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Background: Rheumatoid arthritis is a symmetric peripheral polyarthritis of unknown etiology that, untreated or if unresponsive the therapy, typically leads to deformity and destruction of joints due to erosion of cartilage and bone. Omega-3 fatty acids have been shown to reduce morning stiffness, the number of tender joints and swollen joints in patients with rheumatoid arthritis. This study is designed for evaluation of omega-3 effects on disease activity and remission of rheumatoid arthritis in DMARDs treated patients and on weight changes and reduction of analgesic drugs consumption versus placebo.
Methods: Sixty patients with active rheumatoid arthritis (49 female and 11 male) underwent rheumatologist examination and disease activity score were calculated. Then patients were enrolled in this 12 week, double blind, randomized, placebo- controlled study. The patients in both groups continued their pre study standard treatment. The patients were visited every 4 weeks, 4 times and data were recorded.
Results: Significant improvement in the patient’s global evaluation and in the physician’s assessment of disease was observed in those taking omega-3. The proportions of patients who improved and of those who were able to reduce their concomitant analgesic medication were significantly greater with omega-3 consumption. There were no weight changes.
Conclusion: Daily supplementation with omega-3 results has significant clinical benefit and may reduce the need for concomitant analgesic consumption without weight changes.
Source: Elham Rajaei, Karim Mowla, Ali Ghorbani, Sara Bahadoram, Mohammad Bahadoram, Mehrdad Dargahi-Malamir. “The Effect of Omega-3 Fatty Acids in Patients With Active Rheumatoid Arthritis Receiving DMARDs Therapy: Double-Blind Randomized Controlled Trial” Global Journal of Health Science (2016): 8(7): 18–25.
Many clinical trials of omega-3 fatty acids, supplied as fish oil supplements, have been carried out in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis, and osteoarthritis (OA) over the past 3 decades. This review attempts to summarize the highlights of these studies to evaluate the clinical efficacy for omega-3 fatty acids to be added alongside existing treatment regimens. A total of 20 clinical trials have been carried out in RA, of which 16 exhibited significant improvements in multiple disease clinical outcomes. Nine clinical trials have been completed in SLE and lupus nephritis, of which 6 exhibited significant improvements in 1 or more clinical outcomes. A total of 4 clinical trials have been conducted in OA, of which 3 exhibited significant improvements in at least 1 clinical parameter. Multiple mechanisms for the clinical effects of omega-3 fatty acids have been implicated, including the modulation of eicosanoid synthesis toward a more anti-inflammatory profile and suppressed production of proinflammatory cytokines. Overall, fish oil supplements appear to be a safe and effective agent that could be added to the current treatment regimens in RA. Longer-term trials with larger patient cohort sizes are warranted to establish any long-term benefits of fish oil supplements in SLE, lupus nephritis, and OA.
Source: Umair Akbar, BS, Melissa Yang, BS, Divya Kurian, BS, Chandra Mohan, MD, PhD. “Omega-3 Fatty Acids in Rheumatic Diseases – A Critical Review” Journal of Clinical Rheumatology (2017): Volume 23, Issue 6, 330-339.
Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oil—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—are more biologically potent than α-linolenic acid (ALA). Some of the effects of omega-3 PUFA are brought about by modulation of the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases. Coronary heart disease, major depression, aging and cancer are characterized by an increased level of interleukin 1 (IL-1), a proinflammatory cytokine. Similarly, arthritis, Crohn’s disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB4 produced by omega-6 fatty acids. There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn’s disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches. Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs.
Source: Simopoulos, Artemis P. “Omega-3 fatty acids in inflammation and autoimmune diseases.” Journal of the American College of nutrition 21.6 (2002): 495-505.
Between 40% and 60% of Americans use complementary and alternative medicine to manage medical conditions, prevent disease, and promote health and well-being. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been used to treat joint pain associated with several inflammatory conditions. We conducted a meta-analysis of 17 randomized, controlled trials assessing the pain relieving effects of ω-3 PUFAs in patients with rheumatoid arthritis or joint pain secondary to inflammatory bowel disease and dysmenorrhea. Meta-analysis was conducted with Cochrane Review Manager 4.2.8. for six separate outcomes using standardized mean differences (SMDs) as a measure of effect size: (1) patient assessed pain, (2) physician assessed pain, (3) duration of morning stiffness, (4) number of painful and/or tender joints, (5) Ritchie articular index, and (6) nonselective nonsteroidal anti-inflammatory drug consumption. Supplementation with ω-3 PUFAs for 3–4 months reduces patient reported joint pain intensity (SMD: −0.26; 95% CI: −0.49 to −0.03, p = 0.03), minutes of morning stiffness (SMD: −0.43; 95% CI: −0.72 to −0.15, p = 0.003), number of painful and/or tender joints (SMD: −0.29; 95% CI: −0.48 to −0.10, p = 0.003), and NSAIDconsumption (SMD: −0.40; 95% CI: −0.72 to − 0.08, p = 0.01). Significant effects were not detected for physician assessed pain (SMD: −0.14; 95% CI: −0.49 to 0.22, p = 0.45) or Ritchie articular index (SMD: 0.15; 95% CI: − 0.19 to 0.49, p = 0.40) at 3–4 months. The results suggest that ω-3 PUFAs are an attractive adjunctive treatment for joint pain associated with rheumatoid arthritis, inflammatory bowel disease, and dysmenorrhea.
