Targeting chronic innate inflammatory pathways, the main road to prevention of osteoarthritis progression

Herrero‐Beaumont, Gabriel; Pérez-Baos, Sandra; Sánchez‐Pernaute, Olga; Roman‐Blas, Jorge A.; Lamuedra, Ana; Largo, Raquel

doi:10.1016/j.bcp.2019.02.030

Cited by 77 publications

(73 citation statements)

References 99 publications

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“…Along the same vein, CEP might be useful to limit the progression of osteoarthritis, a chronic degenerative joint disease incredibly prevalent in older age. CEP would not repair the already degraded cartilage, but the drug might avoid damage extension to the surrounding tissue, by limiting the production of pro-inflammatory cytokines and chemokines (Herrero-Beaumont et al, 2019). In particular, osteoarthritis patients suffering from a cancer and treated with a regulator of the PD1/PDL1 immune checkpoint might face an aggravation of their osteoarthritis due to a treatment-induced elevated expression of inflammatory cytokine in macrophages (Liu et al, 2019).…”

Section: Baillymentioning

confidence: 99%

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

2019

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A B S T R A C TBackground: Cepharanthine (CEP) is a drug used in Japan since the 1950s to treat a number of acute and chronic diseases, including treatment of leukopenia, snake bites, xerostomia and alopecia. It is the only approved drug for Human use in the large class of bisbenzylisoquinoline alkaloids. This natural product, mainly isolated from the plant Stephania cephalantha Hayata, exhibits multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, anti-cancer, anti-viral and anti-parasitic properties. Purpose: The mechanism of action of CEP is multifactorial. The drug exerts membrane effects (modulation of efflux pumps, membrane rigidification) as well as different intracellular and nuclear effects. CEP interferes with several metabolic axes, primarily with the AMP-activated protein kinase (AMPK) and NFκB signaling pathways. In particular, the anti-inflammatory effects of CEP rely on AMPK activation and NFκB inhibition. Conclusion: In this review, the historical discovery and development of CEP are retraced, and the key mediators involved in its mode of action are presented. The past, present, and future of CEP are recapitulated. This review also suggests new opportunities to extend the clinical applications of this well-tolerated old Japanese drug.

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Section: Baillymentioning

confidence: 99%

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

2019

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“…OA FLS (Cell Applications, USA) were isolated from synovial tissues from de-identified patients undergoing knee replacement surgery (n=4; 2 males and 2 females; 62-69 years old). Cells were received in their second passage and were cultured as previously described [20]. OA FLS were used between the 3 rd and 6 th passages to avoid alterations in gene expression pattern and cell proliferation rate [41].…”

Section: Impact Of Prg4 and Ha Treatments On Acta2 Expression α-Sma mentioning

confidence: 99%

“…Macroscopic evidence of synovial inflammation or synovitis is a common finding in up to 74% of patients with knee OA of different grades and 95% of patients with moderate to severe OA [14][15][16]. OA synovitis is likely caused by an innate immune response, mediated by the toll-like receptors 2 and 4 (TLR2 and TLR4) in the synovium, and resultant expression of inflammatory cytokines, chemokines and matrix degrading enzymes [17][18][19][20][21]. The extent of synovitis is a strong predictor of OA progression across multiple studies, and therefore treating synovial inflammation is a potentially important target for therapeutic intervention, especially during the early stage of OA [14,[22][23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Proteoglycan-4 Regulates Fibroblast to Myofibroblast Transition and Expression of Fibrotic Genes in the Synovium

