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Ziyadullaev SK, Khudaiberdiev SS, Aripova TU, Chirumbolo S, Kamalov ZS, Bjørklund G, Rizaev JA, Tashkenbaeva EN, Khamidov OA, Gaffarov UB. Synovial Fluid as a Crucial Component of the Joint Microenvironment in Rheumatoid Arthritis. Immune Netw 2025; 25:e2. [PMID: 40342839 PMCID: PMC12056296 DOI: 10.4110/in.2025.25.e2] [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: 05/23/2024] [Revised: 12/17/2024] [Accepted: 12/22/2024] [Indexed: 05/11/2025] Open
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease closely associated with synovial tissue proliferation, pannus formation in small joints such as the hands, wrists, and feet, cartilage destruction, and systemic complications such as pulmonary, cardiovascular, neurological, and skeletal muscle lesions, glucocorticoid-induced osteoporosis and infections. The importance of confirming the diagnosis and determining local activity is given to the study of synovial fluid. A deep understanding of the pathological process in the joint in RA, characterized by changes in autoreactive CD4+ T cells, B cells, macrophages, inflammatory cytokines, chemokines, and autoantibodies, has now been achieved, although much remains to be explored. This article provides an updated overview of the pathogenesis of RA, revealing even more therapeutic targets for the intra-articular pathological process.
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Affiliation(s)
| | | | | | | | | | - Geir Bjørklund
- Council for Nutritional and Environmental Medicine, Mo i Rana 8622, Norway
| | | | | | - Obid Abdurakhmanovich Khamidov
- Rehabilitology and Sports Medicine Research Institute of the Samarkand State Medical University, Samarkand 140100, Uzbekistan
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Yang M, Lu S, Li J, Zhu L. Carboxyaminotriazole: A bone savior in collagen-induced arthritis-Halting osteoclastogenesis via interleukin-1β downregulation. Life Sci 2025; 364:123440. [PMID: 39920985 DOI: 10.1016/j.lfs.2025.123440] [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: 11/13/2024] [Revised: 01/19/2025] [Accepted: 01/31/2025] [Indexed: 02/10/2025]
Abstract
AIMS Rheumatoid arthritis (RA), a prevalent autoimmune disease, features inflammation and bone erosion, correlating with osteoclast hyperactivation and enhanced responsiveness to inflammatory factors. Reducing osteoclast formation and inflammatory mediator expression might avert bone erosion in RA. Carboxyaminotriazole (CAI) holds potential for treating autoinflammatory disorders and impeding cancer-related bone metastases. Yet, its bone-protective role and mechanism remain elusive. This study targets to explore the impacts and underlying mechanisms of CAI in preventing bone erosion in RA. MATERIALS AND METHODS A collagen-induced arthritis (CIA) rat model was utilized to evaluate the anti-RA potential of CAI. CCK-8, TRAP staining, TRAP activity assay, pit formation assay, RT-qPCR, Western blotting, immunofluorescence, and ELISA, were conducted to assess the effects and potential mechanisms of CAI in the management of RA. KEY FINDINGS CAI not only reduces inflammatory symptoms, but it also offers superior bone protection compared to methotrexate (MTX) and works synergistically with MTX, the preferred anchoring agent for the treatment of RA. In vitro studies show that CAI inhibits osteoclast differentiation and function, as well as the expression of specific genes, by inhibiting NF-κB/MAPK pathways and reducing IL-1β levels. The deletion of Il-1 and the application of IL-1β inhibitors suggest that CAI retards osteoclastogenesis through the downregulation of IL-1β. SIGNIFICANCE CAI may have therapeutic value in treating RA-related bone erosion, likely due to its inhibition of overactive osteoclasts by suppressing the NF-κB/MAPK pathways and the subsequent expression of IL-1β.
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Affiliation(s)
- Mei Yang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Shan Lu
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Juan Li
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Lei Zhu
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China; Medical Epigenetics Research Center, Chinese Academy of Medical Sciences, Beijing 100005, China.
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Gao P, Yuan S, Wang Y, Wang Y, Li X, Liu T, Zheng Y, Wang J, Liu D, Xu L, Jiang Y, Zeng K, Tu P. Corydalis decumbens and tetrahydropalmatrubin inhibit macrophages inflammation to relieve rheumatoid arthritis by targeting Fosl2. JOURNAL OF ETHNOPHARMACOLOGY 2025; 341:119348. [PMID: 39805480 DOI: 10.1016/j.jep.2025.119348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/05/2025] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Corydalisdecumbens (Thunb.) (CD) is a traditional Chinese medicine and as a single herb or formula has been used to treat RA for decades. Rheumatoid arthritis (RA) is a persistent, systemic autoimmune inflammatory disease. However, the anti-inflammatory target, effective constituents and mechanism was unclear. AIM OF THE STUDY The purpose of this study was to identify anti-RA and anti-inflammatory targets of CD, elucidate effective constituents and molecular pharmacological mechanism. MATERIALS AND METHODS Anti-RA and anti-inflammatory effect of CD were evaluated on CIA-rats and in LPS-induced RAW264.7 cells respectively. The anti-inflammatory target of CD was identified using thermal proteome profiling (TPP). The recombinant Fosl2 protein was expressed and purified and the target-based effective constituents was screened with bio-layer interferometry (BLI) analysis. Combining photoaffinity probe, LC-MS/MS analysis, docking and point mutation, the binding site was confirmed between Fosl2 and THP. Furtherly, immunofluorescence (IF), co-immunoprecipitation (co-IP) were used to research the pharmacological mechanism of THP and the THP-influenced downstream pathways were elucidated by transcriptomics analysis. RESULTS CD had therapeutic effect on CIA-rats and a significant anti-inflammation on macrophages. Fosl2 was identified as a target of CD and we elucidated the target-based effective constituents was protoberberine-type alkaloids. THP can inhibit inflammation and transcription of AP-1 via targeting Fosl2 on LPS-induced RAW264.7 cells. For mechanism, THP promoted Fosl2 nuclear translocating and interacting with c-Jun. CONCLUSIONS These findings firstly elucidated the target and effective constituents of CD treating RA, and found that "undruggable target" Fosl2 can be used as therapeutic targets for RA. Meanwhile, our research suggested that THP has a significant potential for the treatment of RA.
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Affiliation(s)
- Peng Gao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Shuo Yuan
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yanhang Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yuqi Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Xiaoshuang Li
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Tingting Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yongzhe Zheng
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Jing Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Dan Liu
- Medical and Healthy Analytical Center, Peking University Health Science Center, Beijing, 100191, China
| | - Luzheng Xu
- Medical and Healthy Analytical Center, Peking University Health Science Center, Beijing, 100191, China
| | - Yong Jiang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Kewu Zeng
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Pengfei Tu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
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Miyamoto T. Osteoporosis and Rheumatoid Arthritis: Mechanisms Underlying Osteoclast Differentiation and Activation or Factors Associated with Hip Fractures. J Clin Med 2025; 14:1138. [PMID: 40004668 PMCID: PMC11856638 DOI: 10.3390/jcm14041138] [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: 01/10/2025] [Revised: 02/06/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
Osteoporosis is defined as a condition of increased risk of fracture due to decreased bone strength. In developed countries, the number of patients with osteoporosis and fragility fractures has been increasing in recent years due to the growing elderly population, posing a social challenge not only to fracture patients and their families but also to the social healthcare economy. Osteoporosis can be divided into two categories: primary osteoporosis caused by aging or menopause and secondary osteoporosis caused by metabolic or inflammatory diseases or drugs such as glucocorticoids. The majority of patients have primary osteoporosis, and the pathogenesis of postmenopausal osteoporosis and factors associated with fragility fractures in the elderly have been elucidated. On the other hand, rheumatoid arthritis (RA) is one of the causes of secondary osteoporosis. RA is a chronic inflammatory disease characterized by joint swelling and destruction. Most often, treatment focuses on suppressing these symptoms. However, physicians should be aware of the risk of osteoporosis in RA patients, because (1) RA is a chronic inflammatory disease, which itself can be a risk factor for osteoporosis; (2) glucocorticoids, which are sometimes administered to treat RA, can be a risk factor for osteoporosis; and (3) patients with RA are becoming older, and aging is an osteoporosis risk factor. A comprehensive understanding of the pathogenesis of osteoporosis and its fragility fractures requires elucidating the mechanisms underlying osteoclast activation, which drives their development. Furthermore, identifying the factors associated with fragility fractures is essential. This review summarizes the pathogenesis of osteoporosis, the factors associated with fragility fractures, and the associations between RA and osteoporosis development.
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Affiliation(s)
- Takeshi Miyamoto
- Department of Orthopedic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan
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Riaz M, Rasool G, Yousaf R, Fatima H, Munir N, Ejaz H. Anti-Rheumatic potential of biological DMARDS and protagonistic role of bio-markers in early detection and management of rheumatoid arthritis. Innate Immun 2025; 31:17534259251324820. [PMID: 40091354 PMCID: PMC11912179 DOI: 10.1177/17534259251324820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 02/07/2025] [Indexed: 03/19/2025] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects the synovial joint linings, resulting in progressive disability, increased mortality, and considerable economic costs. Early treatment with disease-modifying antirheumatic medications (DMARDs) can significantly improve the overall outlook for people with RA. Contemporary pharmaceutical interventions, encompassing standard, biological, and emerging small molecule disease- modifying anti-rheumatic medications continue to be the cornerstone of RA management, with substantial advancements made in the pursuit of achieving remission from the disease and preventing joint deformities. Nevertheless, a substantial segment of individuals with RA do not experience a satisfactory response to existing treatments, underscoring the pressing need for novel therapeutic options. Biologic DMARDs are among the therapy choices. Non-tumor necrosis factor inhibitors (Non-TNFi) such as abatacept, rituximab, tocilizumab, and sarilumab are examples, as are anti-tumor necrosis factor (TNF) medications such as infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol. More recent biomarkers have emerged and showed usefulness in the early detection of RA. These biomarkers, often referred to simply as "biomarkers", are quantifiable indicators of normal or pathologic processes, and they can also gauge treatment response. The assessment of RA treatment response typically combines patient-reported outcomes, physical evaluations, and laboratory findings, as there isn't a single biomarker that has proven sufficient for measuring disease activity. This review explores the usage of biologic DMARDs as a therapeutic approach for RA, as well as the biomarkers typically used for RA early diagnosis, prognosis prediction, and disease activity evaluation.
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Affiliation(s)
- Muhammad Riaz
- Department of Allied Health Sciences, University of Sargodha, Sargodha, Pakistan
| | - Ghulam Rasool
- Department of Allied Health Sciences, University of Sargodha, Sargodha, Pakistan
| | - Ruhamah Yousaf
- Department of Health Professional Technologies, The University of Lahore, Lahore, Pakistan
| | - Hina Fatima
- Department of Biochemistry, Government College Women University, Faisalabad, Pakistan
| | - Naveed Munir
- Department of Biomedical Lab Sciences, School of Health Sciences, University of Management and Technology, Lahore, Pakistan
| | - Hasan Ejaz
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia
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Ma X, Zhu N, Yu X, Wang W, Wu W. Research on preventive effect of Akkermansia muciniphilaAKK PROBIO on acute gouty arthritis in mice. Food Sci Nutr 2024; 12:7644-7656. [PMID: 39479687 PMCID: PMC11521663 DOI: 10.1002/fsn3.4367] [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: 11/01/2023] [Revised: 07/13/2024] [Accepted: 07/15/2024] [Indexed: 11/02/2024] Open
Abstract
In mice with acute gouty arthritis, this study intends to examine the mechanism of action of Akkermansia muciniphila AKK PROBIO. We developed a mouse model of acute gouty arthritis using sodium urate. The efficiency and mechanism of AKK PROBIO in preventing acute gouty arthritis in mice were then determined by examining the degree of foot swelling, pain threshold, blood biochemical indicators, histological alterations, and messenger RNA (mRNA) expression changes. The results of the animal experiment showed that AKK PROBIO can lessen mouse foot edema severity and increase pain threshold. AKK PROBIO can enhance the enzyme activity of superoxide dismutase (SOD) and the level of glutathione (GSH) in the ankle joint tissues of mice with acute arthritis while decreasing the enzyme activity of myeloperoxidase (MPO) and the level of malondialdehyde (MDA). Interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) levels are all reduced by AKK PROBIO in the blood of mice with acute arthritis. Results from histopathology showed that AKK PROBIO reduced tissue damage in the mouse ankle and foot joints. In the tissues of the ankle joints of mice with acute arthritis, the results of the quantitative polymerase chain reaction (qPCR) and Western blot experiments suggested that AKK PROBIO may inhibit the mRNA and protein expression of extracellular signal-regulated kinase 1/2 (ERK1/2), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) in the tissues. AKK PROBIO can also regulate gut microbiota, inhibit harmful bacteria, and enhance valeric acid in the intestine, isobutyric acid, and isovaleric acid. Therefore, it is evident that AKK PROBIO prevents acute gouty arthritis better than glucosamine sulfate. It is a strain that has probiotic potential.