Source: Robert J. Goldberg, Joel Katz “A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain” Pain (2007): Volume 129, Issues 1–2, 210-223.
Eicosapentaenoic acid (EPA) is essential for normal cell growth, and may play an important role in inflammatory and autoimmune disorders including rheumatoid arthritis. We investigate that EPA could suppress the proliferation of fibroblast like synoviocytes in vitro. We treated synoviocytes with 1 to 50 µM EPA and measured cell viabilities by the modified MTT assay. We sorted the number of them in sub G1 stage by fluorescence-activated cell sorting caliber. And we stained them by light green or Hoechst 33258, and investigate microscopic appearance. The cell viabilities were decreased at 30 µM, 40 µM, and 50 µM of EPA comparing to 0 µM of EPA. The half maximal concentration of synoviocytes inhibition was approximately 25 µM. At day 1 and day 3, cell number was also decreased at 50 µM EPA comparing to control. FACS caliber indicated the number of synoviocytes in sub G1 stage did not increase in each concentration of EPA. Hoechst staining indicated normal chromatin pattern and no change in a nuclear morphology both in EPA treated synoviocytes and in untreated synoviocytes. These findings suggest that EPA could suppress the proliferation of synoviocytes in vivo dose dependently and time dependently, however, the mechanism is not due to apoptosis.
Source: Masahide Hamaguchi, Yutaka Kawahito, Atsushi Omoto, Yasunori Tsubouchi, Masataka Kohno, Takahiro Seno, Masatoshi Kadoya, Aihiro Yamamoto, Hidetaka Ishino, Masahide Matsuyama, Rikio Yoshimura, Toshikazu Yoshikawa. “Eicosapentaenoic Acid Suppresses the Proliferation of Synoviocytes from Rheumatoid Arthritis” Journal of Clinical Biochemistry and Nutrition (2008) Sep; 43(2): 126–128.
The TIMPs play an important role in regulating the activity of the secreted metalloproteinases (collagenases, stromelysins, gelatinases). Two different TIMPs have been well characterized, each capable of inhibiting all tested eukaryotic metalloproteinases but showing specific binding to a particular gelatinase at a site distinct from the active site. They influence the activation of the prometalloproteinase and act to modulate proteolysis of extracellular matrix, notably during tissue remodeling and inflammatory processes. On certain cell types, they can exhibit growth factor-like activity, and they can inhibit the tumorigenic and metastatic phenotype of cancer cells.
Source: David T.Denhardt, Bo Feng, Dylan R.Edwards, Enzo T.Cocuzzi, Uriel M.Malyankar. “Tissue inhibitor of metalloproteinases (TIMP, aka EPA): Structure, control of expression and biological functions” Pharmacology & Therapeutics (1993) Volume 59, Issue 3, 329-341.
Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints and bones. Omega-3 (ω3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines and eicosanoids involved in RA pathogenesis. The aim of this study was to determine the therapeutic potential of ω3 monoglyceride (MAG-ω3) compounds in an in vivo rat model of RA induced by Complete Freund’s Adjuvant (CFA).
Method: CFA rats were untreated or treated per os with three specific compounds, namely, MAG-docosahexaenoic acid (MAG-DHA), MAG-eicosapentaenoic acid (MAG-EPA) and MAG-docosapentaenoic acid (MAG-DPA). Morphological and histological analyses, as well as pro-inflammatory marker levels were determined following MAG-ω3 treatments.
Results: Morphological and histological analyses revealed that MAG-EPA and MAG-DPA exhibited strong activity in reducing the progression and severity of arthritic disease in CFA rats. Following MAG-EPA and MAG-DPA treatments, plasma levels of the pro-inflammatory cytokines; interleukin 17A (IL-17A), IL-1β, IL-6 and tumor necrosis factor α (TNFα) were markedly lower when compared to CFA-untreated rats. Results also revealed a decreased activation of p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor-kappa B (NFκB) pathways correlated with a reduced expression of TNFα, cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2) and MMP-9 in paw homogenates derived from MAG-EPA and MAG-DPA-treated rats. Of interest, the combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in CFA rats.
Conclusion: Altogether, the present data suggest that MAG-EPA, without vitamin E, represents a new potential therapeutic strategy for resolving inflammation in arthritis.
Source: Caroline Morin, Pierre U. Blier, Samuel Fortin. “Eicosapentaenoic acid and docosapentaenoic acid monoglycerides are more potent than docosahexaenoic acid monoglyceride to resolve inflammation in a rheumatoid arthritis model” Arthritis Research & Therapy (2015): 17: 142.