Qadri

Jay

Zhang

et al. 2020

Preprint

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Background: Synovial tissue fibrosis is common in advanced OA with features including the presence of stress fiber-positive myofibroblasts and deposition of cross-linked collagen type-I. Proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and is a major component of synovial fluid. PRG4 is a ligand of the CD44 receptor. Our objective was to examine the role of PRG4-CD44 interaction in regulating synovial tissue fibrosis in vitro and in vivo. Methods: OA synoviocytes were treated with TGF-β ± PRG4 for 24 hours and α-SMA content was determined using immunofluorescence. Rhodamine labeled rhPRG4 was incubated with OA synoviocytes ± anti-CD44 or isotype control antibodies and cellular uptake of rhPRG4 was determined following a 30-min incubation and a-SMA expression following a 24-hour incubation. HEK-TGF-β cells were treated with TGF-β ± rhPRG4 and Smad3 phosphorylation was determined using immunofluorescence and TGF-β/Smad pathway activation was determined colorimetrically. We probed for stress fibers and focal adhesions (FAs) in TGF-β treated murine fibroblasts and fibroblast migration was quantified ± rhPRG4. Synovial expression of fibrotic markers: α-SMA, collagen type-I and PLOD2 in Prg4 gene trap (Prg4GT) and recombined Prg4GTR animals was studied at 2 and 9 months of age. Synovial expression of α-SMA and PLOD2 was determined in 2-months old Prg4GT/GT&Cd44-/- and Prg4GTR/GTR&Cd44-/- animals. Results: PRG4 reduced α-SMA content in OA synoviocytes (p<0.001). rhPRG4 was internalized by OA synoviocytes via CD44 and CD44 neutralization attenuated rhPRG4’s antifibrotic effect (p<0.05). rhPRG4 reduced pSmad3 signal in HEK-TGF-β cells (p<0.001) and TGF-β/Smad pathway activation (p<0.001). rhPRG4 reduced the number of stress fiber-positive myofibroblasts, FAs mean size, and cell migration in TGF-β treated NIH3T3 fibroblasts (p<0.05). rhPRG4 inhibited fibroblast migration in a macrophage and fibroblast co-culture model without altering active or total TGF-β levels. Synovial tissues of 9-months old Prg4GT/GT animals had higher α-SMA, collagen type-I and PLOD2 (p<0.001) content and Prg4 re-expression reduced these markers (p<0.01). Prg4 re-expression also reduced α-SMA and PLOD2 staining in CD44-deficient mice. Conclusion: PRG4 is an endogenous antifibrotic modulator in the joint and its effect on myofibroblast formation is partially mediated by CD44, but CD44 is not required to demonstrate an antifibrotic effect in vivo.

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“…Systemic and focal in ammation in synovium play an important role. In ammation is generally induced by microfragments of cartilages or danger-associated molecular pattern (DAMPS) in synovial uids and releases several proteases and cytokines, which accelerate the degeneration of articular tissues [38][39][40] . The infrapatellar fat pad is a major source of adiponectin in synovial uid; adiponectins are closely related to the metabolic syndrome and degenerative pathological changes in the cartilage and bone during OA 41 .…”

Section: Discussionmentioning

confidence: 99%

Epidemiological study on the relationship among menopausal condition, bone fragility, and knee osteoarthritis

Sasaki¹,

Chiba²,

Ota³

et al. 2020

Preprint

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Background: Knee osteoarthritis (KOA) occurs more often in middle-aged females. While this age-group experiences comorbid osteoporosis with menopause, its influence on KOA has not been clarified. This epidemiological study aimed to investigate the relationship between menopausal conditions, bone mineral density (BMD), and KOA. Methods: A total of 518 female volunteers who participated in the Iwaki cohort study were enrolled and divided into groups (pre- and post-menopause). Antimullerian hormone (AMH) was measured as a predictive marker for menopause in the pre-menopausal subjects. Weight-bearing anterior-posterior knee radiographs were classified by Kellgren-Lawrence grade, and grade ≥ 2 was defined as definitive KOA (DKOA). Early KOA (EKOA) was defined by Luyten’s criteria, and BMD was measured at a distal radius. The relationship between menopausal condition, BMD, and KOA was analyzed by ROC and regression analysis. Results: Fifty-two participants (10.0%) were diagnosed with EKOA and 204 (39.4%) with DKOA. A total of 393 (75.9%) females began menopause, and the prevalence of DKOA was up to 48.1% and >12.0% in pre-menopause females (p < 0.001, Odds ratio: 6.79). From the ROC analysis in pre-menopausal females, cut-off value of AMH for detecting EKOA was 0.08 ng/ml (AUC: 0.712, p5%CI: 0.527 to 0.897, p-value: 0.025, Odds ratio: 8.28). Regression analysis showed that lower AMH was related to EKOA (p=0.035, Odds ratio: 5.55) and DKOA (p=0.032, Odds 1.59), and lower BMD and high turnover bone metabolism were correlated with DKOA. Conclusions: KOA increased after menopause and was correlated with lower BMD. Furthermore, reduction in AMH was a valuable biomarker for the detection of EKOA.

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Targeting chronic innate inflammatory pathways, the main road to prevention of osteoarthritis progression

Cited by 77 publications

References 99 publications

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

Proteoglycan-4 Regulates Fibroblast to Myofibroblast Transition and Expression of Fibrotic Genes in the Synovium

Epidemiological study on the relationship among menopausal condition, bone fragility, and knee osteoarthritis

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