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Affiliation(s)
- Xin Ma
- State Key Laboratory of Bioreactor EngineeringEast China University of Science and TechnologyShanghaiChina
| | - Na Zhu
- Department of AnesthesiaFirst Affiliated Hospital of Chengdu Medical CollegeChengduChina
| | - Xueping Yu
- State Key Laboratory of Bioreactor EngineeringEast China University of Science and TechnologyShanghaiChina
| | - Wei Wang
- State Key Laboratory of Bioreactor EngineeringEast China University of Science and TechnologyShanghaiChina
| | - Wenzhong Wu
- Heilongjiang Red Cross Sengong General HospitalHarbinHeilongjiangChina
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Wang Y, Chen J, Shen ZY, Zhang J, Zhu YJ, Xia XQ. Screening of Diagnostic Biomarkers and Immune Infiltration Characteristics Linking Rheumatoid Arthritis and Rosacea Based on Bioinformatics Analysis. J Inflamm Res 2024; 17:5177-5195. [PMID: 39104909 PMCID: PMC11299729 DOI: 10.2147/jir.s467760] [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] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 07/20/2024] [Indexed: 08/07/2024] Open
Abstract
Introduction Both rheumatoid arthritis (RA) and rosacea represent common chronic systemic autoimmune conditions. Recent research indicates a heightened RA risk among individuals with rosacea. However, the molecular mechanisms linking these diseases remain largely unknown. This study aims to uncover shared molecular regulatory networks and immune cell infiltration patterns in both rosacea and RA. Methods The gene expression profiles of RA (GSE12021, GSE55457), and the rosacea gene expression profile (GSE6591), were downloaded from Gene Expression Omnibus (GEO) databases, and obtained to screen differentially expressed genes (DEGs) by using "limma" package in R software. Various analyses including GO, KEGG, protein-protein interaction (PPI) network, and weighted gene co-expression network analyses (WGCNA) were conducted to explore potential biological functions and signaling pathways. CIBERSORT was used to assess the abundance of immune cells. Pearson coefficients were used to calculate the correlations between overlapped genes and the leukocyte gene signature matrix. Flow cytometry (FCM) analysis confirmed the most abundant immune cells detected in rheumatoid arthritis and rosacea. Receiver operator characteristic (ROC) analysis, enzyme-linked immunosorbent assay (ELISA), and qRT-PCR were used to confirm biomarkers and functions. Results Two hundred seventy-seven co-expressed DEGs were identified from these datasets. Functional enrichment analysis indicated that these DEGs were associated with immune processes and chemokine-mediated signaling pathways. Fourteen and 17 hub genes overlapped between cytoHubba and WGCNA were identified in RA and rosacea, respectively. Macrophages and dendritic cells were RA and rosacea's most abundant immune cells, respectively. The ROC curves demonstrated potential diagnostic values of CXCL10 and CCL27, showing higher levels in the serum of patients with RA or rosacea, and suggesting possible regulation in the densities and functions of macrophages and dendritic cells from RA and rosacea, which were validated by FCM and qRT-PCR. Conclusion Importantly, our findings may contribute to the scientific basis for biomarkers and therapeutic targets for patients with RA and rosacea in the future.
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Affiliation(s)
- Yun Wang
- Department of Dermatology, Shanghai Ninth People’s Hospital Affiliated Shanghai JiaoTong University School of Medicine, Shanghai, 200080, People’s Republic of China
| | - Jun Chen
- Department of Dermatology, Shanghai Ninth People’s Hospital Affiliated Shanghai JiaoTong University School of Medicine, Shanghai, 200080, People’s Republic of China
| | - Zheng-Yu Shen
- Department of Dermatology, Shanghai Ninth People’s Hospital Affiliated Shanghai JiaoTong University School of Medicine, Shanghai, 200080, People’s Republic of China
| | - Jie Zhang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Yu-Jie Zhu
- Department of Dermatology, Shanghai Ninth People’s Hospital Affiliated Shanghai JiaoTong University School of Medicine, Shanghai, 200080, People’s Republic of China
| | - Xu-Qiong Xia
- Department of Dermatology, Shanghai Ninth People’s Hospital Affiliated Shanghai JiaoTong University School of Medicine, Shanghai, 200080, People’s Republic of China
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Terashima A, Ono K, Omata Y, Tanaka S, Saito T. Inflammatory diseases causing joint and bone destruction: rheumatoid arthritis and hemophilic arthropathy. J Bone Miner Metab 2024; 42:455-462. [PMID: 38856919 DOI: 10.1007/s00774-024-01520-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 05/20/2024] [Indexed: 06/11/2024]
Abstract
Various diseases and conditions cause joint disorders. Osteoarthritis (OA) is characterized by the degeneration of articular cartilage, synovitis, and anabolic changes in surrounding bone tissues. In contrast, rheumatoid arthritis (RA) and hemophilic arthropathy (HA) display marked destruction of bone tissues caused by synovitis. RA is a representative autoimmune disease. The primary tissue of RA pathogenesis is the synovial membrane and involves various immune cells that produce catabolic cytokines and enzymes. Hemophilia is a genetic disorder caused by a deficiency in blood clotting factors. Recurrent intra-articular bleeding leads to chronic synovitis through excessive iron deposition and results in the destruction of affected joints. Although the triggers for these two joint diseases are completely different, many cytokines and enzymes are common in the pathogenesis of both RA and HA. This review focuses on the similarities between joint and bone destruction in RA and HA. The insights may be useful in developing better treatments for hemophilia patients with arthropathy and osteoporosis by leveraging advanced therapeutics for RA.
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Affiliation(s)
- Asuka Terashima
- Bone and Cartilage Regenerative Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Kumiko Ono
- Department of Joint Surgery, Research Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
- Orthopaedic Surgery, Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Yasunori Omata
- Bone and Cartilage Regenerative Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
- Orthopaedic Surgery, Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Sakae Tanaka
- Orthopaedic Surgery, Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Taku Saito
- Orthopaedic Surgery, Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
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Gad HA, Abbas H, El Sayed NS, Khattab MA, El Hassab MA, Mansour M. Berberine loaded thermosensitive lipid nanoparticles: in vitro characterization, in silico study, and in vivo anti-arthritic effect. J Liposome Res 2024; 34:303-315. [PMID: 37856332 DOI: 10.1080/08982104.2023.2273390] [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: 05/30/2023] [Accepted: 10/16/2023] [Indexed: 10/21/2023]
Abstract
Thermoresponsive drug delivery systems have been used to treat diseases that cause hyperthermia or elevated body tissue temperatures, viz., rheumatoid arthritis and different cancers. The aim of the study was to enhance berberine (BER) release using thermosensitive nanostructured lipid carriers (TNLCs) through intra-articular administration for the management of arthritis. TNLCs were prepared using binary mixtures of stearic acid and decanoic acid as solid and liquid lipids, respectively. Lipid mixtures with an optimum melting point were assessed using differential scanning calorimetry studies. In vitro characterization of the BER TNLCs included particle size, zeta potential, entrapment efficiency, and drug release at 37 °C and 41 °C. Joint diameter measurement, real-time polymerase chain reaction (RT-PC) analysis, enzyme-linked immunosorbent assay (ELISA) for inflammatory markers, and histological evaluation of the dissected joints were all performed in vivo on rats with adjuvant-induced arthritis. In vitro characterization revealed negatively charged BER-loaded TNLCs with a spherical shape, particle size less than 500 nm, BER entrapment efficiency up to 79%, and a high drug release rate at an elevated temperature of 41 °C. In silico studies revealed the affinity of BER to different formula components and to the measured biomarkers. In vivo assessment of the optimum TNLCs showed that BER TNLCs were superior to the BER solution suspension regarding their effect on inflammatory biomarkers, joint diameter, and histological studies.
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Affiliation(s)
- Heba A Gad
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Haidy Abbas
- Department of Pharmaceutics, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Nesrine S El Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mohamed A Khattab
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Mahmoud A El Hassab
- Department of Medicinal Chemistry, Faculty of Pharmacy, King Salman International University (KSIU), Egypt
| | - Mai Mansour
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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Chen J, Wen Y, Lin L, Cui Y, Chen Z, Gao J, Zhuang Y, Chen Q. Fosl2 Deficiency Predisposes Mice to Osteopetrosis, Leading to Bone Marrow Failure. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1081-1093. [PMID: 38380993 DOI: 10.4049/jimmunol.2300592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 01/16/2024] [Indexed: 02/22/2024]
Abstract
Arthritis causes Fos-like 2 (Fosl2) inactivation, and various immune cells contribute to its pathogenesis. However, little is known about the role of Fosl2 in hematopoiesis and the possible pathological role of Fosl2 inactivation in the hematopoietic system in arthritis. In this study, we show that Fosl2 maintains hematopoietic stem cell (HSC) quiescence and differentiation while controlling the inflammatory response via macrophages. Fosl2-specific deletion in the hematopoietic system caused the expansion of HSCs and myeloid cell growth while affecting erythroid and B cell differentiation. Fosl2 inactivation enhanced macrophage M1 polarization and stimulated proinflammatory cytokines and myeloid growth factors, skewing HSCs toward myeloid cell differentiation, similar to hematopoietic alterations in arthritic mice. Loss of Fosl2 mediated by Vav-iCre also displays an unexpected deletion in embryonic erythro-myeloid progenitor-derived osteoclasts, leading to osteopetrosis and anemia. The reduced bone marrow cellularity in Vav-iCreFosl2f/f mice is a consequence of the reduced bone marrow space in osteopetrotic mice rather than a direct role of Fosl2 in hematopoiesis. Thus, Fosl2 is indispensable for erythro-myeloid progenitor-derived osteoclasts to maintain the medullary cavity to ensure normal hematopoiesis. These findings improve our understanding of the pathogenesis of bone-destructive diseases and provide important implications for developing therapeutic approaches for these diseases.
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Affiliation(s)
- Jinfeng Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
| | - Yi Wen
- Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Lili Lin
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
| | - Yuchen Cui
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
| | - Zhenyu Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
| | - Jing Gao
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
| | - Yifang Zhuang
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
| | - Qi Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
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Rufino AT, Freitas M, Proença C, Ferreira de Oliveira JMP, Fernandes E, Ribeiro D. Rheumatoid arthritis molecular targets and their importance to flavonoid-based therapy. Med Res Rev 2024; 44:497-538. [PMID: 37602483 DOI: 10.1002/med.21990] [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: 02/28/2022] [Revised: 04/18/2023] [Accepted: 08/05/2023] [Indexed: 08/22/2023]
Abstract
Rheumatoid arthritis (RA) is a progressive, chronic, autoimmune, inflammatory, and systemic condition that primarily affects the synovial joints and adjacent tissues, including bone, muscle, and tendons. The World Health Organization recognizes RA as one of the most prevalent chronic inflammatory diseases. In the last decade, there was an expansion on the available RA therapeutic options which aimed to improve patient's quality of life. Despite the extensive research and the emergence of new therapeutic approaches and drugs, there are still significant unwanted side effects associated to these drugs and still a vast number of patients that do not respond positively to the existing therapeutic strategies. Over the years, several references to the use of flavonoids in the quest for new treatments for RA have emerged. This review aimed to summarize the existing literature about the flavonoids' effects on the major pathogenic/molecular targets of RA and their potential use as lead compounds for the development of new effective molecules for RA treatment. It is demonstrated that flavonoids can modulate various players in synovial inflammation, regulate immune cell function, decrease synoviocytes proliferation and balance the apoptotic process, decrease angiogenesis, and stop/prevent bone and cartilage degradation, which are all dominant features of RA. Although further investigation is necessary to determine the effectiveness of flavonoids in humans, the available data from in vitro and in vivo models suggest their potential as new disease-modifying anti-rheumatic drugs. This review highlights the use of flavonoids as a promising avenue for future research in the treatment of RA.
