An Alcohol Extract Prepared From the Male Flower of Eucommia Ulmoides Oliv. Promotes Synovial Cell Apoptosis, Inhibits Osteoclast Differentiation and Ameliorates Bone Destruction in Rheumatoid Arthritis

Abstract Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease with a complex pathogenesis and is dominated by synovial hyperplasia and bone destruction. Previous research has shown that the male flower of Eucommia ulmoides Oliv. (EF) can exert effect on the inflammation caused by rheumatoid arthritis. However, the effect of EF on synovial cell apoptosis and bone destruction on RA have yet to be investigated. In this study, the effects of the synovial cell apoptosis of the male flower of Eucommia ulmoides Oliv.(EF) on human fibroblast-like synoviocyte -RA (HFLS-RA) cells, the osteoclast differentiation of EF on RAW264.7 cells and the bone destruction of effects of EF on collagen-induced arthritis (CIA) rats were explored.Materials and methods: In vitro, we investigated the anti-proliferative and pro-apoptotic effects of EF on HFLS-RA cells by immunofluorescence assays, flow cytometry, RT-qPCR (Real-time quantitative polymerase chain reaction), and western blotting. We investigated the differentiation into osteoclasts effects of EF on RAW264.7 cells by the TRAP staining and western blotting. In vivo, we used a rat model of collagen-induced arthritis (CIA) to investigate the relative effects of EF on anti-arthritis activity, the toe swelling arthritis score, the serum levels of metabolic bone factors, and pathological conditions. Micro-computed tomography (micro-CT) was used to scan ankle joints while the mRNA and protein levels of factors related to the NF-κB pathway were determined by RT-qPCR and western blotting, respectively. Finally, the main chemical components of EF were identified by HPLC (High Performance Liquid Chromatography). Results: EF inhibited the proliferation of synovial cells and promoted apoptosis in a dose-dependent manner, inhibited the differentiation of osteoclast by inhibiting activation of the NF-κB pathway. We also found that EF reduced articular inflammation in CIA rats, inhibited the expression of pro-angiogenic factors, and delayed the destruction of articular cartilage and bone. Our data indicate that EF acts via a mechanism related to bone metabolism that is induced by the NF-κB pathway. Conclusions: Our findings indicate that EF exerts a potential therapeutic effect on rheumatoid arthritis. Our research will help to elucidate the potential pharmacological mechanisms associated with the beneficial effects of EF and provide an experimental basis for the application of EF in future clinical treatments.

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An alcohol extract prepared from the male flower of Eucommia ulmoides Oliv. promotes synoviocyte apoptosis and ameliorates bone destruction in rheumatoid arthritis

Chinese Medicine ◽

10.1186/s13020-021-00522-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Yan Zhang ◽

Jian-Ying Wang ◽

Hao Wang ◽

Xiao-Yun Chen ◽

Lei Zhang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Western Blotting ◽

Quantitative Polymerase Chain Reaction ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Male Flower ◽

Raw264.7 Cells ◽

Eucommia Ulmoides ◽

Dependent Manner ◽

Alcohol Extract

Abstract Background Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease dominated by synovial hyperplasia and bone destruction. The male flower of Eucommia ulmoides Oliv. (EF) has been shown to exert effects on the inflammation caused by RA. However, how EF affects synoviocyte apoptosis and bone destruction on RA have not been investigated thoroughly. The effects of EF on apoptosis of human fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA) cells, osteoclast differentiation of RAW264.7 cells, and bone destruction in a collagen-induced arthritis (CIA) model in rats were explored. Methods First, the main components of EF were identified by high-performance liquid chromatography. In vitro, we investigated the anti-proliferative and pro-apoptotic effects of EF on HFLS-RA cells by immunofluorescence assays, flow cytometry, real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting; we also investigated how EF influenced the differentiation of RAW264.7 cells into osteoclasts. In vivo, we used a rat model of CIA to investigate the effects of EF on anti-arthritis activity, toe swelling, Arthritis Score, serum levels of metabolic bone factors, and pathologic conditions. Micro-computed tomography was used to scan ankle joints. mRNA and protein expression of factors related to the nuclear factor-kappa B (NF-κB) pathway were determined by RT-qPCR and western blotting, respectively. Results EF inhibited synoviocyte proliferation and promoted apoptosis in a dose-dependent manner. EF inhibited osteoclast differentiation by inhibiting activation of the NF-κB pathway. EF reduced articular inflammation in CIA rats, inhibited the expression of pro-angiogenic factors, and delayed the destruction of articular cartilage and bone. Our data indicated that EF acted via a mechanism related to bone metabolism induced by the NF-κB pathway. Conclusions EF exerts a potential therapeutic effect upon RA. Our research will help to elucidate the potential pharmacologic mechanisms associated with the beneficial effects of EF, and provide an experimental basis for EF application in clinical treatments. Graphical Abstract