A model of early osteoarthritis (OA) induced in ovine joints by medial meniscectomy was used to study the effects of two hyaluronan (HA) preparations (AHA and DHA) on cartilage composition and proteoglycan (PG) metabolism. DHA was an HA preparation with an average molecular weight (MW) of ∼2.0 × 106 d, and AHA had an MW of ∼8.0 × 105 d. Both preparations were administered intraarticularly once a week for 5 weeks starting 16 weeks after meniscectomy, and animals (n = 5) were killed 5 weeks after the last injection. Meniscectomized, saline-injected (n = 5) and nonoperated (n = 5) animals were used for controls. At necropsy, 3-mm-diameter full-depth cartilage plugs were sampled under sterile conditions from specific locations on the medial and lateral femoral condyles, tibial plateaus, patella, and trochlear groove. The cartilage plugs were cultured in Hams-F12 medium supplemented with 10% fetal calf serum for 24 hours, then for a further 48 hours in the presence of H235SO4 to determine the biosynthesis of PGs. The percentage of 35S-PGs and sulfated glycosami-noglycans released into the media was also ascertained. The cartilage adjacent to the plugs was analyzed for collagen and proteoglycan content and differential extractability with guanidine hydrochloride (GuHCl) solutions. The extractability of PGs with 0.4 mol/L GuHCI (nondissociative conditions) was lower from the medial femoral cartilages of the DH A-treated group than from the corresponding saline-treated group. In contrast, the release of 35S-PGs from the tibial cartilages of the DHA-treated animals was higher than in the saline-treated group. The biosynthesis of 35S-PGs, determined in vitro, for cartilage derived from the medial compartment was generally lower than for the lateral regions of the meniscectomized joints. The biosynthetic activity was further reduced in joints injected with the two HA preparations, but DHA reduced >35SO4 incorporation into PGs more than AHA. It was concluded that reduced biosynthesis of 35S-PGs and secretion into media was a consequence of increased loading of joints in the HA-treated animals rather than a direct effect of these preparations on chondrocyte metabolism.
Source: Peter Ghosh, Richard Read, Yukiko Numata, Suzanne Smith, Sarah Armstrong, Diana Wilson. “The effects of intraarticular administration of hyaluronan in a model of early osteoarthritis in sheep II. Cartilage composition and proteoglycan metabolism” Seminars in Arthritis and Rheumatism (1993) Volume 22, Issue 6, Supplement 1, 31-42.
Osteoarthritis (OA) is the most common form of arthritis. Obesity has been believed to be an important risk factor for OA development and the progression of not only load-bearing joints, but low-load-bearing joints as well. Increased leptin has been the focus of a link between obesity and OA. In this study, the effects of pathological (100ng/ml) or supra-pathological (10μg/ml) concentrations of leptin alone or in combination with IL1β on cartilage metabolisms were studied in porcine cartilage explant. The involved mechanisms were examined in human articular chondrocytes (HACs). Moreover, the protective effect of omega-3 polyunsaturated acids, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) was also investigated. Leptin (10μg/ml) alone or in combination with IL1β could induce cartilage destruction, although lower concentrations had no effect. Leptin activated NFκB, ERK, JNK and p38 in HACs, which led to the induction of MMP3, MMP13 and ADAMTS4 secretions. The combined effect could further induce those enzymes through the additive effect on activation of NFκB and JNK. Interestingly, both EPA and DHA could inhibit cartilage damage induced by leptin plus IL1β by reducing the activation of NFκB and JNK, which led to the decrease of ADAMTS4 secretion. Altogether, only a supra-pathological concentration of leptin alone or in combination with IL1β could induce cartilage destruction, whereas a pathological one could not. This effect could be inhibited by EPA and DHA. To gain greater understanding of the link between leptin and OA, the effect of different levels of leptin on several states of OA cartilage requires further investigation.
Source: Thanyaluck Phitak, Kanchanit Boonmaleerat, Peraphan Pothacharoen, Dumnoensun Pruksakorn, Prachya Kongtawelert. “Leptin alone and in combination with interleukin-1-beta induced cartilage degradation potentially inhibited by EPA and DHA” Connective Tissue Research (2017): 316-331.
Although turmeric and its curcumin-enriched extracts have been used for treating arthritis, no systematic review and meta-analysis of randomized clinical trials (RCTs) have been conducted to evaluate the strength of the research. We systemically evaluated all RCTs of turmeric extracts and curcumin for treating arthritis symptoms to elucidate the efficacy of curcuma for alleviating the symptoms of arthritis. Literature searches were conducted using 12 electronic databases, including PubMed, Embase, Cochrane Library, Korean databases, Chinese medical databases, and Indian scientific database. Search terms used were “turmeric,” “curcuma,” “curcumin,” “arthritis,” and “osteoarthritis.” A pain visual analogue score (PVAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used for the major outcomes of arthritis. Initial searches yielded 29 articles, of which 8 met specific selection criteria. Three among the included RCTs reported reduction of PVAS (mean difference: −2.04 [−2.85, −1.24]) with turmeric/curcumin in comparison with placebo (P < .00001), whereas meta-analysis of four studies showed a decrease of WOMAC with turmeric/curcumin treatment (mean difference: −15.36 [−26.9, −3.77]; P = .009). Furthermore, there was no significant mean difference in PVAS between turmeric/curcumin and pain medicine in meta-analysis of five studies. Eight RCTs included in the review exhibited low to moderate risk of bias. There was no publication bias in the meta-analysis. In conclusion, these RCTs provide scientific evidence that supports the efficacy of turmeric extract (about 1000 mg/day of curcumin) in the treatment of arthritis. However, the total number of RCTs included in the analysis, the total sample size, and the methodological quality of the primary studies were not sufficient to draw definitive conclusions. Thus, more rigorous and larger studies are needed to confirm the therapeutic efficacy of turmeric for arthritis.
Source: James W. Daily, Mini Yang, Sunmin Park. “Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials” Journal of Medicinal Food (2016): 19(8): 717–729.
Objective: Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well‐characterized turmeric extract using an animal model of rheumatoid arthritis (RA).