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Affiliation(s)
- Ana T Rufino
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Marisa Freitas
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Carina Proença
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - José M P Ferreira de Oliveira
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Eduarda Fernandes
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Daniela Ribeiro
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
- Faculty of Agrarian Sciences and Environment, University of the Azores, Açores, Portugal
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12
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Yang M, Zhu L. Osteoimmunology: The Crosstalk between T Cells, B Cells, and Osteoclasts in Rheumatoid Arthritis. Int J Mol Sci 2024; 25:2688. [PMID: 38473934 DOI: 10.3390/ijms25052688] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 02/22/2024] [Accepted: 02/24/2024] [Indexed: 03/14/2024] Open
Abstract
Rheumatoid arthritis (RA) is an ongoing inflammatory condition that affects the joints and can lead to severe damage to cartilage and bones, resulting in significant disability. This condition occurs when the immune system becomes overactive, causing osteoclasts, cells responsible for breaking down bone, to become more active than necessary, leading to bone breakdown. RA disrupts the equilibrium between osteoclasts and osteoblasts, resulting in serious complications such as localized bone erosion, weakened bones surrounding the joints, and even widespread osteoporosis. Antibodies against the receptor activator of nuclear factor-κB ligand (RANKL), a crucial stimulator of osteoclast differentiation, have shown great effectiveness both in laboratory settings and actual patient cases. Researchers are increasingly focusing on osteoclasts as significant contributors to bone erosion in RA. Given that RA involves an overactive immune system, T cells and B cells play a pivotal role by intensifying the immune response. The imbalance between Th17 cells and Treg cells, premature aging of T cells, and excessive production of antibodies by B cells not only exacerbate inflammation but also accelerate bone destruction. Understanding the connection between the immune system and osteoclasts is crucial for comprehending the impact of RA on bone health. By delving into the immune mechanisms that lead to joint damage, exploring the interactions between the immune system and osteoclasts, and investigating new biomarkers for RA, we can significantly improve early diagnosis, treatment, and prognosis of this condition.
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Affiliation(s)
- Mei Yang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
- Medical Epigenetics Research Center, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Lei Zhu
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
- Medical Epigenetics Research Center, Chinese Academy of Medical Sciences, Beijing 100005, China
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13
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Zheng H, Liu Y, Deng Y, Li Y, Liu S, Yang Y, Qiu Y, Li B, Sheng W, Liu J, Peng C, Wang W, Yu H. Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets. Mol Med 2024; 30:20. [PMID: 38310228 PMCID: PMC10838448 DOI: 10.1186/s10020-024-00788-w] [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: 12/07/2023] [Accepted: 01/22/2024] [Indexed: 02/05/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by inflammation of the synovial tissue and joint bone destruction, often leading to significant disability. The main pathological manifestation of joint deformity in RA patients is bone destruction, which occurs due to the differentiation and proliferation of osteoclasts. The transcription factor nuclear factor-activated T cell 1 (NFATc1) plays a crucial role in this process. The regulation of NFATc1 in osteoclast differentiation is influenced by three main factors. Firstly, NFATc1 is activated through the upstream nuclear factor kappa-B ligand (RANKL)/RANK signaling pathway. Secondly, the Ca2+-related co-stimulatory signaling pathway amplifies NFATc1 activity. Finally, negative regulation of NFATc1 occurs through the action of cytokines such as B-cell Lymphoma 6 (Bcl-6), interferon regulatory factor 8 (IRF8), MAF basic leucine zipper transcription factor B (MafB), and LIM homeobox 2 (Lhx2). These three phases collectively govern NFATc1 transcription and subsequently affect the expression of downstream target genes including TRAF6 and NF-κB. Ultimately, this intricate regulatory network mediates osteoclast differentiation, fusion, and the degradation of both organic and inorganic components of the bone matrix. This review provides a comprehensive summary of recent advances in understanding the mechanism of NFATc1 in the context of RA-related bone destruction and discusses potential therapeutic agents that target NFATc1, with the aim of offering valuable insights for future research in the field of RA. To assess their potential as therapeutic agents for RA, we conducted a drug-like analysis of potential drugs with precise structures.
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Affiliation(s)
- Hao Zheng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Yuexuan Liu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Yasi Deng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Yunzhe Li
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Shiqi Liu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Yong Yang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Yun Qiu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Bin Li
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Wenbing Sheng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Jinzhi Liu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Caiyun Peng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Wei Wang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China.
| | - Huanghe Yu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China.
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14
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Chen N, Diao CY, Huang X, Tan WX, Chen YB, Qian XY, Gao J, Zhao DB. RhoA Promotes Synovial Proliferation and Bone Erosion in Rheumatoid Arthritis through Wnt/PCP Pathway. Mediators Inflamm 2023; 2023:5057009. [PMID: 38022686 PMCID: PMC10667059 DOI: 10.1155/2023/5057009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 10/07/2023] [Accepted: 10/07/2023] [Indexed: 12/01/2023] Open
Abstract
Ras homolog gene family member A (RhoA) plays a major role in the Wnt/planar cell polarity (PCP) pathway, which is significantly activated in patients with rheumatoid arthritis (RA). The function of RhoA in RA synovitis and bone erosion is still elusive. Here, we not only explored the impact of RhoA on the proliferation and invasion of RA fibroblast-like synoviocytes (FLSs) but also elucidated its effect on mouse osteoclast and a mouse model of collagen-induced arthritis (CIA). Results showed that RhoA was overexpressed in RA and CIA synovial tissues. Lentivirus-mediated silencing of RhoA increased apoptosis, attenuated invasion, and dramatically upregulated osteoprotegerin/receptor activator of nuclear factor-κB ligand (OPG/RANKL) ratio in RA-FLSs. Additionally, the silencing of RhoA inhibited mouse osteoclast differentiation in vitro and alleviated synovial hyperplasia and bone erosion in the CIA mouse model. These effects in RA-FLSs and osteoclasts were all regulated by RhoA/Rho-associated protein kinase 2 (ROCK2) and might interact with Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways.
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Affiliation(s)
- Ning Chen
- Department of Rheumatology and Immunology, Changhai Hospital, Naval Medical University, Shanghai, China
- Department of Rheumatology and Immunology, The First People's Hospital of Yancheng, The Fourth Affiliated Hospital of Nantong University, Yancheng, China
| | - Chao-Yue Diao
- Department of Rheumatology and Immunology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xin Huang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Wei-Xing Tan
- Air Force Health Care Center for Special Services, Hangzhou, China
| | - Ya-Bing Chen
- Department of Rheumatology and Immunology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xin-Yu Qian
- Department of Rheumatology and Immunology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jie Gao
- Department of Rheumatology and Immunology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Dong-Bao Zhao
- Department of Rheumatology and Immunology, Changhai Hospital, Naval Medical University, Shanghai, China
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Komagamine M, Komatsu N, Ling R, Okamoto K, Tianshu S, Matsuda K, Takeuchi T, Kaneko Y, Takayanagi H. Effect of JAK inhibitors on the three forms of bone damage in autoimmune arthritis: joint erosion, periarticular osteopenia, and systemic bone loss. Inflamm Regen 2023; 43:44. [PMID: 37726797 PMCID: PMC10507845 DOI: 10.1186/s41232-023-00293-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/17/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND The types of bone damage in rheumatoid arthritis (RA) include joint erosion, periarticular osteoporosis, and systemic osteoporosis. Janus kinase (JAK) inhibitors ameliorate inflammation and joint erosion in RA, but their effect on the three types of bone loss have not been reportedly explored in depth. We aimed to clarify how JAK inhibitors influence the various types of bone loss in arthritis by modulating osteoclastic bone resorption and/or osteoblastic bone formation. METHODS Collagen-induced arthritis (CIA) mice were treated with a JAK inhibitor after the onset of arthritis. Micro-computed tomography (μCT) and histological analyses (bone morphometric analyses) on the erosive calcaneocuboid joint, periarticular bone (distal femur or proximal tibia), and vertebrae were performed. The effect of four different JAK inhibitors on osteoclastogenesis under various conditions was examined in vitro. RESULTS The JAK inhibitor ameliorated joint erosion, periarticular osteopenia and systemic bone loss. It reduced the osteoclast number in all the three types of bone damage. The JAK inhibitor enhanced osteoblastic bone formation in the calcaneus distal to inflammatory synovium in the calcaneocuboid joints, periarticular region of the tibia and vertebrae, but not the inflamed calcaneocuboid joint. All the JAK inhibitors suppressed osteoclastogenesis in vitro to a similar extent in the presence of osteoblastic cells. Most of the JAK inhibitors abrogated the suppressive effect of Th1 cells on osteoclastogenesis by inhibiting IFN-γ signaling in osteoclast precursor cells, while a JAK inhibitor did not affect this effect due to less ability to inhibit IFN-γ signaling. CONCLUSIONS The JAK inhibitor suppressed joint erosion mainly by inhibiting osteoclastogenesis, while it ameliorated periarticular osteopenia and systemic bone loss by both inhibiting osteoclastogenesis and promoting osteoblastogenesis. These results indicate that the effect of JAK inhibitors on osteoclastogenesis and osteoblastogenesis depends on the bone damage type and the affected bone area. In vitro studies suggest that while JAK inhibitors inhibit osteoclastic bone resorption, their effects on osteoclastogenesis in inflammatory environments vary depending on the cytokine milieu, JAK selectivity and cytokine signaling specificity. The findings reported here should contribute to the strategic use of antirheumatic drugs against structural damages in RA.
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Affiliation(s)
- Masatsugu Komagamine
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Noriko Komatsu
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Rui Ling
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuo Okamoto
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shi Tianshu
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kotaro Matsuda
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Saitama Medical University, Saitama, Japan
| | - Yuko Kaneko
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Takayanagi
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
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16
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Peng Q, Wang J, Han M, Zhao M, Li K, Lu T, Guo Q, Jiang Q. Tanshinone IIA inhibits osteoclastogenesis in rheumatoid arthritis via LDHC-regulated ROS generation. Chin Med 2023; 18:54. [PMID: 37189204 PMCID: PMC10184368 DOI: 10.1186/s13020-023-00765-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 05/05/2023] [Indexed: 05/17/2023] Open
Abstract
Rheumatoid arthritis (RA) is characterized by bone destruction in the afflicted joints, and during the process of bone destruction, osteoclasts play a crucial role. Tanshinone IIA (Tan IIA) has shown anti-inflammatory effects in RA. However, the exact molecular mechanisms by which it delays bone destruction remain largely unexplained. Here, we found that Tan IIA decreased the severity of and ameliorated bone loss in an AIA rat model. In vitro, Tan IIA inhibited RANKL-induced osteoclast differentiation. By activity-based protein analysis (ABPP) combined with LC‒MS/MS, we discovered that Tan IIA covalently binds to the lactate dehydrogenase subunit LDHC and inhibits its enzymatic activity. Moreover, we found that Tan IIA inhibits the generation of osteoclast-specific markers by reducing the accumulation of reactive oxygen species (ROS), thus reducing osteoclast differentiation. Finally, our results reveal that Tan IIA suppresses osteoclast differentiation via LDHC-mediated ROS generation in osteoclasts. Tan IIA can thus be regarded as an effective drug for the treatment of bone damage in RA.
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Affiliation(s)
- Qiuwei Peng
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Jian Wang
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Man Han
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Minghong Zhao
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, 341000, China
| | - Kesong Li
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Tianming Lu
- School of Public Health, Guangxi Medical University, Guangxi, 530021, China
| | - Qiuyan Guo
- Artemisnin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Quan Jiang
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
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Liu Y, Chen L, Chen Z, Liu M, Li X, Kou Y, Hou M, Wang H, Li X, Tian B, Dong J. Multifunctional Janus Nanoplatform for Efficiently Synergistic Theranostics of Rheumatoid Arthritis. ACS NANO 2023; 17:8167-8182. [PMID: 37083341 DOI: 10.1021/acsnano.2c11777] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
Progress has been made in the application of nanomedicine in rheumatoid arthritis (RA) treatment. However, the whole process of monitoring and treatment of RA remains a formidable challenge due to the complexity of the chronic autoimmune disease. In this study, we develop a Janus nanoplatform (denoted as Janus-CPS) composed of CeO2-Pt nanozyme subunit on one side and periodic mesoporous organosilica (PMO) subunit on another side for simultaneous early diagnosis and synergistic therapy of RA. The Janus nanostructure, which enables more active sites to be exposed, enhances the reactive oxygen species scavenging capability of CeO2-Pt nanozyme subunit as compared to their core-shell counterpart. Furthermore, micheliolide (MCL), an extracted compound from natural plants with anti-osteoclastogenesis effects, is loaded into the mesopores of PMO subunit to synergize with the anti-inflammation effect of nanozymes for efficient RA treatment, which has been demonstrated by in vitro cellular experiments and in vivo collagen-induced arthritis (CIA) model. In addition, by taking advantage of the second near-infrared window (NIR-II) fluorescent imaging, indocyanine green (ICG)-loaded Janus-CPS exhibits desirable effectiveness in detecting RA lesions at a very early stage. It is anticipated that such a Janus nanoplatform may offer an alternative strategy of functional integration for versatile theranostics.