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Propionibacterium freudenreichii Inhibits RANKL-Induced Osteoclast Differentiation and Ameliorates Rheumatoid Arthritis in Collagen-Induced Arthritis Mice

Microorganisms ◽

10.3390/microorganisms10010048 ◽

2021 ◽

Vol 10 (1) ◽

pp. 48

Author(s):

Jiah Yeom ◽

Dong Joon Yim ◽

Seongho Ma ◽

Young-Hee Lim

Keyword(s):

Rheumatoid Arthritis ◽

Mouse Model ◽

Bone Erosion ◽

Osteoclast Differentiation ◽

Joint Damage ◽

Bone Destruction ◽

In Vivo Studies ◽

Propionibacterium Freudenreichii ◽

Limited Information ◽

Collagen Induced Arthritis

Osteoclast differentiation is crucial for bone absorption, and osteoclasts are involved in bone destruction in rheumatoid arthritis (RA). Dairy Propionibacterium freudenreichii is used as a cheese starter and possesses prebiotic and postbiotic properties. It is known to stimulate the growth of bifidobacteria and produces valuable metabolites, such as vitamin B12 and propionic acid. However, limited information is available on the beneficial effects of P. freudenreichii on human disease. Herein, we aimed to investigate the inhibitory effect of P. freudenreichii MJ2 (MJ2) isolated from raw milk on osteoclast differentiation and evaluate the improvement in RA. The murine macrophage cell line, RAW 264.7, and a collagen-induced arthritis (CIA) mouse model were used to perform in vitro and in vivo studies, respectively. Heat-killed P. freudenreichii MJ2 (hkMJ2)-treated cells significantly inhibited RANKL-induced osteoclast differentiation and TRAP activity. HkMJ2-treated cells exhibited significantly decreased expression of genes and proteins related to RANKL-induced osteoclast differentiation. MJ2 administration decreased the arthritic score in the CIA mouse model. Live and dead MJ2 inhibited bone loss and afforded protection against bone erosion and joint damage in CIA mice. MJ2 decreased the levels of collagen-specific antibodies and inflammatory cytokines and the expression of osteoclast differentiation-related genes and proteins in CIA mice. Interestingly, live and dead MJ2 showed similar RA improvement effects in CIA mice. In conclusion, P. freudenreichii MJ2 inhibited osteoclast differentiation by inhibiting the NF-κB signaling pathway and ameliorated CIA.

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Inhibition of Rheumatoid Arthritis Using Bark, Leaf, and Male Flower Extracts of Eucommia ulmoides

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/3260278 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Yun-Yun Xing ◽