Methods: The composition of commercial turmeric dietary supplements was determined by high‐performance liquid chromatography. A curcuminoid‐containing turmeric extract similar in composition to these supplements was isolated and administered intraperitoneally to female Lewis rats prior to or after the onset of streptococcal cell wall–induced arthritis. Efficacy in preventing joint swelling and destruction was determined clinically, histologically, and by measurement of bone mineral density. Mechanism of action was elucidated by analysis of turmeric’s effect on articular transcription factor activation, microarray analysis of articular gene expression, and verification of the physiologic effects of alterations in gene expression.
Results: A turmeric fraction depleted of essential oils profoundly inhibited joint inflammation and periarticular joint destruction in a dose‐dependent manner. In vivo treatment prevented local activation of NF‐κB and the subsequent expression of NF‐κB–regulated genes mediating joint inflammation and destruction, including chemokines, cyclooxygenase 2, and RANKL. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E2, and periarticular osteoclast formation were inhibited by turmeric extract treatment.
Conclusion: These translational studies demonstrate in vivo efficacy and identify a mechanism of action for a well‐characterized turmeric extract that supports further clinical evaluation of turmeric dietary supplements in the treatment of RA.
Source: Janet L. Funk, Jennifer B. Frye, Janice N. Oyarzo, Nesrin Kuscuoglu. “Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis” Arthritis and Rheumatology (2006).
Although turmeric and its curcumin-enriched extracts have been used for treating arthritis, no systematic review and meta-analysis of randomized clinical trials (RCTs) have been conducted to evaluate the strength of the research. We systemically evaluated all RCTs of turmeric extracts and curcumin for treating arthritis symptoms to elucidate the efficacy of curcuma for alleviating the symptoms of arthritis. Literature searches were conducted using 12 electronic databases, including PubMed, Embase, Cochrane Library, Korean databases, Chinese medical databases, and Indian scientific database. Search terms used were “turmeric,” “curcuma,” “curcumin,” “arthritis,” and “osteoarthritis.” A pain visual analogue score (PVAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used for the major outcomes of arthritis. Initial searches yielded 29 articles, of which 8 met specific selection criteria. Three among the included RCTs reported reduction of PVAS (mean difference: −2.04 [−2.85, −1.24]) with turmeric/curcumin in comparison with placebo (P < .00001), whereas meta-analysis of four studies showed a decrease of WOMAC with turmeric/curcumin treatment (mean difference: −15.36 [−26.9, −3.77]; P = .009). Furthermore, there was no significant mean difference in PVAS between turmeric/curcumin and pain medicine in meta-analysis of five studies. Eight RCTs included in the review exhibited low to moderate risk of bias. There was no publication bias in the meta-analysis. In conclusion, these RCTs provide scientific evidence that supports the efficacy of turmeric extract (about 1000 mg/day of curcumin) in the treatment of arthritis. However, the total number of RCTs included in the analysis, the total sample size, and the methodological quality of the primary studies were not sufficient to draw definitive conclusions. Thus, more rigorous and larger studies are needed to confirm the therapeutic efficacy of turmeric for arthritis.
Source: James W. Daily, Mini Yang, Sunmin Park. “Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials” Journal of Medicinal Food (2016) Vol. 19, No. 8.
Trans-resveratrol (t-Res) is a natural compound of a family of hydroxystilbenes found in a variety of spermatophyte plants. Because of its effects on lipids and arachidonic acid metabolisms, and its antioxidant activity, t-Res is considered as the major cardioprotective component of red wine, leading to the “French Paradox” health concept. In the past decade, research on the effects of resveratrol on human health has developed considerably in diverse fields such as cancer, neurodegenerative and cardiovascular diseases, and metabolic disorders. In the field of rheumatic disorders, in vitro evidence suggest anti-inflammatory, anti-catabolic, anti-apoptotic and anti-oxidative properties of t-Res in various articular cell types, including chondrocytes and synoviocytes, along with immunomodulation properties on T and B lymphocytes. In preclinical models of osteoarthritis and rheumatoid arthritis, resveratrol has shown joint protective effects, mainly mediated by decreased production of pro-inflammatory and pro-degradative soluble factors, and modulation of cellular and humoral responses. Herein, we comprehensively reviewed evidence supporting a potential therapeutic interest of t-Res in treating symptoms related to rheumatic disorders.
Source: Christelle Nguyen, Jean-François Savouret, Magdalena Widerak, Marie-Thérèse Corvol, and François Rannou. “Resveratrol, Potential Therapeutic Interest in Joint Disorders: A Critical Narrative Review” Nutrients (2017): 9(1): 45.
We investigated the feasibility of the intra‐articular injection of resveratrol for preventing the progression of existing cartilage degeneration in a mouse model of osteoarthritis (OA). The effects of resveratrol on the expression of silent information regulator 2 types 1 (SIRT1), hypoxia‐inducible factor‐2α (HIF‐2α) and catabolic factors in OA cartilage was explored. OA was induced in the mouse knee via destabilization of the medial meniscus (DMM). Resveratrol was injected weekly into the operated knee beginning 4 weeks after surgery. The OA phenotype was evaluated via histological and immunohistochemical analyses at 8 weeks after DMM. Western blot analysis was performed to identify whether resveratrol modulated the interleukin (IL)‐1β‐induced expression of HIF‐2α in human chondrocytes. Histologically, resveratrol treatment preserved the structural homeostasis of the articular cartilage and the subchondral bone. Following resveratrol injection, the expression of collagen type II was retained, but the expression of inducible nitric oxide synthase and matrix metalloproteinase‐13 was reduced in OA cartilage. Moreover, the administration of resveratrol significantly induced the activation of SIRT1 and the inhibition of HIF‐2α expression in mouse OA cartilage and in IL‐1β‐treated human chondrocytes. These findings indicate that the intra‐articular injection of resveratrol significantly prevents the destruction of OA cartilage by activating SIRT1 and thereby suppressing the expression of HIF‐2α and catabolic factors. © 2015 Orthopaedic Research Society.