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Affiliation(s)
- Yuyi Liu
- Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Liang Chen
- Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai 200444, P. R. China
| | - Zhiyang Chen
- Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Minchao Liu
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, iChem, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433, P. R. China
| | - Xilei Li
- Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Yufang Kou
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, iChem, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433, P. R. China
| | - MengMeng Hou
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, iChem, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433, P. R. China
| | - Huiren Wang
- Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Xiaomin Li
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, iChem, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433, P. R. China
| | - Bo Tian
- Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Jian Dong
- Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
- Department of Orthopaedic Surgery, Shanghai Baoshan District Wusong Center Hospital, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai 200940, P. R. China
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Matsuda K, Shiba N, Hiraoka K. New Insights into the Role of Synovial Fibroblasts Leading to Joint Destruction in Rheumatoid Arthritis. Int J Mol Sci 2023; 24:ijms24065173. [PMID: 36982247 PMCID: PMC10049180 DOI: 10.3390/ijms24065173] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by multiple-joint synovitis with subsequent destruction of bone and cartilage. The excessive autoimmune responses cause an imbalance in bone metabolism, promoting bone resorption and inhibiting bone formation. Preliminary studies have revealed that receptor activator of NF-κB ligand (RANKL)-mediated osteoclast induction is an important component of bone destruction in RA. Synovial fibroblasts are the crucial producers of RANKL in the RA synovium; novel analytical techniques, primarily, single-cell RNA sequencing, have confirmed that synovial fibroblasts include heterogeneous subsets of both pro-inflammatory and tissue-destructive cell types. The heterogeneity of immune cells in the RA synovium and the interaction of synovial fibroblasts with immune cells have recently received considerable attention. The current review focused on the latest findings regarding the crosstalk between synovial fibroblasts and immune cells, and the pivotal role played by synovial fibroblasts in joint destruction in RA.
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Affiliation(s)
- Kotaro Matsuda
- Department of Orthopedic Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Fukuoka, Japan
| | - Naoto Shiba
- Department of Orthopedic Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Fukuoka, Japan
| | - Koji Hiraoka
- Department of Orthopedic Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Fukuoka, Japan
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Signaling pathways in rheumatoid arthritis: implications for targeted therapy. Signal Transduct Target Ther 2023; 8:68. [PMID: 36797236 PMCID: PMC9935929 DOI: 10.1038/s41392-023-01331-9] [Citation(s) in RCA: 163] [Impact Index Per Article: 81.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/16/2022] [Accepted: 01/18/2023] [Indexed: 02/18/2023] Open
Abstract
Rheumatoid arthritis (RA) is an incurable systemic autoimmune disease. Disease progression leads to joint deformity and associated loss of function, which significantly impacts the quality of life for sufferers and adds to losses in the labor force. In the past few decades, RA has attracted increased attention from researchers, the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA, which provides important evidence for understanding this complex disease and developing novel RA-linked intervention targets. The current review intends to provide a comprehensive overview of RA, including a general introduction to the disease, historical events, epidemiology, risk factors, and pathological process, highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms, including genetic factors, epigenetic factors, summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating RA. therapeutic interventions including approved drugs, clinical drugs, pre-clinical drugs, and cutting-edge therapeutic technologies. These developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future.
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20
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The Flavonoid Naringenin Alleviates Collagen-Induced Arthritis through Curbing the Migration and Polarization of CD4 + T Lymphocyte Driven by Regulating Mitochondrial Fission. Int J Mol Sci 2022; 24:ijms24010279. [PMID: 36613721 PMCID: PMC9820519 DOI: 10.3390/ijms24010279] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/19/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
Rheumatoid arthritis (RA) is a progressive autoimmune disease. Due to local infiltration and damage to the joints, activated CD4+ T cells play a crucial role in the progression of RA. However, the exact regulatory mechanisms are perplexing, which makes the effective management of RA frustrating. This study aimed to investigate the effect of mitochondria fission on the polarization and migration of CD4+ T cells as well as the regulatory mechanism of NAR, so as to provide enlightenment on therapeutic targets and novel strategies for the treatment of RA. In this study, a collagen-induced arthritis (CIA) model was established, and rats were randomly given saline or naringenin (NAR, 10 mg/kg, 20 mg/kg, 50 mg/kg, i.p.) once a day, before being euthanized on the 42nd day of primary immunization. The pain-like behavior, articular index scores, account of synovial-infiltrated CD4+ T cells, and inflammatory factors were investigated in each group. In vitro, spleen CD4+ T lymphocytes were derived from each group. In addition, mitochondrial division inhibitor 1 (Mdivi-1) or NAR was added to the cell medium containing C-X-C motif chemokine ligand 12 (CXCL12) in order to induce CD4+ T lymphocytes, respectively. The polarization capacity of CD4+ T cells was evaluated through the immunofluorescence intensity of the F-actin and myosin light chain phosphorylated at Ser19 (pMLC S19), and the mitochondrial distribution was determined by co-localization analysis of the translocase of outer mitochondrial membrane 20 (TOM20, the mitochondrial marker) and intercellular adhesion molecule 1 (ICAM1, the uropod marker). The mitochondrial fission was investigated by detecting dynamin-related protein 1 (Drp1) and mitochondrial fission protein 1 (Fis1) using Western blot and immunofluorescence. This study revealed that high-dose NAR (50 mg/kg, i.p.) alleviated pain-like behavior and articular index scores, reduced the serum level of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), and accounted for CD4+ T lymphocytes that infiltrated into the synovial membrane of the CIA group. Meanwhile, NAR (50 mg/kg, i.p.) suppressed the polarization of spleen CD4+ T lymphocytes, reduced the redistribution of mitochondria in the uropod, and inhibited the expression of Drp1 and Fis1 in the CIA model. Furthermore, the in vitro experiments confirmed that NAR reduced mitochondrial fission, which in turn inhibited the CXCL12-induced polarization and migration of CD4+ T lymphocytes. Our results demonstrated that the flavonoid NAR was a promising drug for the treatment of RA, which could effectively interfere with mitochondrial fission, thus inhibiting the polarization and migration of CD4+ T cells in the synovial membrane.
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Niu Q, Gao J, Wang L, Liu J, Zhang L. Regulation of differentiation and generation of osteoclasts in rheumatoid arthritis. Front Immunol 2022; 13:1034050. [PMID: 36466887 PMCID: PMC9716075 DOI: 10.3389/fimmu.2022.1034050] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/31/2022] [Indexed: 09/25/2023] Open
Abstract
INTRODUCTION Rheumatoid arthritis (RA), which affects nearly 1% of the world's population, is a debilitating autoimmune disease. Bone erosion caused by periarticular osteopenia and synovial pannus formation is the most destructive pathological changes of RA, also leads to joint deformity and loss of function,and ultimately affects the quality of life of patients. Osteoclasts (OCs) are the only known bone resorption cells and their abnormal differentiation and production play an important role in the occurrence and development of RA bone destruction; this remains the main culprit behind RA. METHOD Based on the latest published literature and research progress at home and abroad, this paper reviews the abnormal regulation mechanism of OC generation and differentiation in RA and the possible targeted therapy. RESULT OC-mediated bone destruction is achieved through the regulation of a variety of cytokines and cell-to-cell interactions, including gene transcription, epigenetics and environmental factors. At present, most methods for the treatment of RA are based on the regulation of inflammation, the inhibition of bone injury and joint deformities remains unexplored. DISCUSSION This article will review the mechanism of abnormal differentiation of OC in RA, and summarise the current treatment oftargeting cytokines in the process of OC generation and differentiation to reduce bone destruction in patients with RA, which isexpected to become a valuable treatment choice to inhibit bone destruction in RA.
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Affiliation(s)
- Qing Niu
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Jinfang Gao
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Lei Wang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Jiaxi Liu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Liyun Zhang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
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Zhu S, Dang J, Shi Y, Feng X, Hu Y, Lin L, Huang J. Sonic hedgehog promotes synovial inflammation and articular damage through p38 mitogen-activated protein kinase signaling in experimental arthritis. J Autoimmun 2022; 132:102902. [PMID: 36088884 DOI: 10.1016/j.jaut.2022.102902] [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] [Received: 06/14/2022] [Revised: 08/18/2022] [Accepted: 08/23/2022] [Indexed: 11/25/2022]
Abstract
Activated fibroblast-like synoviocytes (FLS) play a pivotal role in synovial inflammation and joint destruction of rheumatoid arthritis (RA). The mechanisms by which sonic hedgehog (SHH) signaling promotes RA FLS-mediated chronic inflammation and tissue damage are not fully understood. The present study aims to determine the role of SHH signaling in the pathogenesis of RA and to explore the potential mechanism(s). We found that the components of SHH signaling were highly expressed in FLS and synovial tissue from patients with RA and in the joint tissue of collagen-induced arthritis (CIA) mice. Overexpression of SHH aggravated the synovial inflammation and joint destruction of CIA and exacerbated cartilage degradation in the cartilage and RA FLS-engrafted severe combined immunodeficiency (SCID) model. Conversely, inhibition of SHH signaling significantly alleviated arthritis severity and reduced cartilage destruction caused by the invasion of RA FLS in vivo. Moreover, we found that p38 mitogen-activated protein kinase (MAPK) cascade was regulated by SHH signaling in RA FLS and the level of phospho-p38 in the joint tissue of CIA was decreased after blockade of SHH signaling. Inhibition of p38 MAPK abolished the effect of SHH overexpression on synovial inflammation and articular destruction of CIA and suppressed the aggressive properties of RA FLS, which were promoted by SHH agonist. In conclusion, our study suggests that SHH signaling aggravates synovial inflammation and joint destruction of experimental arthritis and promotes the abnormal behavior of RA FLS in a p38-dependent manner. SHH-p38 MAPK signaling could be a potential target for the treatment of RA.
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Affiliation(s)
- Shangling Zhu
- Department of Rheumatology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, PR China
| | - Junlong Dang
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, PR China; Department of Clinical Immunology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, PR China
| | - Yiming Shi
- Department of Intensive Care Unit, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, PR China
| | - Xiaoxue Feng
- Department of Rheumatology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, PR China
| | - Yudan Hu
- Department of Rheumatology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, PR China
| | - Lang Lin
- Department of Rheumatology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, PR China
| | - Jianlin Huang
- Department of Rheumatology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, PR China.
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Andreev D, Kachler K, Schett G, Bozec A. Rheumatoid arthritis and osteoimmunology: The adverse impact of a deregulated immune system on bone metabolism. Bone 2022; 162:116468. [PMID: 35688359 DOI: 10.1016/j.bone.2022.116468] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/30/2022] [Accepted: 06/06/2022] [Indexed: 11/20/2022]
Abstract
The term osteoimmunology describes an interdisciplinary research field that links the investigation of osteology (bone cells) with immunology. The crosstalk between innate and adaptive immune cells and cells involved in bone remodeling, mainly bone-resorbing osteoclasts and bone-forming osteoblasts, becomes particularly obvious in the inflammatory autoimmune disease rheumatoid arthritis (RA). Besides striking inflammation of the joints, RA causes bone loss, leading to joint damage and disabilities as well as generalized osteoporosis. Mechanistically, RA-associated immune cells (macrophages, T cells, B cells etc.) produce high levels of pro-inflammatory cytokines, receptor activator of nuclear factor κB ligand (RANKL) and autoantibodies that promote bone degradation and at the same time counteract new bone formation. Today, antirheumatic therapy effectively ceases joint inflammation and arrests bone erosion. However, the repair of established bone lesions still presents a challenging task and requires improved treatment options. In this review, we outline the knowledge gained over the past years about the immunopathogenesis of RA and the impact of a dysregulated immune system on bone metabolism.
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Affiliation(s)
- Darja Andreev
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Katerina Kachler
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany.
| | - Georg Schett
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany.
