2020; 22:ijms22010325. [PMID: 33396907 PMCID: PMC7795180 DOI: 10.3390/ijms22010325] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 12/24/2020] [Accepted: 12/27/2020] [Indexed: 02/01/2023] Open
Abstract
Near the bone remodeling compartments (BRC), extracellular calcium concentration (Ca2+o) is locally elevated and bone marrow stromal cells (BMSCs) close to the BRC can be exposed to high calcium concentration. The calcium-sensing receptor (CaSR) is known to play a key role in maintaining extracellular calcium homeostasis by sensing fluctuations in the levels of extracellular calcium (Ca2+o). When human BMSCs (hBMSCs) were exposed to various calcium concentrations (1.8, 3, 5, 10, 30 mM), moderate-high extracellular calcium concentrations (3–5 mM) stimulated proliferation, while a high calcium concentration (30 mM) inhibited the proliferation. Exposure to various calcium concentrations did not induce significant differences in the apoptotic cell fraction. Evaluation of multi-lineage differentiation potential showed no significant difference among various calcium concentration groups, except for the high calcium concentration (30 mM) treated group, which resulted in increased calcification after in vitro osteogenic differentiation. Treatment of NPS2143, a CaSR inhibitor, abolished the stimulatory effect on hBMSCs proliferation and migration indicating that CaSR is involved. These results suggest that the calcium concentration gradient near the BRC may play an important role in bone remodeling by acting as an osteoblast–osteoclast coupling mechanism through CaSR.
Collapse
Affiliation(s)
- Hyunji Cho
- College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seochon-dong, Kiheung-go, Yongin-si, Geonggi-do 17104, Korea;
| | - Jisoo Lee
- Department of Medical Engineering, Graduate School, Kyung Hee University, Seoul 02447, Korea; (J.L.); (S.J.)
| | - Seoyoung Jang
- Department of Medical Engineering, Graduate School, Kyung Hee University, Seoul 02447, Korea; (J.L.); (S.J.)
| | - Jungsun Lee
- R&D Institute, Biosolution Inc., Seoul 18111, Korea;
| | - Tong In Oh
- Department of Biomedical Engineering, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
| | - Youngsook Son
- Department of Genetic Engineering, College of Life Science, Kyung Hee University, Seochon-dong, Kiheung-go, Yongin-si, Geonggi-do 17104, Korea
- Correspondence: (Y.S.); (E.L.); Tel.: +82-31-201-3822 (Y.S.); +82-10-3751-7532 (E.L.)
| | - EunAh Lee
- Impedance Imaging Research Center, Kyung Hee University, Seoul 02447, Korea
- Correspondence: (Y.S.); (E.L.); Tel.: +82-31-201-3822 (Y.S.); +82-10-3751-7532 (E.L.)
| |
Collapse
|
|
19
|
Li X, Chen S, Hu Z, Chen D, Wang J, Li Z, Li Z, Cui H, Dai G, Liu L, Wang H, Zhang K, Zheng Z, Zhan Z, Liu H. Aberrant upregulation of CaSR promotes pathological new bone formation in ankylosing spondylitis. EMBO Mol Med 2020; 12:e12109. [PMID: 33259138 PMCID: PMC7721361 DOI: 10.15252/emmm.202012109] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/28/2022] Open
Abstract
Pathological new bone formation is a typical pathological feature in ankylosing spondylitis (AS), and the underlying molecular mechanism remains elusive. Previous studies have shown that the calcium‐sensing receptor (CaSR) is critical for osteogenic differentiation while also being highly involved in many inflammatory diseases. However, whether it plays a role in pathological new bone formation of AS has not been reported. Here, we report the first piece of evidence that expression of CaSR is aberrantly upregulated in entheseal tissues collected from AS patients and animal models with different hypothetical types of pathogenesis. Systemic inhibition of CaSR reduced the incidence of pathological new bone formation and the severity of the ankylosing phenotype in animal models. Activation of PLCγ signalling by CaSR promoted bone formation both in vitro and in vivo. In addition, various inflammatory cytokines induced upregulation of CaSR through NF‐κB/p65 and JAK/Stat3 pathways in osteoblasts. These novel findings suggest that inflammation‐induced aberrant upregulation of CaSR and activation of CaSR‐PLCγ signalling in osteoblasts act as mediators of inflammation, affecting pathological new bone formation in AS.
Collapse
Affiliation(s)
- Xiang Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Siwen Chen
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Zaiying Hu
- Department of Rheumatology and Immunology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dongying Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianru Wang
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Zemin Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Zihao Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Haowen Cui
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Guo Dai
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Lei Liu
- Department of Spine Surgery, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Haitao Wang
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Kuibo Zhang
- Department of Spine Surgery, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhaomin Zheng
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Zhongping Zhan
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Liu
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| |
Collapse
|