Source: Li, Wuyin, et al. “Intra‐articular resveratrol injection prevents osteoarthritis progression in a mouse model by activating SIRT1 and thereby silencing HIF‐2α.” Journal of Orthopaedic Research 33.7 (2015): 1061-1070.
Summary: Nuclear factor kappa B (NF-κB), is a pivotal transcription factor involved in the activation of the TNF-α and IL-1β genes. Activation of NF-κB in synovial cells is a feature seen in arthritis patients. Resveratrol, a polyphenolic, a natural phytoalexin found with particularly high levels in grape skin and red wine, is a potent and specific inhibitor of TNF-α and IL-1β induced NF-κB activation. We aimed to determine the in vivo effects of intra-articular injections of resveratrol on cartilage and synovium in an experimental rabbit inflammatory arthritis model.
Materials and methods: Arthritis was induced by intra-articular injection of three times of 50 μg lipopolysaccharide (LPS) at day 0, 4 and 8 at 4-day intervals into the knee joints of rabbits. To the test group, 10 μMol/kg resveratrol in the DMSO was injected in the knees at day 0 and then it was continued once daily for 2 weeks. To the control group at the same time and amount of DMSO was injected into the knees of rabbits. All rabbits were killed 1 week after the last injection and cartilage tissue and synovium was evaluated with semiquantitative scoring histologically.
Results: According to the control group in the resveratrol group, significantly decreased cartilage destruction was determined by H&E staining (p = 0.04). Loss of matrix proteoglycan content in the cartilage was much lower, as determined by safranin O staining (p = 0.03). We also observed marked synovial inflammation after intra-articular injection to control knees, but not in the resveratrol-treated group knees (p = 0.01).
Conclusion: This study suggests that intra-articular injection of resveratrol may protect cartilage against the development of experimentally induced IA.
Source: Elmali, N., et al. “Effects of resveratrol in inflammatory arthritis.” Inflammation 30.1-2 (2007): 1-6.
Conclusions and clinical relevance: Results suggested that in performance horses with lameness localized to the distal tarsal joints, injection of triamcinolone in the centrodistal and tarsometatarsal joints of both hind limbs followed by oral supplementation with resveratrol for 4 months resulted in reduced lameness, compared with triamcinolone injection and supplementation with placebo.
Source: Watts, Ashlee E., et al. “A randomized, controlled trial of the effects of resveratrol administration in performance horses with lameness localized to the distal tarsal joints.” Journal of the American Veterinary Medical Association 249.6 (2016): 650-659.
Introduction: Accumulation of advanced glycation end products (AGEs) in joints contributes to the pathogenesis of cartilage damage in osteoarthritis (OA). We aim to explore the potential chondroprotective effects of resveratrol on AGEs-stimulated porcine chondrocytes and cartilage explants.
Methods: Chondrocytes were isolated from pig joints. Activation of the IκB kinase (IKK)-IκBα-nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK)-activator protein-1 (AP-1) pathways were assessed by electrophoretic mobility shift assay (EMSA), Western blot and transfection assay. The levels of inducible nitric oxide synthase (iNOS)-NO and cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) were measured by Western blot, Griess reaction or ELISA. The expression and enzyme activity of matrix metalloproteinase-13 (MMP-13) were determined by real-time RT/PCR and gelatin zymography, respectively.
Results: We show that AGEs-induced expression of iNOS and COX-2 and production of NO and PGE2 were suppressed by resveratrol. Such effects of resveratrol were likely mediated through inhibiting IKK-IκBα-NF-κB and JNK/ERK-AP-1 signaling pathways induced by AGEs. By targeting these critical signaling pathways, resveratrol decreased AGEs-stimulated expression and activity of MMP-13 and prevented AGEs-mediated destruction of collagen II. Histochemistry analysis further confirms that resveratrol could prevent AGEs-induced degradation of proteoglycan and aggrecan in cartilage explants.
Conclusions: The present study reveals not only the effects and mechanisms regarding how resveratrol may protect cartilage from AGEs-mediated damage but also the potential therapeutic benefit of resveratrol in the treatment of OA.
Source: Liu, Feng-Cheng, et al. “Chondroprotective effects and mechanisms of resveratrol in advanced glycation end products-stimulated chondrocytes.” Arthritis research & therapy 12.5 (2010): R167.
Background: The purpose of this study was to assess the effect of 8-weeks ingestion of a commercialized joint pain dietary supplement (InstaflexTM Joint Support, Direct Digital, Charlotte, NC) compared to placebo on joint pain, stiffness, and function in adults with self-reported joint pain. InstaflexTM is a joint pain supplement containing glucosamine sulfate, methylsulfonylmethane (MSM), white willow bark extract (15% salicin), ginger root concentrate, Boswellia Serrata extract (65% boswellic acid), turmeric root extract, cayenne, and hyaluronic acid.