Jian-Ying Wang ◽

Kai Wang ◽

Yan Zhang ◽

Kun Liu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Bone Erosion ◽

Bone Destruction ◽

Male Flower ◽

Joint Inflammation ◽

Inflammatory Factors ◽

Enzyme Linked Immunosorbent Assay ◽

Eucommia Ulmoides

Eucommia ulmoides Oliv., a native Chinese plant species, has been used as a traditional Chinese medicine formulation to treat rheumatoid arthritis (RA), strengthen bones and muscles, and lower blood pressure. Various parts of this plant such as the bark, leaves, and flowers have been found to have anti-inflammatory properties. E. ulmoides has potential applications as a therapeutic agent against bone disorders, which were investigated in this study. In vitro, RA joint fibroblast-like synoviocytes (RA-FLS) were treated with different concentrations (0, 25, 50, 100, 200, 400, 800, and 1000 μg/mL) of E. ulmoides bark, leaf, and male flower alcoholic extracts (EB, EL, and EF, respectively) to determine their potential cytotoxicity. Tumor necrosis factor- (TNF-) α and nitric oxide (NO) levels in RA-FLS were quantified using enzyme-linked immunosorbent assay (ELISA). Furthermore, collagen-induced arthritis (CIA) rats were treated with EB, EL, EF, Tripterygium wilfordii polyglycoside (TG) or the normal control (Nor), and then ankle joint pathology, bone morphology, and serum and spleen inflammatory cytokine levels were evaluated. The results showed that, in RA-FLS, EB, EL, and EF were not cytotoxic; EB and EF reduced TNF-α supernatant levels; and EB, EL, and EF reduced NO levels. The results of in vivo experiments showed that EB, EL, and EF alleviated ankle swelling and joint inflammation, while all extracts diminished inflammatory cell infiltration, pannus and bone destruction, and bone erosion. All tested extracts inhibited interleukin- (IL-) 6, IL-17, and TNF-α mRNA in the spleen of CIA rats, while EB most effectively reduced osteoclasts and inhibited bone erosion. EF showed the most obvious inhibition of inflammatory factors and pannus. Thus, EB, EL, and EF may alleviate bone destruction by inhibiting inflammation.

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The Impact of Proinflammatory Cytokynes of Rheumatoid Polyarthritis on the Generalized Loss of Bone Mass

Revista de Chimie ◽

10.37358/rc.18.9.6572 ◽

2018 ◽

Vol 69 (9) ◽

pp. 2541-2545

Author(s):

Raluca Barzoi ◽

Elena Rezus ◽

Codruta Badescu ◽

Razan Al Namat ◽

Manuela Ciocoiu

Keyword(s):

Rheumatoid Arthritis ◽

Immune Cells ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Nuclear Factor ◽

Receptor Activator ◽

Level Function ◽

Rheumatoid Polyarthritis ◽

The Impact ◽

Nuclear Factor Kb

There is a bidirectional interaction between most immune cells and osteoblasts, osteoclasts and their precursor cells. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK/osteoprotegerin (OPG) system plays an essential role in the formation of osteoblasts, but it also has implications in osteoclast biology and implicitly on the diseases characterized by bone loss. Proinflammatory cytokines existing at synovial level function as direct or indirect stimulators of osteoclast differentiation, but also of its survival or activity, although some cytokines may also play an antiosteocastogenic role. The fate of bone destruction is determined by the balance between osteoclastogenic and antiosteoclastogenic mediators. Our study has shown that the early initiation of the therapy with anti-TNF and anti-IL6 biological agents, in patients with rheumatoid arthritis, inhibits bone destruction, regardless of the anti-inflammatory activity in patients with rheumatoid arthritis.

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Total Flavonoids of Bidens pilosa Ameliorates Bone Destruction in Collagen-Induced Arthritis

Planta Medica ◽

10.1055/a-1352-5124 ◽

2021 ◽

Author(s):

Mengqin Hong ◽

Xingyu Fan ◽

Shengxiang Liang ◽

Wang Xiang ◽

Liting Chen ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Proinflammatory Cytokines ◽

Bone Destruction ◽

Nuclear Factor Κb ◽

Total Flavonoids ◽

Nuclear Factor ◽

Collagen Induced Arthritis ◽

Bidens Pilosa ◽

X Ray ◽

Receptor Activator

AbstractRheumatoid arthritis is a chronic autoimmune disease characterized by the infiltration of synovial inflammatory cells and progressive joint destruction. Total flavonoids of Bidens pilosa have been used against inflammation in rheumatoid arthritis, but its role in bone destruction remains to be explored. The aim of this paper was to study whether total flavonoids of B. pilosa relieve the severity of collagen-induced arthritis in rats, particularly whether it regulates the production of proinflammatory cytokines and the receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin signaling pathway. In this research, a collagen-induced disease model was induced in adult rats by subcutaneous injection of collagen II. Total flavonoids of B. pilosa at different doses (40, 80, and 160 mg/kg/d) were administered intragastrically, while methotrexate (1 mg/kg/w) was injected intraperitoneally as a positive control. Paw swelling, arthritis score, and body weight were assessed and evaluated. The severity of joint damage was determined using X-ray and confirmed by histopathology. The expression levels of receptor activator of nuclear factor-κB ligand, osteoprotegerin, IL-1β, IL-17, and TNF in the serum and tissue were assayed using ELISA and immunohistochemistry. We found that total flavonoids of B. pilosa attenuated collagen-induced arthritis at the macroscopic level, and total flavonoids of B. pilosa-treated rats showed reduced paw swelling, arthritis scores, and X-ray appearance of collagen-induced arthritis in addition to improved histopathological results. These findings were consistent with reduced serum and tissue receptor activator of nuclear factor-κB ligand, TNF, IL-1β, and IL-17 levels but increased osteoprotegerin levels. Our data suggest that total flavonoids of B. pilosa attenuate collagen-induced arthritis by suppressing the receptor activator of nuclear factor-κB ligand/receptor activator of nuclear factor-κB/osteoprotegerin pathway and the subsequent production of proinflammatory cytokines. In addition, total flavonoids of B. pilosa may be a promising therapeutic candidate for the management of rheumatoid arthritis.

