scholarly journals Implication of IL-17 in Bone Loss and Structural Damage in Inflammatory Rheumatic Diseases

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Benoit Le Goff ◽  
Béatrice Bouvard ◽  
Thierry Lequerre ◽  
Eric Lespessailles ◽  
Hubert Marotte ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Bone Loss ◽  
Proinflammatory Cytokines ◽  
Inflammatory Arthritis ◽  
Structural Damage ◽  
Inflammatory Diseases ◽  
Cartilage Damage ◽  
Inflammatory Rheumatic Diseases ◽  
Bone Homeostasis ◽  
And Cartilage

Proinflammatory cytokines play an important role in the systemic and focal bone loss associated with chronic inflammatory diseases. Targeting these cytokines with biologics and small molecules has led to a major improvement of the bone health of patients with inflammatory arthritis. Cytokines from the IL-17 family have been shown to be involved in the pathogenesis of several diseases such as spondyloarthritis, psoriatic arthritis, or psoriasis. IL-17A has been the first described and the most studied. The recent development of targeted therapies against IL-17A or its receptor and their efficacy has confirmed the importance of this cytokine in the development of inflammatory diseases. The aim of this review was to describe the effects of the IL-17 family and more particularly of IL-17A on bone and cartilage tissues. At the cellular level, IL-17A is proosteoclastogenic whereas its effects on osteoblasts depend on the stage of differentiation of these cells. In vivo, IL-17A is not required for normal bone homeostasis but plays an important role in bone loss notably in an ovariectomized mouse model of osteoporosis. Preliminary data from clinical trials showed a stabilisation of bone density in patients treated with anti-IL-17A antibodies. IL-17A plays a central role in the cartilage damage through the induction of collagenases and by decreasing the expression of their inhibitors in synergy with the other proinflammatory cytokines. The prevention of structural damage by anti-IL-17A therapies has been demonstrated in several pivotal clinical trials. Overall, blocking the IL-17A pathway seems to have a positive effect on the bone and cartilage damage observed in inflammatory arthritis. Differences and specificity of these effects compared to those already described with other biologics such as anti-TNF therapies remain to be explored.

scholarly journals Mediators of Inflammation-Induced Bone Damage in Arthritis and Their Control by Herbal Products

2013 ◽  
Vol 2013 ◽  
pp. 1-20 ◽  
Author(s):  
Siddaraju M. Nanjundaiah ◽  
Brian Astry ◽  
Kamal D. Moudgil
Keyword(s):  
Inflammatory Arthritis ◽  
Adverse Reactions ◽  
Cartilage Damage ◽  
Therapeutic Agents ◽  
Herbal Products ◽  
Mediators Of Inflammation ◽  
Bone Damage ◽  
Target Molecules ◽  
Severe Adverse Reactions ◽  
And Cartilage

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints leading to bone and cartilage damage. Untreated inflammatory arthritis can result in severe deformities and disability. The use of anti-inflammatory agents and biologics has been the mainstay of treatment of RA. However, the prolonged use of such agents may lead to severe adverse reactions. In addition, many of these drugs are quite expensive. These limitations have necessitated the search for newer therapeutic agents for RA. Natural plant products offer a promising resource for potential antiarthritic agents. We describe here the cellular and soluble mediators of inflammation-induced bone damage (osteoimmunology) in arthritis. We also elaborate upon various herbal products that possess antiarthritic activity, particularly mentioning the specific target molecules. As the use of natural product supplements by RA patients is increasing, this paper presents timely and useful information about the mechanism of action of promising herbal products that can inhibit the progression of inflammation and bone damage in the course of arthritis.

scholarly journals Cytokine-Mediated Bone Destruction in Rheumatoid Arthritis

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Seung Min Jung ◽  
Kyoung Woon Kim ◽  
Chul-Woo Yang ◽  
Sung-Hwan Park ◽  
Ji Hyeon Ju
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Loss ◽  
Proinflammatory Cytokines ◽  
Immune Cells ◽  
Joint Destruction ◽  
Bone Destruction ◽  
Bone Homeostasis ◽  
Important Process ◽  
Effector Cells ◽  
Pathological Conditions

Bone homeostasis, which involves formation and resorption, is an important process for maintaining adequate bone mass in humans. Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and bone loss, leading to joint destruction and deformity, and is a representative disease of disrupted bone homeostasis. The bone loss and joint destruction are mediated by immunological insults by proinflammatory cytokines and various immune cells. The connection between bone and immunity has been intensely studied and comprises the emerging field of osteoimmunology. Osteoimmunology is an interdisciplinary science investigating the interplay between the skeletal and the immune systems. The main contributors in osteoimmunology are the bone effector cells, such as osteoclasts or osteoblasts, and the immune cells, particularly lymphocytes and monocytes. Physiologically, osteoclasts originate from immune cells, and immune cells regulate osteoblasts and vice versa. Pathological conditions such as RA might affect these interactions, thereby altering bone homeostasis, resulting in the unfavorable outcome of bone destruction. In this review, we describe the osteoclastogenic roles of the proinflammatory cytokines and immune cells that are important in the pathophysiology of RA.