Methods: Subjects included 100 men and women, ages 50-75 years, with a history (>3 months) of joint pain, and were randomized to Instaflex™ or placebo (3 colored gel capsules per day for 8 weeks, double-blind administration). Subjects agreed to avoid the use of non-steroidal anti-inflammatory drugs (NSAID) and all other medications and supplements targeted for joint pain. Primary outcome measures were obtained pre- and post-study and included joint pain severity, stiffness, and function (Western Ontario and McMaster Universities [WOMAC]), and secondary outcome measures included health-related quality of life (Short Form 36 or SF-36), systemic inflammation (serum C-reactive protein and 9 plasma cytokines), and physical function (6-minute walk test). Joint pain symptom severity was assessed bi-weekly using a 12-point Likert visual scale (12-VS).
Results: Joint pain severity was significantly reduced in Instaflex™ compared to placebo (8-week WOMAC, ↓37% versus ↓16%, respectively, interaction effect P = 0.025), with group differences using the 12-VS emerging by week 4 of the study (interaction effect, P = 0.0125). Improvements in the ability to perform daily activities and stiffness scores in Instaflex™ compared to placebo were most evident for the 74% of subjects reporting knee pain (8-week WOMAC function score, ↓39% versus ↓14%, respectively, interaction effect P = 0.027; stiffness score, ↓30% versus ↓12%, respectively, interaction effect P = 0.081). Patterns of change in SF-36, systemic inflammation biomarkers, and the 6-minute walk test did not differ significantly between groups during the 8-week study.
Conclusions: Results from this randomized, double-blind, placebo-controlled community trial support the use of the Instaflex™ dietary supplement in alleviating joint pain severity in middle-aged and older adults, with mitigation of difficulty performing daily activities most apparent in subjects with knee pain.
Source: Nieman, David C., et al. “A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial.” Nutrition journal 12.1 (2013): 154.
The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in medicines since time immemorial. Boswellia serrata (Salai/Salai guggul), is a moderate to large sized branching tree of family Burseraceae (Genus Boswellia), grows in dry mountainous regions of India, Northern Africa and Middle East. Oleo gum-resin is tapped from the incision made on the trunk of the tree and is then stored in specially made bamboo basket for removal of oil content and getting the resin solidified. After processing, the gum-resin is then graded according to its flavour, colour, shape and size. In India, the States of Andhra Pradesh, Gujarat, Madhya Pradesh, Jharkhand and Chhattisgarh are the main source of Boswellia serrata. Regionally, it is also known by different names. The oleo gum-resins contain 30-60% resin, 5-10% essential oils, which are soluble in the organic solvents, and the rest is made up of polysaccharides. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes, triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl-11-keto-β-boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for inflammation.
Source: M. Z. Siddiqui. “Boswellia Serrata, A Potential Antiinflammatory Agent: An Overview” Indian Journal of Pharmaceutical Sciences (2011): 73(3): 255–261.
Summary: Osteoarthritis is a common, chronic, progressive, skeletal, degenerative disorder, which commonly affects the knee joint. Boswellia serrata tree is commonly found in India. The therapeutic value of its gum (Guggulu) has been known. It possesses good anti-inflammatory, anti-arthritic and analgesic activity. A randomized double-blind placebo-controlled crossover study was conducted to assess the efficacy, safety, and tolerability of Boswellia serrata Extract (BSE) in 30 patients of osteoarthritis of the knee, 15 each receiving active drug or placebo for eight weeks. After the first intervention, washout was given and then the groups were crossed over to receive the opposite intervention for eight weeks. All patients receiving drug treatment reported a decrease in knee pain, increased knee flexion and increased walking distance. The frequency of swelling in the knee joint was decreased. Radiologically there was no change. The observed differences between drug-treated and placebo being statistically significant, are clinically relevant. BSE was well tolerated by the subjects except for minor gastrointestinal ADRs. BSE is recommended in the patients of osteoarthritis of the knee with possible therapeutic use in other arthritis.
Source: N. Kimmatkara, V. Thawanib, L. Hingoranic, R. Khiyanid. “Efficacy and tolerability of Boswellia serrata extract in the treatment of osteoarthritis of knee – A randomized double-blind placebo-controlled trial” Phytomedicine (2003): V10, Issue 1; P3-7.
Objective: The aim of this randomized controlled study was to evaluate the efficacy of oral native type II collagen treatment on the symptoms and biological markers of cartilage degradation, when given concomitantly with acetaminophen in patients with knee osteoarthritis.
Materials and Methods: Thirty-nine patients diagnosed with knee osteoarthritis were included and randomly distributed into two groups: one treated with 1500 mg/day of acetaminophen (group AC; n=19) and the other treated with 1500 mg/day of acetaminophen plus 10 mg/day of native type II collagen (group AC+CII; n=20) for 3 months. Visual Analogue Scale (VAS) at rest and during walking, Western Ontario McMaster (WOMAC) pain, WOMAC function, and Short Form-36 (SF-36) scores, were recorded. Coll2-1, Coll2-1NO2 and Fibulin-3 levels were quantified in urine as biomarkers of disease progression. ClinicalTrials.gov: NCT02237989.