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N6-Methyladenosine and Rheumatoid Arthritis: A Comprehensive Review

Frontiers in Immunology ◽

10.3389/fimmu.2021.731842 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sha Wu ◽

Xiao-Feng Li ◽

Yuan-Yuan Wu ◽

Su-Qin Yin ◽

Cheng Huang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Immune Cells ◽

Myeloid Leukemia ◽

Immune Cell ◽

Bone Destruction ◽

Synovial Cell ◽

Biological Processes ◽

Cell Life ◽

History Of ◽

The Relationship

Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by immune cell infiltration, fibroblast-like synovial cell hyperproliferation, and cartilage and bone destruction. To date, numerous studies have demonstrated that immune cells are one of the key targets for the treatment of RA. N6-methyladenosine (m6A) is the most common internal modification to eukaryotic mRNA, which is involved in the splicing, stability, export, and degradation of RNA metabolism. m6A methylated-related genes are divided into writers, erasers, and readers, and they are critical for the regulation of cell life. They play a significant role in various biological processes, such as virus replication and cell differentiation by controlling gene expression. Furthermore, a growing number of studies have indicated that m6A is associated with the occurrence of numerous diseases, such as lung cancer, bladder cancer, gastric cancer, acute myeloid leukemia, and hepatocellular carcinoma. In this review, we summarize the history of m6A research and recent progress on RA research concerning m6A enzymes. The relationship between m6A enzymes, immune cells, and RA suggests that m6A modification offers evidence for the pathogenesis of RA, which will help in the development of new therapies for RA.

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SAT0022 CXCL7 PROMOTES OSTEOCLASTOGENESIS IN RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1474 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 941.1-941

Author(s):

X. Wang ◽

L. Sun ◽

J. Zhao

Keyword(s):

Rheumatoid Arthritis ◽

Bone Marrow ◽

Bone Resorption ◽

Bone Destruction ◽

Osteoclast Formation ◽

Raw264.7 Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Bone Marrow Niche ◽