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Dynamic changes in O-GlcNAcylation regulate osteoclast differentiation and bone loss via nucleoporin 153. Bone Res 2022; 10:51. [PMID: 35879285 PMCID: PMC9314416 DOI: 10.1038/s41413-022-00218-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 01/25/2022] [Accepted: 02/28/2022] [Indexed: 11/08/2022] Open
Abstract
Bone mass is maintained by the balance between osteoclast-induced bone resorption and osteoblast-triggered bone formation. In inflammatory arthritis such as rheumatoid arthritis (RA), however, increased osteoclast differentiation and activity skew this balance resulting in progressive bone loss. O-GlcNAcylation is a posttranslational modification with attachment of a single O-linked β-D-N-acetylglucosamine (O-GlcNAc) residue to serine or threonine residues of target proteins. Although O-GlcNAcylation is one of the most common protein modifications, its role in bone homeostasis has not been systematically investigated. We demonstrate that dynamic changes in O-GlcNAcylation are required for osteoclastogenesis. Increased O-GlcNAcylation promotes osteoclast differentiation during the early stages, whereas its downregulation is required for osteoclast maturation. At the molecular level, O-GlcNAcylation affects several pathways including oxidative phosphorylation and cell-cell fusion. TNFα fosters the dynamic regulation of O-GlcNAcylation to promote osteoclastogenesis in inflammatory arthritis. Targeted pharmaceutical or genetic inhibition of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) arrests osteoclast differentiation during early stages of differentiation and during later maturation, respectively, and ameliorates bone loss in experimental arthritis. Knockdown of NUP153, an O-GlcNAcylation target, has similar effects as OGT inhibition and inhibits osteoclastogenesis. These findings highlight an important role of O-GlcNAcylation in osteoclastogenesis and may offer the potential to therapeutically interfere with pathologic bone resorption.
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Komatsu N, Takayanagi H. Mechanisms of joint destruction in rheumatoid arthritis - immune cell-fibroblast-bone interactions. Nat Rev Rheumatol 2022; 18:415-429. [PMID: 35705856 DOI: 10.1038/s41584-022-00793-5] [Citation(s) in RCA: 247] [Impact Index Per Article: 82.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2022] [Indexed: 12/29/2022]
Abstract
Rheumatoid arthritis (RA) is characterized by inflammation and destruction of bone and cartilage in affected joints. Autoimmune responses lead to increased osteoclastic bone resorption and impaired osteoblastic bone formation, the imbalance of which underlies bone loss in RA, which includes bone erosion, periarticular bone loss and systemic osteoporosis. The crucial role of osteoclasts in bone erosion has been demonstrated in basic studies as well as by the clinical efficacy of antibodies targeting RANKL, an important mediator of osteoclastogenesis. Synovial fibroblasts contribute to joint damage by stimulating both pro-inflammatory and tissue-destructive pathways. New technologies, such as single-cell RNA sequencing, have revealed the heterogeneity of synovial fibroblasts and of immune cells including T cells and macrophages. To understand the mechanisms of bone damage in RA, it is important to clarify how the immune system promotes the tissue-destructive properties of synovial fibroblasts and influences bone cells. The interaction between immune cells and fibroblasts underlies the imbalance between regulatory T cells and T helper 17 cells, which in turn exacerbates not only inflammation but also bone destruction, mainly by promoting RANKL expression on synovial fibroblasts. An improved understanding of the immune mechanisms underlying joint damage and the interplay between the immune system, synovial fibroblasts and bone will contribute to the identification of novel therapeutic targets in RA.
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Affiliation(s)
- Noriko Komatsu
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Takayanagi
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
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26
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Abstract
Rheumatoid arthritis is a common chronic inflammatory disease with substantial economic, social, and personal costs. Its pathogenesis is multifactorial and complex. The ultimate goal of rheumatoid arthritis treatment is stopping or slowing down the disease progression. In the past two decades, invention of new medicines, especially biologic agents, revolutionized the management of this disease. These agents have been associated with an improved prognosis and clinical remission, especially in patients who did not respond to traditional disease-modifying anti-rheumatic drugs (DMARDs). Improvement in the understanding of the rheumatoid arthritis pathogenesis leads to the development of novel biologic therapeutic approaches. In the present paper, we summarized the current therapeutics, especially biologic agents, available for the treatment of rheumatoid arthritis.
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Deng W, Ding Z, Wang Y, Zou B, Zheng J, Tan Y, Yang Q, Ke M, Chen Y, Wang S, Li X. Dendrobine attenuates osteoclast differentiation through modulating ROS/NFATc1/ MMP9 pathway and prevents inflammatory bone destruction. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 96:153838. [PMID: 34801352 DOI: 10.1016/j.phymed.2021.153838] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/08/2021] [Accepted: 10/27/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Osteolytic diseases share symptoms such as bone loss, fracture and pain, which are caused by over-activated osteoclasts. Targeting osteoclast differentiation has emerged as a therapeutic strategy clinically. Dendrobine is an alkaloid isolated from Chinese herb Dendrobium nobile, with knowing effects of analgesia and anti-inflammation. The roles of dendrobine on osteoclasts and osteolysis remain unclear. PURPOSE Herein, the possible roles of dendrobine in osteoclastogenesis, inflammatory osteolysis and the underlying mechanism were explored. METHODS Bone marrow-derived macrophages (BMMs) and RAW264.7 cells were employed to evaluate the roles of dendrobine on osteoclastogenesis, bone absorption and the underlying mechanism in vitro. LPS injection was used to cause inflammatory osteolysis in vivo. RESULTS Dendrobine repressed osteoclastogenesis, bone resorption induced by receptor activator of nuclear factor kappa B ligand (RANKL) in vitro. Mechanistically, dendrobine inhibited RANKL-upregulated intracellular (ROS), p-p38, c-Fos expression and nuclear factor of activated T cells (NFATc1) nuclear translocation. Osteoclastic genes were reduced, and among them matrix metalloproteinase 9 (MMP9) mRNA was dramatically blocked by dendrobine. Moreover, it substantially suppressed MMP9 protein expression during osteoclastogenesis in vitro. Accordingly, oral 20 mg/kg/day dendrobine was capable of preventing LPS-induced osteolysis with decreased osteoclasts in vivo. CONCLUSION Taken together, dendrobine suppresses osteoclastogenesis through restraining ROS, p38-c-Fos and NFATc1-MMP9 in vitro, thus attenuates inflammatory osteolysis in vivo. This finding supports the discover of dendrobine as a novel osteoclast inhibitor for impeding bone erosion in the future.
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Affiliation(s)
- Wende Deng
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Zongbao Ding
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yiyuan Wang
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Binhua Zou
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jiehuang Zheng
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yanhui Tan
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qin Yang
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Minhong Ke
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yan Chen
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Song Wang
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Surgery Department, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong, China.
| | - Xiaojuan Li
- Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
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Noguchi T, Kitaura H, Marahleh A, Ohori F, Nara Y, Pramusita A, Kinjo R, Ma J, Kanou K, Mizoguchi I. Tumor necrosis factor-α enhances the expression of vascular endothelial growth factor in a mouse orthodontic tooth movement model. J Dent Sci 2022; 17:415-420. [PMID: 35028065 PMCID: PMC8739756 DOI: 10.1016/j.jds.2021.08.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/19/2021] [Indexed: 12/22/2022] Open
Abstract
Background/purpose Tooth movement that is achieved using orthodontic mechanical principles relies on bone resorption which takes place on the compression side via osteoclasts. Tumor necrosis factor-α (TNF-α) has been known to affect osteoclast formation in orthodontic tooth movement (OTM). Vascular endothelial growth factor (VEGF), which is one of the mediators of angiogenesis, also plays an important role in OTM by inducing vascular permeability and chemotaxis of osteoclast precursors. Therefore, the purpose of this research was to evaluate the effect of TNF-α on VEGF expression during OTM. Materials and methods In order to demonstrate the effect of TNF-α on VEGF expression during OTM, a nickel titanium closed coil spring was fixed to the upper left first molar and the alveolar bone beneath the upper incisors of both wild type (WT) and TNF receptors (TNFRs) deficient mice resulting in a mesial movement of the molar for 12 days. The maxilla was removed for histological analysis and real-time RCR analysis of VEGF expression. Results Immunohistochemical analysis revealed that there were fewer VEGF-positive cells in the periodontal membrane on the mesial side of the distobuccal root in TNFRs-deficient mice than that in WT mice during the OTM for 12 days. Furthermore, expression of VEGF mRNA is lower level in TNFRs-deficient mice than that in WT mice. Conclusion Our results indicate that TNF-α plays an important role in VEGF expression during tooth movement.
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Affiliation(s)
- Takahiro Noguchi
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Hideki Kitaura
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Aseel Marahleh
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Fumitoshi Ohori
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Yasuhiko Nara
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Adya Pramusita
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Ria Kinjo
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Jinghan Ma
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Kayoko Kanou
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Itaru Mizoguchi
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
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Regulation of TNF-Induced Osteoclast Differentiation. Cells 2021; 11:cells11010132. [PMID: 35011694 PMCID: PMC8750957 DOI: 10.3390/cells11010132] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/24/2021] [Accepted: 12/28/2021] [Indexed: 12/27/2022] Open
Abstract
Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.
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[Tumor necrosis factor-α promotes osteoclast differentiation via sialylation in mice]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:1773-1779. [PMID: 35012907 PMCID: PMC8752434 DOI: 10.12122/j.issn.1673-4254.2021.12.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To explore the mechanism through which tumor necrosis factor-α (TNF-α) promotes osteoclast differentiation. METHODS Bilateral knee joint samples were collected from 4-month-old wild-type mice and TNF-α transgenic mice for CT scan analysis, TRAP staining and sialic acid staining analysis. The osteoclast precursor (RAW264.7) cells were cultured for 3 days in induction medium in the presence of vehicle, TNF-α, or TNF-α and sialidase, and were then examined with RT-qPCR, TRAP staining, and sialic acid immunofluorescence co-localization staining. Bone marrow-derived macrophages isolated from the wild-type mice and TNF-α transgenic mouse and cultured in induction medium with or without the addition of sialidase, and TRAP and sialic acid staining was performed after 3 days of cell culture. RESULTS TRAP staining showed that the number of osteoclasts increased significantly in TNF-α transgenic mice as compared with the wild-type mice (P < 0.0001), and micro-CT analysis revealed significant reductions of BV/TV, Tb.N, and Tb.Th in TNF-α transgenic mice (P < 0.001). The osteoclasts in TNF-α transgenic mice also showed a significantly increased expression of sialic acid (P=0.004). In the cell experiment, RAW264.7 cells cultured with TNF-α showed a significantly higher expression of sialic acid (P < 0.0001) and a greater osteoclast formation rate (P=0.0007) than the the control cells, while the addition of sialidase significantly reduced sialic acid expression, osteoclast formation rate and TRAP mRNA level in TNF-α-treated cells (P < 0.0001). Similarly, in the bone marrow-derived macrophages, sialic acid expression and osteoclast formation rate were significantly increased by incubation with TNF-α (P < 0.0001), but the increments were obviously reduced by addition of sialidase in the medium (P < 0.0001). CONCLUSION TNF-α can promote the differentiation and activity of osteoclasts by increasing the sialylation level in the osteoclasts.
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Sepehri NZ, Raeisi T, Razi B, Janmohammadi P, Darand M, Alizadeh S. The association between psoriasis and psoriatic arthritis with the risk of osteoporosis, osteopenia and bone fractures: A systematic review and meta-analysis. Int J Clin Pract 2021; 75:e14630. [PMID: 34260133 DOI: 10.1111/ijcp.14630] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/05/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND AND AIMS The possible association between psoriatic/psoriatic arthritis (PsA) and bone loss has been observed; however, studies have yielded inconclusive results. This meta-analysis aimed to assess whether there is an increase in the risk of osteoporosis, osteopenia and fractures in patients with psoriasis/PsA, compared with healthy individuals. METHODS PubMed and Scopus were systematically searched from their inception to September 2020 to identify relevant studies. Relative risk, hazard ratio or odds ratio (OR), with their corresponding 95% confidence intervals (95% CI) were calculated and pooled using a random-effects model. RESULTS A total of 12 different studies, with a total of 199 389 296 participants, were included. Overall, no significant relationship was observed between psoriasis/PsA and the risk of osteoporosis (psoriasis: OR = 1.28, 95%CI = 0.86-1.90; PsA: OR = 1.32, 95%CI = 0.79-2.19) and osteopenia (psoriasis: OR = 1.50, 95%CI = 0.75-3.02; PsA: OR = 1.61, 95%CI = 0.67-3.85). However, in the subgroup analysis, psoriasis was significantly associated with an increased risk of osteoporosis in men (OR = 1.27, 95%CI = 1.02-1.59) and studies with cohort design (OR = 1.04, 95%CI = 1.003-1.09). Psoriasis was also related to the risk of osteopenia in studies on a combination of both genders (OR = 2.86, 95%CI = 2.70-3.02). The pooled analysis demonstrated a significantly higher risk of fractures among patients with psoriasis (OR = 1.29, 95%CI = 1.02-1.63) and PsA (OR = 2.88, 95%CI = 1.51-5.48), compared with participants without psoriasis/PsA. CONCLUSIONS Patients with psoriasis/PsA have an increased risk of fractures. There is little evidence supporting the relation of psoriasis to osteoporosis/osteopenia.