Results: After 3 months of treatment, significant improvements compared to baseline were reported in joint pain (VAS walking), function (WOMAC) and quality of life (SF-36) in the AC+CII group, while only improvements in some subscales of the SF-36 survey and VAS walking were detected in the AC group. Comparisons between the groups revealed a significant difference in VAS walking score in favour of the AC+CII group as compared to AC group. Biochemical markers of cartilage degradation in urine did not significantly improve in any of the groups.
Conclusion: All in all, these results suggest that native type II collagen treatment combined with acetaminophen is superior to only acetaminophen for symptomatic treatment of patients with knee osteoarthritis.
Source: Fulya Bakilan, Onur Armagan, Merih Ozgen, Funda Tascioglu, Ozge Bolluk, and Ozkan Alatas. “Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial” The Eurasian Journal of Medicine (2016): 48(2): 95–101.
Rheumatoid arthritis is an inflammatory synovial disease thought to involve T cells reacting to an antigen within the joint. Type II collagen is the major protein in articular cartilage and is a potential autoantigen in this disease. Oral tolerization to autoantigens suppresses animal models of T cell-mediated autoimmune disease, including two models of rheumatoid arthritis. In this randomized, double-blind trial involving 60 patients with severe, active rheumatoid arthritis, a decrease in the number of swollen joints and tender joints occurred in subjects fed chicken type II collagen for 3 months but not in those that received a placebo. Four patients in the collagen group had complete remission of the disease. No side effects were evident. These data demonstrate the clinical efficacy of an oral tolerization approach for rheumatoid arthritis.
Source: Trentham, David E., et al. “Effects of oral administration of type II collagen on rheumatoid arthritis.” Science 261.5129 (1993): 1727-1730.
The developmental sequence of the embryonic joint has been well studied morphologically. There are, however, no definitive studies of cell function during joint development. In order to begin to understand the differentiation events that contribute to the joint formation, we examined the expression of collagen mRNAs encoding types I, IIA, IIB, and XI. In situ hybridization was performed on chicken embryo hind limb buds and digits from day 7 to day 18 (Hamburger and Hamilton stage 31–44). In the day 7 (stage 31) limb bud, there was a condensation of mesenchyme forming the primitive tarsal and metatarsal bones that showed abundant expression of type IIA procollagen message, but no type IIB or type α1(XI) message. By day 8 (stage 33), co‐expression of types IIA, and type XI procollagen mRNAs was observed in the condensations, with an expression of IIB restricted to early chondrocytes with a metachromatically staining matrix. At this stage, DNA fragmentation characteristic of apoptosis was observed in cells near the midline of the Interzone region between the developing anlagen, and in areas between and around the individual digits of the paddle. The presumptive apoptotic cells were more numerous at day 9 (stage 35), and were not found in the developing joint at subsequent time points, including the initiation of spatial cavitation of the joint. From days 11–18, type IIA procollagen mRNA was expressed in flattened cells at the surface of the anlagen, and in the perichondrium and in the developing joint capsule; type IIB mRNA message was found only in chondrocytes. Type XI mRNA was expressed by all type II‐expressing cells. Alpha 1(I) mRNA was expressed early by cells of the Interzone and capsule, but as cavitation progressed, the type I expressing cells of the Interzone merged with the superficial layer of the articular surface. Thus, at the time of joint cavitation, there was a distinct pattern of expression of procollagen messages at the articular surface, with type I being outermost, followed by morphologically similar cells expressing type IIA, then chondrocytes expressing type IIB. The progenitor cells expressing type IIA message define a new population of cells. These cell populations contribute to the molecular heterogeneity of the articular cartilage, and these same populations likely exist in the developing joints of other species. The transient transcription of type II and type XI collagen genes, characteristic of chondrocytes, by cells in the joint capsule demonstrates that these cells may have chondrogenic potential.
Source: Nalin, Andrew M., Theodore K. Greenlee Jr, and Linda J. Sandell. “Collagen gene expression during development of avian synovial joints: transient expression of types II and XI collagen genes in the joint capsule.” Developmental dynamics 203.3 (1995): 352-362.
Hyaluronan (HA) is a component that is particularly abundant in the synovial fluid. Randomized, double-blinded, placebo-controlled trials carried out between 2008 and 2015 have proven the effectiveness of HA for the treatment of symptoms associated with synovitis, and particularly, knee pain, relief of synovial effusion or inflammation, and improvement of muscular knee strength. The mechanism by which HA exerts its effects in the living body, specifically receptor binding in the intestinal epithelia, has gradually been clarified. This review examines the effects of HA upon knee pain as assessed in clinical trials, as well as the mechanism of these effects and the safety of HA.
Source: Mariko Oe, Toshiyuki Tashiro, Hideto Yoshida, Hiroshi Nishiyama, Yasunobu Masuda, Koh Maruyama, Takashi Koikeda, Reiko Maruya, Naoshi Fukui. Nutrition Journal (2016): 15: 11.