scholarly journals Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

2018 ◽  
Author(s):  
Adam P Croft ◽  
Joana Campos ◽  
Kathrin Jansen ◽  
Jason D Turner ◽  
Jennifer Marshall ◽  
...  
Keyword(s):  
Tissue Damage ◽  
Inflammatory Diseases ◽  
Cartilage Damage ◽  
Transcriptional Analysis ◽  
Murine Models ◽  
Synovial Lining ◽  
Immune Effector ◽  
Effector Functions ◽  
Immune Mediated ◽  
And Cartilage

SUMMARYThe identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune mediated inflammatory diseases (IMIDs). However it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue driven processes observed in IMIDs such as inflammation and damage. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of FAPα+ synovial cells suppressed both inflammation and bone erosions in murine models of resolving and persistent arthritis. Single cell transcriptional analysis identified two distinct fibroblast subsets: FAPα+ THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAPα+ THY1- destructive fibroblasts restricted to the synovial lining. When adoptively transferred into the joint, FAP α+ THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation whereas transfer of FAP α+ THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell based therapies aimed at modulating inflammation and tissue damage.

scholarly journals The Effect of Proinflammatory Cytokines on the Proliferation, Migration and Secretory Activity of Mesenchymal Stem/Stromal Cells (WJ-MSCs) under 5% O2 and 21% O2 Culture Conditions

2021 ◽  
Vol 10 (9) ◽  
pp. 1813
Author(s):  
Aleksandra Wedzinska ◽  
Anna Figiel-Dabrowska ◽  
Hanna Kozlowska ◽  
Anna Sarnowska
Keyword(s):  
Clinical Trials ◽  
Proinflammatory Cytokines ◽  
Stromal Cells ◽  
Acute Inflammation ◽  
Inflammatory Diseases ◽  
Secretory Activity ◽  
Inflammatory Factors ◽  
Migration Activity ◽  
Aerobic Conditions

Treatment with Mesenchymal Stem/Stromal Cells (MSCs) in clinical trials is becoming one of the most-popular and fast-developing branches of modern regenerative medicine, as it is still in an experimental phase. The cross-section of diseases to which these cells are applied is very wide, ranging from degenerative diseases, through autoimmune processes and to acute inflammatory diseases, e.g., viral infections. Indeed, now that first clinical trials applying MSCs against COVID-19 have started, important questions concern not only the therapeutic properties of MSCs, but also the changes that might occur in the cell features as a response to the “cytokine storm” present in the acute phase of an infection and capable of posing a risk to a patient. The aim of our study was thus to assess changes potentially occurring in the biology of MSCs in the active inflammatory environment, e.g., in regards to the cell cycle, cell migration and secretory capacity. The study using MSCs derived from Wharton’s jelly (WJ-MSCs) was conducted under two aerobic conditions: 21% O2 vs. 5% O2, since oxygen concentration is one of the key factors in inflammation. Under both oxygen conditions cells were exposed to proinflammatory cytokines involved significantly in acute inflammation, i.e., IFNγ, TNFα and IL-1β at different concentrations. Regardless of the aerobic conditions, WJ-MSCs in the inflammatory environment do not lose features typical for mesenchymal cells, and their proliferation dynamic remains unchanged. Sudden fluctuations in proliferation, the early indicator of potential genetic disturbance, were not observed, while the cells’ migration activity increased. The presence of pro-inflammatory factors was also found to increase the secretion of such anti-inflammatory cytokines as IL-4 and IL-10. It is concluded that the inflammatory milieu in vitro does not cause phenotype changes or give rise to proliferation disruption of WJ-MSCs, and nor does it inhibit the secretory properties providing for their use against acute inflammation.

scholarly journals TNF Produced by Inflammatory Blood Mononuclear Cells Directly Contributes to Cartilage Damage in Arthritis

2020 ◽  
Author(s):  
Anna Yarilina ◽  
Terry Melim ◽  
Zehra Kaymakcalan
Keyword(s):  
Mouse Model ◽  
Structural Damage ◽  
Mononuclear Cells ◽  
Colorimetric Detection ◽  
Cartilage Damage ◽  
Cartilage Explants ◽  
Human Chondrocytes ◽  
Blood Mononuclear Cells ◽  
Bovine Cartilage ◽  
And Cartilage