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Affiliation(s)
| | - Tahereh Raeisi
- Department of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Bahman Razi
- Department of Hematology and Blood Banking, School of Medicine, Tarbiat Modares University (TMU), Tehran, Iran
| | - Parisa Janmohammadi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mina Darand
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shahab Alizadeh
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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Jiang Y, Ma H, Zhang Q, Shi J, Gao Y, Sun C, Zhang W. Integrative analyses reveal RNA regulatory network in Ti particles induced inflammation. EUR J INFLAMM 2021. [DOI: 10.1177/20587392211044863] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Introduction Wear particles induced inflammatory osteolysis is the most important initiating factors in the mechanism of aseptic loosening. However, the molecular network changes in this process remain largely elusive. Methods Here, we performed whole transcriptome analysis using Ti particles induced RAW264.7 cell model to identify specific genes and pathways. Results Sequencing results totally identified 159 mRNAs, 96 lncRNAs, 31 circRNAs, and 12 miRNAs were significantly differently expressed. Of these, we selected two of each RNA for qRT-PCR validation and the results were highly consistent with the RNA-seq data. GSEA analysis shows that upregulated gene sets were related to the three classical inflammation pathway, cytokine–cytokine receptor interaction, TNF, and NF-kappa B signaling pathway. The enriched genes included not only IL-1β and TNF- α, which were independently verified before sequencing, but also other inflammatory osteolysis-related genes such as Mmp9, Fas, and Ccl2. Co-differentially expressed RNAs were employed to construct the ceRNA co-regulatory network. Conclusion: The results revealed that 4 lncRNAs and 2 circRNAs formed a regulatory network to simultaneously regulate miR-3065-3p targeting Myo18a. The present study helps to comprehensively understand the molecular mechanisms and regulatory interaction networks during early inflammatory response.
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Affiliation(s)
- Yonghui Jiang
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Huanzhi Ma
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qin Zhang
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jun Shi
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yutong Gao
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chengliang Sun
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Wei Zhang
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Marahleh A, Kitaura H, Ohori F, Noguchi T, Nara Y, Pramusita A, Kinjo R, Ma J, Kanou K, Mizoguchi I. Effect of TNF-α on osteocyte RANKL expression during orthodontic tooth movement. J Dent Sci 2021; 16:1191-1197. [PMID: 34484587 PMCID: PMC8403810 DOI: 10.1016/j.jds.2021.03.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/11/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND/PURPOSE Orthodontic tooth movement (OTM) is facilitated by two events; bone resorption on the compression side and bone formation on the tension side simultaneously termed bone remodeling. Osteocytes play a critical role in bone remodeling during OTM, as they have been described as the critical source of nuclear factor-κB ligand (RANKL) necessary for bone remodeling during OTM. Tumor necrosis factor (TNF)-α is a cytokine that acts by amplifying RANKL expression in osteocytes. In this study, we evaluated the effects of TNF-α on RANKL expression in osteocyte during OTM. MATERIALS AND METHODS We assessed whether TNF-α influenced RANKL expression in osteocyte during orthodontic tooth movement by using wild-type (WT) and TNF receptor I and II deficient (TNFRsKO) mice. A Nickel-titanium closed coil spring was attached to the maxillary alveolar bone near the incisors and the upper left first molar, and the first molars were moved mesially in WT and TNFRsKO mice. After OTM, the number of RANKL-positive osteocytes in the alveolar bone was evaluated by immunohistochemistry. RESULTS The number of RANKL-positive osteocyte in the alveolar bone significantly increased in WT mice than in TNFRsKO mice after OTM. CONCLUSION The results indicate that TNF-α induces the expression of RANKL in osteocyte during OTM.
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Affiliation(s)
- Aseel Marahleh
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Hideki Kitaura
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Fumitoshi Ohori
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Takahiro Noguchi
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Yasuhiko Nara
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Adya Pramusita
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Ria Kinjo
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Jinghan Ma
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Kayoko Kanou
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Itaru Mizoguchi
- Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, Sendai, Japan
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Interleukin-9 Facilitates Osteoclastogenesis in Rheumatoid Arthritis. Int J Mol Sci 2021; 22:ijms221910397. [PMID: 34638736 PMCID: PMC8508938 DOI: 10.3390/ijms221910397] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/06/2021] [Accepted: 09/11/2021] [Indexed: 12/29/2022] Open
Abstract
In rheumatoid arthritis (RA), inflammatory cytokines play a pivotal role in triggering abnormal osteoclastogenesis leading to articular destruction. Recent studies have demonstrated enhanced levels of interleukin-9 (IL-9) in the serum and synovial fluid of patients with RA. In RA, strong correlation has been observed between tissue inflammation and IL-9 expression in synovial tissue. Therefore, we investigated whether IL-9 influences osteoclastogenesis in patients with RA. We conducted the study in active RA patients. For inducing osteoclast differentiation, mononuclear cells were stimulated with soluble receptor activator of NF-kB ligand (sRANKL) and macrophage-colony-stimulating factor (M-CSF) in the presence or absence of recombinant (r) IL-9. IL-9 stimulation significantly enhanced M-CSF/sRANKL-mediated osteoclast formation and function. Transcriptome analysis revealed differential gene expression induced with IL-9 stimulation in the process of osteoclast differentiation. IL-9 mainly modulates the expression of genes, which are involved in the metabolic pathway. Moreover, we observed that IL-9 modulates the expression of matrix metalloproteinases (MMPs), which are critical players in bone degradation. Our results indicate that IL-9 has the potential to influence the structural damage in the RA by promoting osteoclastogenesis and modulating the expression of MMPs. Thus, blocking IL-9 pathways might be an attractive immunotherapeutic target for preventing bone degradation in RA.
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Chen X, Zhang H, Zeng W, Wang N, Lo HH, Ip CK, Yang LJ, Hsiao WW, Sin WM, Xia C, Law BYK, Wong VKW. Far infrared irradiation suppresses experimental arthritis in rats by down-regulation of genes involved inflammatory response and autoimmunity. J Adv Res 2021; 38:107-118. [PMID: 35572409 PMCID: PMC9091720 DOI: 10.1016/j.jare.2021.08.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 08/08/2021] [Accepted: 08/28/2021] [Indexed: 12/15/2022] Open
Abstract
FIR treatment improved adjuvant arthritis in rats. FIR exposure inhibited the inflammatory genes expression of synovial tissues in AIA rats. FIR exposure down-regulated inflammatory genes expression mainly through transcription factors AP-1, CEBPα, CEBPβ, c-Fos, GR, HNF-3β, USF-1, and USF-2. FIR irradiation may exhibit anti-arthritic effects through inactivation of the MAPK, PI3K-Akt, and NF-κB signaling pathways. Introduction Objectives Methods Results Conclusion
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Affiliation(s)
- Xi Chen
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR China
| | - Hui Zhang
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR China
| | - Wu Zeng
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR China
| | - Nick Wang
- Nick Wang Technology Limited, TML Tower, 3 Hoi Shing Road, Tsuen Wan, Kowloon, Hong Kong
| | - Hang Hong Lo
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR China
| | - Chi Kio Ip
- School of Life & Medical Sciences, University College London, London, UK
| | - Li Jun Yang
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR China
| | - W.L. Wendy Hsiao
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR China
| | - Wai Man Sin
- Department of Chinese Medicine, Kiang Wu Hospital, Macau, SAR China
| | - Chenglai Xia
- Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan 528000, China
| | - Betty Yuen Kwan Law
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR China
- Corresponding authors at: Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, SAR China.
| | - Vincent Kam Wai Wong
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR China
- Corresponding authors at: Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, SAR China.
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Teufel S, Köckemann P, Fabritius C, Wolff LI, Bertrand J, Pap T, Hartmann C. Loss of the WNT9a ligand aggravates the rheumatoid arthritis-like symptoms in hTNF transgenic mice. Cell Death Dis 2021; 12:494. [PMID: 33990546 PMCID: PMC8121832 DOI: 10.1038/s41419-021-03786-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/23/2021] [Accepted: 05/04/2021] [Indexed: 01/11/2023]
Abstract
Agonists and antagonists of the canonical Wnt signaling pathway are modulators of pathological aspects of rheumatoid arthritis (RA). Their activity is primarily modifying bone loss and bone formation, as shown in animal models of RA. More recently, modulation of Wnt signaling by the antagonist Sclerostin has also been shown to influence soft-tissue-associated inflammatory aspects of the disease pointing towards a role of Wnt signaling in soft-tissue inflammation as well. Yet, nothing is known experimentally about the role of Wnt ligands in RA. Here we provide evidence that altering Wnt signaling at the level of a ligand affects all aspects of the rheumatoid arthritic disease. WNT9a levels are increased in the pannus tissue of RA patients, and stimulation of synovial fibroblasts (SFB) with tumor necrosis factor (TNF) leads to increased transcription of Wnt9a. Loss of Wnt9a in a chronic TNF-dependent RA mouse model results in an aggravation of disease progression with enhanced pannus formation and joint destruction. Yet, loss of its activity in the acute K/BxN serum-transfer induced arthritis (STIA) mouse model, which is independent of TNF signaling, has no effect on disease severity or progression. Thus, suggesting a specific role for WNT9a in TNF-triggered RA. In synovial fibroblasts, WNT9a can activate the canonical Wnt/β-catenin pathway, but it can also activate P38- and downregulate NFκB signaling. Based on in vitro data, we propose that loss of Wnt9a creates a slight proinflammatory and procatabolic environment that boosts the TNF-mediated inflammatory response.
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Affiliation(s)
- Stefan Teufel
- Department of Bone and Skeletal Research, Institute of Musculoskeletal Medicine, Medical Faculty of the Westphalian Wilhelm University, 48149, Münster, Germany
| | - Petra Köckemann
- Department of Bone and Skeletal Research, Institute of Musculoskeletal Medicine, Medical Faculty of the Westphalian Wilhelm University, 48149, Münster, Germany
| | - Christine Fabritius
- Department of Bone and Skeletal Research, Institute of Musculoskeletal Medicine, Medical Faculty of the Westphalian Wilhelm University, 48149, Münster, Germany
| | - Lena I Wolff
- Department of Bone and Skeletal Research, Institute of Musculoskeletal Medicine, Medical Faculty of the Westphalian Wilhelm University, 48149, Münster, Germany
| | - Jessica Bertrand
- Department of Orthopedic Surgery, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany
| | - Thomas Pap
- Department of Molecular Medicine, Institute of Musculoskeletal Medicine, Medical Faculty of the Westphalian Wilhelm University, 48149, Münster, Germany
| | - Christine Hartmann
- Department of Bone and Skeletal Research, Institute of Musculoskeletal Medicine, Medical Faculty of the Westphalian Wilhelm University, 48149, Münster, Germany.
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Al-Bogami M, Bystrom J, Clanchy F, Taher TE, Mangat P, Williams RO, Jawad AS, Mageed RA. TNFα inhibitors reduce bone loss in rheumatoid arthritis independent of clinical response by reducing osteoclast precursors and IL-20. Rheumatology (Oxford) 2021; 60:947-957. [PMID: 32984900 DOI: 10.1093/rheumatology/keaa551] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/17/2020] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES About half of RA patients treated with TNFα inhibitors either do not respond or lose their initial therapeutic response over time. The clinical response is measured by reduction in DAS28, which primarily reflects inflammation. However, other effects of TNFα inhibitors, such as impact on bone erosion, are not assessed by DAS28. We aimed to examine the effect of TNFα inhibitors on bone density, bone biomarkers and cytokine production in responder and non-responder patients and assessed mechanisms of action. METHODS BMD in the lumbar spine and femur neck of 117 RA patients was measured by DEXA scan. Bone turnover biomarkers CTX, osteoprotegerin (OPG), osteocalcin and RANKL were measured by ELISA. Levels of 16 cytokines in plasma and in tissue culture supernatants of ex vivo T cells were measured by multiplex assays and ELISA. The effect of treatment with TNFα inhibitors on blood mononuclear cell (MNC) differentiation to osteoclast precursors (OCP) was measured flow cytometry and microscopy. RESULTS TNFα inhibitors improved lumbar spine BMD but had modest effects on blood bone biomarkers, irrespective of patients' clinical response. Blood OCP numbers and the ability of monocytes to differentiate to OCP in vitro declined after treatment. Treatment also reduced RANK expression and IL-20 production. BMD improvement correlated with reduced levels of IL-20 in responder patients. CONCLUSION This study reveals that TNFα inhibitors reduce lumbar spine bone loss in RA patients irrespective of changes in DAS28. The reduction in bone loss is associated with reduction in IL-20 levels in responder patients.