Healthy Donors ◽

Sat 1

Background:Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by bone destruction[1]. Chemokine signaling by skeletal cells or by other cells of the bone marrow niche regulates bone formation and resorption[2]. Recent studies have found that CXCL7 enhanced the osteoclast formation in mouse bone marrow cells[3, 4]. Whether CXCL7 plays a role in human osteoclastogenesis especially in RA patients remains unclear.Objectives:To examine the functional role of CXCL7 in the induction of osteoclastogenesis in RA.Methods:The level of CXCL7 in CD14+monocyte supernatant was assessed via enzyme-linked immunosorbent assay. Osteoclastogenesis of CD14+monocyte from RA patients and healthy donors were evaluated by TRAP staining and F-actin ring immunofluorescence. Bone resorption pit was observed by scanning electron microscopy. We performed quantitative reverse transcription polymerase chain reaction (RT-PCR) to detect changes in osteoclast markers. RAW264.7 macrophages were also used to investigate specific signaling pathway by which CXCL7 stimulated during osteoclast formation.Results:CXCL7 level in CD14+monocyte supernatant from RA patients (5690 ±627.05 pg/ml) was significantly higher than that in healthy controls (2301 ±535.52 pg/ml) (n=5, P<0.001). In the presence of M-CSF and RANKL, CXCL7 promoted osteoclast formation(Figure 1A and B) and increased bone resorption area(Figure 1C) of CD14+monocyte from healthy donors in the low concentration (10ng/ml) group (n=3, p < 0.05). While in high concentration of CXCL7 (50ng/ml) group, there were no significant changes in the number of osteoclasts. Transcription level of the osteoclast markers RANK, cathepsin K, and MMP-9 was significantly increased in the CXCL7 (10 ng/mL) group after 3 days in the presence of M-CSF and sRANKL (n=3, p < 0.05). When using CD14+ monocyte from RA patients, the optimal concentration of CXCL7 was 50ng/ml, which significantly increased the number of osteoclasts (Figure 2A and B)and bone resorption area (Figure 2C) (n=3, p < 0.01). Flow cytometry analysis revealed that a higher proportion of CD14+monocytes expressed CXCR2 from healthy donors than those from RA patients (n=6, p < 0.01). Consistent with the results obtained in CD14+monocytes, the effects of exogenous CXCL7 on osteoclast formation were also observed in RAW264.7 cells (p < 0.01). The addition of CXCL7 dramatically promoted phosphorylation ERK1/2 in RAW264.7 cells, but it did not affect the phosphorylation of P65.Conclusion:CXCL7 level in CD14+monocyte supernatant was higher in RA patients than that of healthy donors. CXCL7 promoted osteoclastogenesis in CD14+monocyte both from RA patients and healthy donors. CXCL7 could be a potential therapeutic target for bone destruction in RA.References:[1] McInnes, I.B. and G. Schett, The pathogenesis of rheumatoid arthritis. N Engl J Med, 2011. 365(23): p. 2205-19.[2] Brylka, L.J. and T. Schinke, Chemokines in Physiological and Pathological Bone Remodeling. Front Immunol, 2019. 10: p. 2182.[3] Nakao, K., et al., IGF2 modulates the microenvironment for osteoclastogenesis. Biochem Biophys Res Commun, 2009. 378(3): p. 462-6.[4] Goto, Y., et al., CXCR4(+) CD45(-) Cells are Niche Forming for Osteoclastogenesis via the SDF-1, CXCL7, and CX3CL1 Signaling Pathways in Bone Marrow. Stem Cells, 2016. 34(11): p. 2733-2743.Acknowledgments :We gratefully thank the Medical Research Center of Peking University Third Hospital for providing experimental equipment and technical support.Disclosure of Interests:None declared

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Cervus and cucumis peptides ameliorates bone erosion in experimental arthritis by inhibiting osteoclastogenesis

Lupus Science & Medicine ◽

10.1136/lupus-2019-000331 ◽

2019 ◽

Vol 6 (1) ◽

pp. e000331 ◽

Cited By ~ 3

Author(s):

Ze-Min Lin ◽

Yu-Ting Liu ◽

Yan-Sheng Xu ◽

Xiao-Qian Yang ◽

Feng-Hua Zhu ◽

...

Keyword(s):

Immune Cells ◽

Bone Erosion ◽

Joint Destruction ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Experimental Arthritis ◽

Raw264.7 Cells ◽

Therapeutic Effects ◽

Sprague Dawley ◽

Therapeutic Benefits

ObjectiveRheumatoid arthritis is an autoimmune disease characterised by inflammation and bone loss, leading to joint destruction and deformity. The cervus and cucumis polypeptide (CCP) injection, one of the traditional Chinese medicine injections combined extracts from deer horn and sweet melon seeds, is widely used to treat arthritis and bone fracture in China. The present study investigated the therapeutic efficacy and mechanism of CCP on pathological immune cells and bone homoeostasis in rodent experimental arthritis.MethodsThe effects of CCP (4 mg/kg and 2 mg/kg) on clinical arthritis symptoms, bone erosion, proinflammatory cytokines and pathological immune cells induced by complete Freund’s adjuvant was evaluated in male Sprague-Dawley rats. The impacts of CCP (2 mg/kg) on joint erythema and swelling, production of pathogenic antibodies and the proportion of inflammatory cells were assessed in collagen-induced arthritis (CIA) in DBA/1J mice. Regulation of osteoclastogenesis by CCP was observed in the murine macrophage-like RAW264.7 cells treated with receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF).ResultsCCP administration significantly prevented disease progression in both adjuvant-induced arthritis (AIA) rats and CIA mice. The therapeutic benefits were accompanied by reduction of paw oedema, reversed bone destruction, decreased pathological changes and osteoclast numbers in joints in AIA rats, as well as attenuated clinical manifestation and autoantibodies production in CIA mice. Meanwhile, in vitro supplemented of CCP concentration dependently inhibited RANKL/M-CSF-induced osteoclast differentiation, without showing cytotoxicity in RAW264.7 cells. Further, the presence of CCP dampened the augmented downstream signalling transduction as well as activation of osteoclast-specific genes and transcription factors induced by RANKL/M-CSF in RAW264.7 cells.ConclusionOur study suggested that the therapeutic effects of CCP in experimental arthritis could be attributed to its intervention on RANKL-induced osteoclastogenesis signalling pathway in osteoclast precursor cells.