Abstract Background Anti-TNF therapies are effective at preventing inflammation and structural damage in rheumatoid arthritis (RA). However, the role of TNF in cartilage destruction in RA is not well understood. Therefore, we studied the effects of TNF on cartilage and compared TNF production by different cell types involved in joint pathology.Methods Primary human chondrocytes and cartilage explants were cultured with recombinant TNF. Bovine cartilage was co-cultured with activated human peripheral blood mononuclear cells (PBMCs) or fibroblast-like synoviocytes (FLS). Expression of cytokines and metalloproteinases (MMPs) was assessed by qPCR and MSD, and proteoglycan depletion from cartilage was assessed using histomorphometry and colorimetric detection in tissue culture supernatants. D2E7 was used to block TNF both in vitro and in vivo in a human TNF transgenic (hTNF-Tg) mouse model of arthritis.Results TNF elicited strong pro-inflammatory and catabolic effects on isolated human chondrocytes and cartilage explants leading to upregulation of IL-6 and MMPs, as well as proteoglycan depletion from bovine cartilage explants. In an effort to identify cellular sources of TNF, we challenged chondrocytes, FLS and PBMCs with inflammatory stimuli present in RA joints and found that PBMC that were used to model inflammatory cell infiltration produced significantly higher levels of TNF. Moreover, co-culture with activated PBMCs resulted in proteoglycan depletion from bovine cartilage explants. In sharp contrast with stromal cells, TNF failed to induce high amounts of IL-6 and MMPs in PBMCs, suggesting that different cell populations play distinct roles in the triggering and propagation of joint destruction. TNF blockade protected cartilage from damage both in co-culture systems and in a hTNF-Tg mouse model of arthritis.ConclusionsOur data demonstrate that TNF directly triggers a catabolic program in human chondrocytes leading to cartilage damage and further suggest that neutralization of TNF produced by immune cells infiltrating the inflamed joints, decreases catabolic activity of chondrocytes and fibroblasts, which, in turn, contributes to the cartilage protective effects of anti-TNF biologics in arthritis.

scholarly journals Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Scott A. Scarneo ◽  
Liesl S. Eibschutz ◽  
Phillip J. Bendele ◽  
Kelly W. Yang ◽  
Juliane Totzke ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Resorption ◽  
Bone Formation ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Cartilage Damage ◽  
Cytokine Signaling ◽  
Periosteal Bone Formation ◽  
Bone Width

Abstract Objectives To examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells. Methods Following the induction of CIA, mice were treated daily with takinib (50 mg/kg) and clinical scores assessed. Thirty-six days post-CIA induction, histology was performed on various joints of treated and vehicle-treated animals. Inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation were quantified. Furthermore, pharmacokinetics of takinib were evaluated by LC-MS in various tissues. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells were cultured with 10 μM takinib and cytokine secretion analyzed by cytokine/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48 h cultures in the presence or absence of tumor necrosis factor (TNF). Results Here, we show takinib’s ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p < 0.001). TAK1 inhibition reduced inflammation (p < 0.01), cartilage damage (p < 0.01), pannus, bone resorption, and periosteal bone formation and periosteal bone width in all joints of treated mice compared to vehicle treated. Significant reduction of inflammation (p < 0.004) and cartilage damage (p < 0.004) were observed in the knees of diseased treated animals, with moderate reduction seen in the forepaws and hind paws. Furthermore, the pharmacokinetics of takinib show rapid plasma clearance (t½ = 21 min). In stimulated RA-FLS cells, takinib reduced GROα, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling. Conclusion Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.

scholarly journals Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 199
Author(s):  
Urara Tanaka ◽  
Shunichi Kajioka ◽  
Livia S. Finoti ◽  
Daniela B. Palioto ◽  
Denis F. Kinane ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Resorption ◽  
Bone Loss ◽  
Inflammatory Cytokines ◽  
Osteoclast Differentiation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Osteoblastic Cell Line ◽  
Anti Inflammatory

DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14+) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14+ human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing IL10 (interleukin-10), TGFB (transforming growth factor beta-1) in CD14+ monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of IL10 and TGFB. On the contrary, site-directed mutagenesis of KLF2 binding site in IL10 and TFGB abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis.

scholarly journals Future Perspectives of Therapeutic, Diagnostic and Prognostic Aptamers in Eye Pathological Angiogenesis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1455
Author(s):  
Emilio Iturriaga-Goyon ◽  
Beatriz Buentello-Volante ◽  
Fátima Sofía Magaña-Guerrero ◽  
Yonathan Garfias
Keyword(s):  
Clinical Trials ◽  
Macular Degeneration ◽  
Small Molecules ◽  
Inflammatory Diseases ◽  
Age Related Macular Degeneration ◽  
Future Perspectives ◽  
Whole Cells ◽  
Pathological Angiogenesis ◽  
Age Related ◽  
Viral Particles