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Affiliation(s)
- Mohammed Al-Bogami
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Jonas Bystrom
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Felix Clanchy
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Taher E Taher
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Pamela Mangat
- Department of Rheumatology, Royal Free Hospital, NHS Foundation Trust London, London, UK
| | | | - Ali S Jawad
- Department of Rheumatology, Barts Health NHS Trust, London, UK
| | - Rizgar A Mageed
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
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Khanna N, Kumar A, Pawar SV. A Review on Rheumatoid Arthritis Interventions and Current Developments. Curr Drug Targets 2021; 22:463-483. [PMID: 33243118 DOI: 10.2174/1389450121999201125200558] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/08/2020] [Accepted: 10/13/2020] [Indexed: 11/22/2022]
Abstract
Rheumatoid arthritis is a chronic autoimmune disorder characterized by inflammation, swelling, and joint destruction primarily affecting the peripheral joints. In recent years, RA has become an alarming concern affecting more than 1.5% of the population worldwide. The majority of the drugs in clinical trials for rheumatoid arthritis are immunomodulatory. The development of novel drugs for RA is impending and scientists are exploring new strategies through various innovative approaches for RA drug development. Treat-to-target and window of opportunity hypothesis are the new approaches that are used to treat, improve outcomes, and prevent long-term use of ineffective therapy, respectively. Novel therapeutic agents (e.g. GM-CSF inhibitors, Matrix metalloproteinase inhibitors) and delivery systems (e.g., Liposomes, Superparamagnetic iron oxide nano particles (SPIONs)) are under investigation for more target based therapy with reduced side effects and toxicity. The new drug discovery and repositioning of previously FDA-approved drugs are also being considered for chronic inflammatory disorder. The review encompasses a vast array of information, including genetics, etiology, clinical symptoms, current treatment, and newer therapeutics approaches, focused on the development of RA interventions. The introduction of the bioinformatics-based approach in RA has also been significantly discussed in the review. This review provides a general understanding of the challenges and uncertainties in the treatment of RA and summarizes the evolving scenario as well as innovative approaches taken into consideration for drug development in rheumatoid arthritis.
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Affiliation(s)
- Nikita Khanna
- University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, India
| | - Anil Kumar
- University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, India
| | - Sandip V Pawar
- University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, India
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Naujokat H, Sengebusch A, Loger K, Möller B, Açil Y, Wiltfang J. Therapy of antigen-induced arthritis of the temporomandibular joint via platelet-rich plasma injections in domestic pigs. J Craniomaxillofac Surg 2021; 49:726-731. [PMID: 33676818 DOI: 10.1016/j.jcms.2021.02.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 12/08/2020] [Accepted: 02/19/2021] [Indexed: 02/07/2023] Open
Abstract
The aim of this animal study was to investigate the effect of platelet-rich plasma (PRP) injections into the temporomandibular joint (TMJ) to treat antigen-induced arthritis AIA. AIA was induced via the application of bovine serum albumin (BSA) into the TMJ. Clear histological signs and protein analysis results indicating inflammation of the TMJ were observed. Afterwards, two PRP injections were performed over an interval of 2 weeks. Concentration levels of the proinflammatory cytokines IL-1β (PRP: 33.7 ± 5.6 pg/mg, untreated: 50.0 ± 2.9 pg/mg; p = 0.04) and TNF-α (PRP: 20.7 ± 2.5 pg/mg, untreated: 31.4 ± 2.7 pg/mg; p = 0.03) were significantly decreased in the PRP-treated joints. A significant reduction in signs of histological inflammation, such as hyperplasia of the synovial membrane, leucocyte infiltration, cartilage surface alterations, and an increase in cartilage-specific glycosaminoglycan content, was observed. This animal study supports the understanding of the underlying effects of PRP treatment in the TMJ, and may enhance novel PRP therapies in the future.
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Affiliation(s)
- Hendrik Naujokat
- Department of Oral and Maxillofacial Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3 Haus B, 24105, Kiel, Germany.
| | - André Sengebusch
- Department of Oral and Maxillofacial Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3 Haus B, 24105, Kiel, Germany
| | - Klaas Loger
- Department of Oral and Maxillofacial Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3 Haus B, 24105, Kiel, Germany
| | - Björn Möller
- Department of Oral and Maxillofacial Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3 Haus B, 24105, Kiel, Germany
| | - Yahya Açil
- Department of Oral and Maxillofacial Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3 Haus B, 24105, Kiel, Germany
| | - Jörg Wiltfang
- Department of Oral and Maxillofacial Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3 Haus B, 24105, Kiel, Germany
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Hosonuma M, Sakai N, Furuya H, Kurotaki Y, Sato Y, Handa K, Dodo Y, Ishikawa K, Tsubokura Y, Negishi-Koga T, Tsuji M, Kasama T, Kiuchi Y, Takami M, Isozaki T. Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis. Rheumatology (Oxford) 2021; 60:408-419. [PMID: 32770199 DOI: 10.1093/rheumatology/keaa310] [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: 02/09/2020] [Revised: 04/25/2020] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES To determine the expression of hepatocyte growth factor (HGF) in RA biological fluids, the role of HGF in monocyte migration and the therapeutic effect of the c-Met inhibitor savolitinib in an arthritis model mice. METHODS HGF/c-Met expression in serum, SF and synovial tissues (STs) obtained from RA patients and controls, as well as RA fibroblast-like synoviocytes (FLSs), was evaluated by ELISA and immunostaining. To determine the function of HGF in RA SF, we preincubated RA SF with a neutralizing anti-HGF antibody and measured the chemotactic ability of a human acute monocytic leukaemia cell line (THP-1). Additionally, examinations were conducted of SKG mice treated with savolitinib for 4 weeks. RESULTS HGF levels in serum from RA patients were significantly higher than those in the controls and were decreased by drug treatment for 24 weeks. Additionally, the HGF level in SF from RA patients was higher than that in SF from OA patients. HGF and c-Met expression was also noted in RA STs. Stimulation of RA FLSs with TNF-α increased HGF/c-Met expression in a concentration-dependent manner, and c-Met signal inhibition suppressed production of fractalkine/CX3CL1 and macrophage inflammatory protein-1α/CCL3. When HGF was removed by immunoprecipitation, migration of THP-1 in RA SF was suppressed. In SKG mice, savolitinib significantly suppressed ankle bone destruction on µCT, with an associated reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. CONCLUSION HGF produced by inflammation in synovium of RA patients activates monocyte migration to synovium and promotes bone destruction via a chemotactic effect and enhanced chemokine production.
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Affiliation(s)
- Masahiro Hosonuma
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Shinagawa.,Division of Medical Pharmacology, Department of Pharmacology, Showa University School of Medicine, Shinagawa.,Department of Pharmacology, Showa University School of Dentistry, Shinagawa.,Parmacological Research Center, Showa University, Shinagawa
| | - Nobuhiro Sakai
- Department of Pharmacology, Showa University School of Dentistry, Shinagawa.,Parmacological Research Center, Showa University, Shinagawa
| | - Hidekazu Furuya
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Shinagawa
| | - Yutaro Kurotaki
- Department of Pharmacology, Showa University School of Dentistry, Shinagawa.,Parmacological Research Center, Showa University, Shinagawa.,Division of Community-Based Comprehensive Dentistry, Department of Special Needs Dentistry, School of Dentistry, Showa University, Ota
| | - Yurie Sato
- Department of Pharmacology, Showa University School of Dentistry, Shinagawa.,Parmacological Research Center, Showa University, Shinagawa.,Division of Dentistry for Persons with Disabilities, School of Dentistry, Showa University, Ota
| | - Kazuaki Handa
- Division of Medical Pharmacology, Department of Pharmacology, Showa University School of Medicine, Shinagawa.,Department of Pharmacology, Showa University School of Dentistry, Shinagawa.,Parmacological Research Center, Showa University, Shinagawa.,Department of Orthopaedic Surgery, Showa University School of Medicine, Shinagawa
| | - Yusuke Dodo
- Division of Medical Pharmacology, Department of Pharmacology, Showa University School of Medicine, Shinagawa.,Department of Pharmacology, Showa University School of Dentistry, Shinagawa.,Parmacological Research Center, Showa University, Shinagawa.,Department of Orthopaedic Surgery, Showa University School of Medicine, Shinagawa
| | - Koji Ishikawa
- Parmacological Research Center, Showa University, Shinagawa.,Department of Orthopaedic Surgery, Showa University School of Medicine, Shinagawa
| | - Yumi Tsubokura
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Shinagawa
| | - Takako Negishi-Koga
- Department of Pharmacology, Showa University School of Dentistry, Shinagawa.,Parmacological Research Center, Showa University, Shinagawa.,Division of Mucosal Barriology, International Research and Development Centre for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan
| | - Mayumi Tsuji
- Division of Medical Pharmacology, Department of Pharmacology, Showa University School of Medicine, Shinagawa.,Parmacological Research Center, Showa University, Shinagawa
| | - Tsuyoshi Kasama
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Shinagawa
| | - Yuji Kiuchi
- Division of Medical Pharmacology, Department of Pharmacology, Showa University School of Medicine, Shinagawa.,Parmacological Research Center, Showa University, Shinagawa
| | - Masamichi Takami
- Department of Pharmacology, Showa University School of Dentistry, Shinagawa.,Parmacological Research Center, Showa University, Shinagawa
| | - Takeo Isozaki
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Shinagawa
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Tanaka S, Tanaka Y. RANKL as a therapeutic target of rheumatoid arthritis. J Bone Miner Metab 2021; 39:106-112. [PMID: 33070253 DOI: 10.1007/s00774-020-01159-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 09/19/2020] [Indexed: 12/29/2022]
Abstract
Rheumatoid arthritis (RA) is an inflammatory disorder characterized by progressive joint destruction. Recent studies have demonstrated that osteoclasts are responsible for bone destruction in RA. Receptor activator of nuclear factor kappa B ligand (RANKL), an osteoclast differentiation factor, belongs to the tumor necrosis factor superfamily and plays a critical role in osteoclast differentiation. RANKL is highly expressed in the synovial tissues in patients with RA and is involved in osteoclast development and thus bone destruction in RA. Denosumab, a specific antibody to human RANKL, efficiently suppressed the progression of bone destruction in patients with RA in a randomized controlled study and is considered a putative therapeutic option for RA.
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Affiliation(s)
- Sakae Tanaka
- Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Yoshiya Tanaka
- First Department of Internal Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan
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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: 61] [Impact Index Per Article: 12.2] [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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Park JY, Kwon YW, Kim SA, Park SD, Kim CH, Kim JH, Lee JH. Polyherbal formula SC-E3 inhibits rheumatoid arthritis activity in a mouse model of type-II collagen-induced arthritis. JOURNAL OF INTEGRATIVE MEDICINE-JIM 2020; 19:265-273. [PMID: 33349609 DOI: 10.1016/j.joim.2020.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/30/2020] [Indexed: 12/16/2022]
Abstract
OBJECTIVE SC-E3 is a polyherbal formula that contains five medicinal herbs used frequently in traditional herbal medicine. In our previous study, we demonstrated the antioxidant and anti-inflammatory effects of SC-E3. The present study examined the effects of SC-E3 in a mouse model of type-II collagen-induced arthritis (CIA). METHODS In vivo, male DBA/1J mice were immunized by intradermal injection of bovine type-II collagen and complete or incomplete Freund's adjuvant, to induce arthritis. SC-E3 was orally administered daily for 23 days. In vitro, bone marrow-derived macrophages (BMMs) were treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) in the absence or presence of SC-E3. RESULTS Administrations of SC-E3 were found to have anti-arthritic effects in the joints of CIA mice, as evidenced by reduced paw swelling, bone erosion and deformation, inflammatory cell infiltration, and inflammation in synovial membrane. SC-E3 also reduced serum levels of tumor necrosis factor-α, interleukin-1β, aspartate aminotransferase and alanine aminotransferase. Furthermore, tartrate-resistant acid phosphatase-positive osteoclast numbers in the joints were significantly lower in SC-E3-treated CIA mice than in CIA mice. In addition, the differentiations of BMMs to multinucleated osteoclasts induced by M-CSF and RANKL stimulation were dose-dependently reduced by SC-E3. CONCLUSION These results suggest that SC-E3 possesses substantial anti-arthritic activity because it inhibits pro-inflammatory cytokines and osteoclastogenesis, and that SC-E3 has potential therapeutic use for the treatment of rheumatoid arthritis.
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Affiliation(s)
- Ju-Yeon Park
- College of Korean Medicine, Dongguk University, Goyang 10326, Republic of Korea
| | - Young-Won Kwon
- College of Korean Medicine, Dongguk University, Goyang 10326, Republic of Korea
| | - Sun-Ah Kim
- College of Korean Medicine, Dongguk University, Goyang 10326, Republic of Korea
| | - Sun-Dong Park
- College of Korean Medicine, Dongguk University, Goyang 10326, Republic of Korea
| | - Chang-Hyun Kim
- Department of Medicine, College of Medicine, Dongguk University, Goyang 10326, Republic of Korea
| | - Jin-Hee Kim
- Department of Biomedical Laboratory Science, College of Health Science, Cheongju University, Cheongju 28503, Republic of Korea.
| | - Ju-Hee Lee
- College of Korean Medicine, Dongguk University, Goyang 10326, Republic of Korea.