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Neutrophil-mediated carbamylation promotes articular damage in rheumatoid arthritis

Science Advances ◽

10.1126/sciadv.abd2688 ◽

2020 ◽

Vol 6 (44) ◽

pp. eabd2688 ◽

Cited By ~ 1

Author(s):

Liam J. O’Neil ◽

Ana Barrera-Vargas ◽

Donavon Sandoval-Heglund ◽

Javier Merayo-Chalico ◽

Eduardo Aguirre-Aguilar ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Immune Responses ◽

Shared Epitope ◽

Bone Erosion ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Neutrophil Extracellular Traps ◽

Erosive Arthritis ◽

Extracellular Traps ◽

Articular Damage

Formation of autoantibodies to carbamylated proteins (anti-CarP) is considered detrimental in the prognosis of erosive rheumatoid arthritis (RA). The source of carbamylated antigens and the mechanisms by which anti-CarP antibodies promote bone erosion in RA remain unknown. Here, we find that neutrophil extracellular traps (NETs) externalize carbamylated proteins and that RA subjects develop autoantibodies against carbamylated NET (cNET) antigens that, in turn, correlate with levels of anti-CarP. Transgenic mice expressing the human RA shared epitope (HLADRB1* 04:01) immunized with cNETs develop antibodies to citrullinated and carbamylated proteins. Furthermore, anti–carbamylated histone antibodies correlate with radiographic bone erosion in RA subjects. Moreover, anti–carbamylated histone–immunoglobulin G immune complexes promote osteoclast differentiation and potentiate osteoclast-mediated matrix resorption. These results demonstrate that carbamylated proteins present in NETs enhance pathogenic immune responses and bone destruction, which may explain the association between anti-CarP and erosive arthritis in RA.

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Deficiency of sorting nexin 10 prevents bone erosion in collagen-induced mouse arthritis through promoting NFATc1 degradation

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2014-207134 ◽

2015 ◽

Vol 75 (6) ◽

pp. 1211-1218 ◽

Cited By ~ 15

Author(s):

Chun Zhou ◽

Yan You ◽

Weixing Shen ◽

Yi-Zhun Zhu ◽

Jing Peng ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mononuclear Cells ◽

Bone Erosion ◽

Joint Destruction ◽

Osteoclast Differentiation ◽

Critical Index ◽

Bone Destruction ◽

Wild Type ◽

Clinical Role ◽

Sorting Nexin

ObjectivePeriarticular and subchondral bone erosion in rheumatoid arthritis caused by osteoclast differentiation and activation is a critical index for diagnosis, therapy and monitoring of the disease. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting, has been implicated to play an important clinical role in malignant osteopetrosis. Here we studied the roles and precise mechanisms of SNX10 in the bone destruction of collagen-induced arthritis (CIA) mice.MethodsThe role of SNX10 in bone destruction was evaluated by a CIA mice model which was induced in male SNX10−/− mice and wild type littermates. The mechanism was explored in osteoclasts induced by receptor activator of nuclear factor κB ligand from bone marrow mononuclear cells of wild type and SNX10−/− mice.ResultsSNX10 knockout prevented bone loss and joint destruction in CIA mice with reduced serum levels of TNF-α, interleukin 1β and anticollagen IgG 2α antibody. SNX10 deficiency did not block osteoclastogenesis, but significantly impaired osteoclast maturation and bone-resorption function by disturbing the formation of actin belt. The production of TRAP, CtsK and MMP9 in SNX10−/− osteoclasts was significantly inhibited, and partially restored by SNX10 overexpression. We further demonstrated that the degradation of NFATc1 was accelerated in SNX10−/− osteoclasts causing an inhibition of integrin β3-Src-PYK2 signalling.ConclusionsOur study discloses a crucial role and novel mechanism for SNX10 in osteoclast function, and provides evidence for SNX10 as a promising novel therapeutic target for suppression of immune inflammation and bone erosion in rheumatoid arthritis.

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