Aptamers are single-stranded DNA or RNA oligonucleotides that are currently used in clinical trials due to their selectivity and specificity to bind small molecules such as proteins, peptides, viral particles, vitamins, metal ions and even whole cells. Aptamers are highly specific to their targets, they are smaller than antibodies and fragment antibodies, they can be easily conjugated to multiple surfaces and ions and controllable post-production modifications can be performed. Aptamers have been therapeutically used for age-related macular degeneration, cancer, thrombosis and inflammatory diseases. The aim of this review is to highlight the therapeutic, diagnostic and prognostic possibilities associated with aptamers, focusing on eye pathological angiogenesis.

scholarly journals FRI0373 ASSOCIATIONS OF VASCULAR PATHOPHYSIOLOGY AND BONE METABOLISM IN ANTI-TNF- TREATED RHEUMATOID ARTHRITIS AND ANKYLOSING SPONDYLITIS PATIENTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 783.2-784
Author(s):  
M. Czókolyová ◽  
K. Gulyás ◽  
Á. Horváth ◽  
E. Végh ◽  
Z. Pethö ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Ankylosing Spondylitis ◽  
Bone Loss ◽  
Bone Metabolism ◽  
Certolizumab Pegol ◽  
Univariate Analysis ◽  
Inflammatory Rheumatic Diseases ◽  
Ageing Population ◽  
Research Support ◽  
Vascular Markers

Background:Cardiovascular (CV) disease and osteoporosis (OP) have become increasing challenges in the ageing population, even more in patients with inflammatory rheumatic diseases, such as rheumatoid arthritis (RA) and spondyloarthropathies. Both RA and ankylosing spondylitis (AS) have been associated with generalized and localized bone loss, accelerated atherosclerosis, increased CV morbidity and mortality.Objectives:Bone and vascular biomarkers and parameters along with the effect of one-year anti-TNF therapy on these markers were assessed in order to determine correlations between vascular pathophysiology and bone metabolism in RA and AS.Methods:Fifty-three patients including 36 RA patients treated with etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Bone and vascular markers were assessed by ELISA. Bone density was assessed by DXA and quantitative CT (QCT). Flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and pulse-wave velocity (PWV) were assessed by ultrasound. The effects of vascular markers on bone and bone effects on vasculature undergone statistical analysis.Results:Serum levels of vascular endothelial growth factor (VEGF), PDGF-BB, angiopoietin 2 (Ang2) and cathepsin K (CathK) decreased, procollagen type 1 N-propeptide (P1NP) and sclerostin (SOST) levels increased, soluble receptor activator nuclear kappa B ligand (sRANKL) and osteoprotegerin (OPG) levels showed no differences. When bone and vascular markers were correlated with each other, at baseline, OPG correlated with Ang2 and adiponectin. SOST correlated positively with ccIMT. DXA L2-4 BMD, DXA L1 BMD and DXA femoral neck (FN) BMD correlated with FMD and CRP. QCT trabecular BMD correlated with ccIMT and PON1. According to the univariate analysis, FMD correlated with OPG, ccIMT correlated with SOST and QCT trabecular BMD. Ang1, Ang2 and PDGF-BB showed correlation with Dickkopf-1 (DKK1). Ang2 also correlated with OPG. As suggested by the multivariate analysis, OPG determined FMD; DKK1 was an independent predictor of Ang1, Ang2 and PDGF-BB. OPG was a predictor of Ang2.Conclusion:In our study of anti-TNF treated RA and AS patients, vascular and bone parameters showed numerous correlations. The therapy was clinically effective, it halted further bone loss over 1 year and reduced the production of angiogenic markers.Acknowledgments:This research was supported by an investigator-initiated research grant from Pfizer.Disclosure of Interests:Monika Czókolyová: None declared, Katalin Gulyás: None declared, Ágnes Horváth: None declared, Edit Végh: None declared, Zsófia Pethö: None declared, Szilvia Szamosi: None declared, Attila Hamar: None declared, Anita Pusztai: None declared, Emese Balogh: None declared, Nóra Bodnár: None declared, Levente Bodoki: None declared, Agnes Szentpetery: None declared, Harjit Pal Bhattoa: None declared, György Kerekes: None declared, Katalin Hodosi: None declared, Andrea Domjan: None declared, Sándor Szántó: None declared, Gabriella Szücs: None declared, Hennie Raterman Grant/research support from: UCB, Consultant of: Abbvie, Amgen, Bristol-Myers Sqibb, Cellgene and Sanofi Genzyme, WIllem Lems Grant/research support from: Pfizer, Consultant of: Lilly, Pfizer, Zoltán Szekanecz Grant/research support from: Pfizer, UCB, Consultant of: Sanofi, MSD, Abbvie, Pfizer, Roche, Novertis, Lilly, Gedeon Richter, Amgen

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