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Shen P, Jiao Y, Miao L, Chen J, Momtazi‐Borojeni AA. Immunomodulatory effects of berberine on the inflamed joint reveal new therapeutic targets for rheumatoid arthritis management. J Cell Mol Med 2020; 24:12234-12245. [PMID: 32969153 PMCID: PMC7687014 DOI: 10.1111/jcmm.15803] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 07/21/2020] [Accepted: 07/30/2020] [Indexed: 12/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory syndrome designated by synovial joint inflammation leading to cartilage degradation and bone damage as well as progressive disability. Synovial inflammation is promoted through the infiltration of mononuclear immune cells, dominated by CD4+ T cells, macrophages and dendritic cells (DCs), together with fibroblast-like synoviocytes (FLS), into the synovial compartment. Berberine is a bioactive isoquinoline alkaloid compound showing various pharmacological properties that are mainly attributed to immunomodulatory and anti-inflammatory effects. Several lines of experimental study have recently investigated the therapeutic potential of berberine and its underlying mechanisms in treating RA condition. The present review aimed to clarify determinant cellular and molecular targets of berberine in RA and found that berberine through modulating several signalling pathways involved in the joint inflammation, including PI3K/Akt, Wnt1/β-catenin, AMPK/lipogenesis and LPA/LPA1 /ERK/p38 MAPK can inhibit inflammatory proliferation of FLS cells, suppress DC activation and modulate Th17/Treg balance and thus prevent cartilage and bone destruction. Importantly, these molecular targets may explore new therapeutic targets for RA treatment.
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Affiliation(s)
- Peng Shen
- Department of StomatologyClinical Department of Aerospace CityNorthern Beijing Medical DistrictChinese PLA General HospitalBeijingChina
| | - Yang Jiao
- Department of StomatologyThe 7th Medical CenterChinese PLA General HospitalBeijingChina
- Outpatient Department of PLA Macao GarrisonMacaoChina
| | - Li Miao
- Department of StomatologyThe 7th Medical CenterChinese PLA General HospitalBeijingChina
| | - Ji‐hua Chen
- National Clinical Research Center for Oral Diseases & State Key Laboratory of Military Stomatology & Shaanxi Key Laboratory of Oral DiseasesDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anChina
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Matsumoto H, Fujita Y, Asano T, Matsuoka N, Temmoku J, Sato S, Yashiro-Furuya M, Watanabe H, Migita K. T cell immunoglobulin and mucin domain-3 is associated with disease activity and progressive joint damage in rheumatoid arthritis patients. Medicine (Baltimore) 2020; 99:e22892. [PMID: 33126340 PMCID: PMC7598883 DOI: 10.1097/md.0000000000022892] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
T cell immunoglobulin and mucin domain-3 (TIM-3) is a surface molecule expressed on immune cells which play a role in immune regulation. The aims of the present study were to determine whether circulating soluble T cell immunoglobulin domain and mucin-3 (sTIM-3) are elevated in rheumatoid arthritis (RA) patients, and investigate the relationships between sTIM-3 and clinical features of RA.The study included 116 patients with established RA and 27 healthy control subjects. Serum levels of sTIM-3 were measured via the enzyme-linked immunosorbent assays (ELISA). Correlations between serum sTIM-3 and a range of parameters including anti-citrullinated peptide antibody (ACPA) titer, erythrocyte sedimentation rate (ESR), and matrix metalloproteinase-3 (MMP-3) were assessed.Serum sTIM-3 was significantly elevated in RA patients compared with those in healthy subjects, and it was positively correlated with ACPA titer (r = 0.27 P = .005), ESR (r = 0.27, P = .004) and MMP-3 (r = 0.35, P < .001). In RA patients with high ACPA titers (≥200 U/mL), sTIM-3 was not correlated with ESR or MMP-3. Whereas, sTIM-3 was significantly correlated with ESR and MMP-3 in RA patients with low ACPA titers (<200 U/mL).Serum sTIM-3 was increased in RA patients, and it was associated with proinflammatory markers and disease activity in RA patients under a particular ACPA status. Our data suggest that circulating sTIM-3 may be a useful biomarker for the determination of disease activity in RA patients.
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Yan M, Su J, Li Y. Rheumatoid arthritis-associated bone erosions: evolving insights and promising therapeutic strategies. Biosci Trends 2020; 14:342-348. [PMID: 32908076 DOI: 10.5582/bst.2020.03253] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The human immune system has evolved to recognize and eradicate pathogens, a process that is known as "host defense". If, however, the immune system does not work properly, it can mistakenly attack the body's own tissues and induce autoimmune diseases. Rheumatoid arthritis (RA) is such an autoimmune disease in which the synovial joints are predominately attacked by the immune system. Moreover, RA is associated with bone destruction and joint deformity. Although biologic agents have propelled RA treatment forward dramatically over the past 30 years, a considerable number of patients with RA still experience progressive bone damage and joint disability. That is to be expected since current RA therapies are all intended to halt inflammation but not to alleviate bone destruction. A better understanding of bone erosions is crucial to developing a novel strategy to treat RA-associated erosions. This review provides insights into RA-associated bone destruction and perspectives for future clinical interventions.
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Affiliation(s)
- Minglu Yan
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jianling Su
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yang Li
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Ma X, Xia W, Zong Y, Jiang C, Shan H, Lin Y, Yin F, Wang N, Zhou L, Wen G, Zhou Z. Tumor necrosis factor-α promotes Staphylococcus aureus-induced osteomyelitis through downregulating endothelial nitric oxide synthase. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2020; 54:1018-1027. [DOI: 10.1016/j.jmii.2020.08.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/14/2020] [Accepted: 08/05/2020] [Indexed: 12/20/2022]
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Kaur I, Behl T, Bungau S, Zengin G, Kumar A, El-Esawi MA, Khullar G, Venkatachalam T, Arora S. The endocannabinoid signaling pathway as an emerging target in pharmacotherapy, earmarking mitigation of destructive events in rheumatoid arthritis. Life Sci 2020; 257:118109. [PMID: 32698072 DOI: 10.1016/j.lfs.2020.118109] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 02/06/2023]
Abstract
Rheumatoid arthritis is an inflammatory autoimmune disease, characterized by synovial proliferation, destruction to articular cartilage and severe pain. The cannabinoids obtained from Cannabis sativa exhibited their actions via cannabinoid-1 and -2 receptors, which also provides a platform for endocannabinoids to act. The endocannabinoid system comprises endocannabinoid molecules involved in signaling processes, along with G-protein coupled receptors and enzymes associated with ligand biosynthesis, activation and degradation. The action of endocannabinoid system in immune system regulation, via primary CB2 activation, followed by inhibition of production of pro-inflammatory cytokines, auto-antibodies and MMPs, FLSs proliferation and T-cell mediated immune response, are elaborated as potential therapeutic regimes in rheumatoid arthritis. The involvement of endocannabinoid system in immune cells like, B cells, T cells and macrophages, as well as regulatory actions on sensory noniceptors to ameliorate pain is significantly highlighted in the review, elaborating the actions of endocannabinoid signaling in mitigating the disease events. The review also focuses on enhancement of endocannabinoid tone, either by inhibiting the degradation enzymes, like FAAH, MAGL, COX, CytP450, LOX, etc. or by retarding cellular uptake processes. Moreover, the review portrays the optimizing role of endocannabinoid system, in abbreviating the symptoms and complications of rheumatoid arthritis in patients and mitigating inflammation, pain and immune mediated effects significantly.
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Affiliation(s)
- Ishnoor Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 10 1 Decembrie Sq., Oradea, Romania
| | - Gokhan Zengin
- Department of Biology, Faculty of Science, Selcuk University Campus, Konya, Turkey
| | - Arun Kumar
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | | | - Gaurav Khullar
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | | | - Sandeep Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Ahamad N, Prabhakar A, Mehta S, Singh E, Bhatia E, Sharma S, Banerjee R. Trigger-responsive engineered-nanocarriers and image-guided theranostics for rheumatoid arthritis. NANOSCALE 2020; 12:12673-12697. [PMID: 32524107 DOI: 10.1039/d0nr01648a] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Rheumatoid Arthritis (RA), one of the leading causes of disability due to progressive autoimmune destruction of synovial joints, affects ∼1% of the global population. Standard therapy helps in reducing inflammation and delaying the progression of RA but is limited by non-responsiveness on long-term use and several side-effects. The conventional nanocarriers (CNCs), to some extent, minimize toxicity associated with free drug administration while improving the therapeutic efficacy. However, the uncontrolled release of the encapsulated drug even at off-targeted organs limits the application of CNCs. To overcome these challenges, trigger-responsive engineered nanocarriers (ENCs) have been recently explored for RA treatment. Unlike CNCs, ENCs enable precise control over on-demand drug release due to endogenous triggers in arthritic paws like pH, enzyme level, oxidative stress, or exogenously applied triggers like near-infrared light, magnetic field, ultrasonic waves, etc. As the trigger is selectively applied to the inflamed joint, it potentially reduces toxicity at off-target locations. Moreover, ENCs have been strategically coupled with imaging probe(s) for simultaneous monitoring of ENCs inside the body and facilitate an 'image-guided-co-trigger' for site-specific action in arthritic paws. In this review, the progress made in recently emerging 'trigger-responsive' and 'image-guided theranostics' ENCs for RA treatment has been explored with emphasis on the design strategies, mechanism, current status, challenges, and translational perspectives.
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Affiliation(s)
- Nadim Ahamad
- Nanomedicine Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076 India.
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Dai SP, Hsieh WS, Chen CH, Lu YH, Huang HS, Chang DM, Huang SL, Sun WH. TDAG8 deficiency reduces satellite glial number and pro-inflammatory macrophage number to relieve rheumatoid arthritis disease severity and chronic pain. J Neuroinflammation 2020; 17:170. [PMID: 32471455 PMCID: PMC7257243 DOI: 10.1186/s12974-020-01851-z] [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: 06/05/2019] [Accepted: 05/21/2020] [Indexed: 11/12/2022] Open
Abstract
Background The autoimmune disease rheumatoid arthritis (RA) affects approximately 1% of the global population. RA is characterized with chronic joint inflammation and often associated with chronic pain. The imbalance of pro-inflammatory and anti-inflammatory macrophages is a feature of RA progression. Glial cells affecting neuronal sensitivity at both peripheral and central levels may also be important for RA progression and associated pain. Genetic variants in the T cell death-associated gene 8 (TDAG8) locus are found to associate with spondyloarthritis. TDAG8 was also found involved in RA disease progression and associated hyperalgesia in the RA mouse model. However, its modulation in RA remains unclear. Methods To address this question, we intra-articularly injected complete Freund’s adjuvant (CFA) into TDAG8+/+, TDAG8−/− or wild-type mice, followed by pain behavioral tests. Joints and dorsal root ganglia were taken, sectioned, and stained with antibodies to observe the number of immune cells, macrophages, and satellite glial cells (SGCs). For compound treatments, compounds were intraperitoneally or orally administered weekly for 9 consecutive weeks after CFA injection. Results We demonstrated that TDAG8 deletion slightly reduced RA pain in the early phase but dramatically attenuated RA progression and pain in the chronic phase (> 7 weeks). TDAG8 deletion inhibited an increase in SGC number and inhibition of SGC function attenuated chronic phase of RA pain, so TDAG8 could regulate SGC number to control chronic pain. TDAG8 deletion also reduced M1 pro-inflammatory macrophage number at 12 weeks, contributing to the attenuation of chronic RA pain. Such results were further confirmed by using salicylanilide derivatives, CCL-2d or LCC-09, to suppress TDAG8 expression and function. Conclusions This study demonstrates that TDAG8 deletion reduced SGC and M1 macrophage number to relieve RA disease severity and associated chronic pain. M1 macrophages are critical for the development and maintenance of RA disease and pain, but glial activation is also required for the chronic phase of RA pain.
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Affiliation(s)
- Shih-Ping Dai
- Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan
| | - Wei-Shan Hsieh
- Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan
| | - Chien-Hua Chen
- Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan
| | - Yueh-Hao Lu
- Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan
| | - Hsu-Shan Huang
- Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Der-Ming Chang
- Division of Allergy, Immunology, Rheumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shir-Ly Huang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Wei-Hsin Sun
- Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan. .,Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
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