OBJECTIVES–It has been shown previously that hyaluronic acid (HA) has an analgesic action on bradykinin induced pain in the knee joints of rats. This study further clarifies the effects of the molecular weight of HA and its mechanism of action in the same model using HA of molecular weight 800 to 2.3 x 10(6) daltons and a bradykinin antagonist. METHODS–Bradykinin and the test HA preparations were given to rats by intra-articular injection, and the severity of pain was evaluated by a change in the walking behaviour. RESULTS–HA with a molecular weight greater than 40 kilodaltons produces analgesic effects with a simultaneous or earlier injection. The ID50 values of HA with molecular weight 40, 310, 860, and 2300 kilodaltons were greater than 2.5, 0.6, 0.07, and 0.06 mg/joint respectively. The duration of the analgesic effect of 860 and 2300 kilodalton HA was 72 hours at 10 mg/ml, whereas that of 310 kilodalton HA was short, being undetectable after 24 hours. The analgesic action of HA of 860 kilodaltons was not changed by pretreatment with four saccharide HA and inhibited by pretreatment with HA larger than six to eight saccharides, capable of binding to HA receptors. Further, HA did not interfere with the analgesic action of the bradykinin antagonist, indicating that HA does not directly bind with bradykinin receptors. CONCLUSIONS–HA with a molecular weight of greater than 40 kilodaltons produced an analgesic effect, and HA of 860 and 2300 kilodaltons produced high and long-lasting analgesia. These effects of HA appear to be caused by the interaction between HA and HA receptors.
Source: S. Gotoh, J. Onaya, M. Abe, K. Miyazaki, A. Hamai, K. Horie, K. Tokuyasu. “Effects of the molecular weight of hyaluronic acid and its action mechanisms on experimental joint pain in rats” Annals of the Rheumatic Diseases (1993): 52:817-822.
Osteoarthritis is a critical disease that comes from the degeneration of cartilage tissue. In severe cases, surgery is generally required. Tissue engineering using scaffolds with stem cell transplantation is an attractive approach and a challenge for orthopedic surgery. For sample preparation, silk fibroin (SF)/hyaluronic acid (HA) scaffolds in different ratios of SF/HA (w/w) (i.e., 100:0, 90:10, 80:20, and 70:30) were formed by freeze-drying. The morphological, mechanical, and physical clues were considered in this research. The morphological structure of the scaffolds was observed by a scanning electron microscope. The mechanical and physical properties of the scaffolds were analyzed by compressive and swelling ratio testing, respectively. For the cell experiments, scaffolds were seeded and cultured with human umbilical cord-derived mesenchymal stem cells (HUMSCs). The cultured scaffolds were tested for cell viability, histochemistry, immunohistochemistry, and gene expression. The SF with HA scaffolds showed regular porous structures. Those scaffolds had a soft and elastic characteristic with a high swelling ratio and water uptake. The SF/HA scaffolds showed a spheroid structure of the cells in the porous structure particularly in the SF80 and SF70 scaffolds. Cells could express Col2a, Agg, and Sox9 which are markers for chondrogenesis. It could be deduced that SF/HA scaffolds showed significant clues for suitability in cartilage tissue engineering and in surgery for osteoarthritis.
Source: Jirayut Jaipaew et. al., Mimicked cartilage scaffolds of silk fibroin/hyaluronic acid with stem cells for osteoarthritis surgery: Morphological, mechanical, and physical clues. Materials Science and Engineering: C. July 1, 2016: V64, P173-182. doi:10.1016/j.msec.2016.03.063
Introduction: The objective of this study was to determine the anti-inflammatory, nociceptive, and antiarthritic effects of piperine, the active phenolic component in black pepper extract.
Methods: The in vitro anti-inflammatory activity of piperine was tested on interleukin 1β (IL1β)-stimulated fibroblast-like synoviocytes derived form patients with rheumatoid arthritis. The levels of IL6, matrix metalloproteinase (MMPs), cyclo-oxygenase 2 (COX-2), and prostaglandin E2 (PGE2) were investigated by ELISA and RT-PCR analysis. The analgesic and antiarthritic activities of piperine were investigated on rat models of carrageenan-induced acute paw pain and arthritis. The former were evaluated with a paw pressure test, and the latter by measuring the squeaking score, paw volume, and weight distribution ratio. Piperine was administrated orally to rats at 20 and 100 mg/kg/day for 8 days.
Results: Piperine inhibited the expression of IL6 and MMP13 and reduced the production of PGE2 in a dose dependant manner at concentrations of 10 to 100 μg/ml. In particular, the production of PGE2 was significantly inhibited even at 10 μg/ml of piperine. Piperine inhibited the migration of activator protein 1 (AP-1), but not nuclear factor (NF)κB, into the nucleus in IL1β-treated synoviocytes. In rats, piperine significantly reduced nociceptive and arthritic symptoms at days 8 and 4, respectively. Histological staining showed that piperine significantly reduced the inflammatory area in the ankle joints.
Conclusions: These results suggest that piperine has anti-inflammatory, antinociceptive, and antiarthritic effects in an arthritis animal model. Thus, piperine should be further studied with regard to use either as a pharmaceutical or as a dietary supplement for the treatment of arthritis.
Source: Jun Soo Bang, Da Hee Oh, Hyun Mi Choi, Bong-Jun Sur, Sung-Jig Lim, Jung Yeon Kim, Hyung-In Yang, Myung Chul Yoo, Dae-Hyun Hahm, and Kyoung Soo Kim. “Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models” Arthritis Research and Therapy (2009): 11(2): R49.
A dietary supplement for nutritionally promoting healthy joint function in human subjects is disclosed. The supplement includes as a major ingredient a protein derived from the enzymatic hydrolysis of collagen in combination with lesser proportions of glucosamine sulfate, ginkgo biloba, borage oil powder, turmeric, Boswellia Serrata, ashwagandha, piper nigrum extract, and an herbal blend.
Source: Hastings, Carl W., David J. Barnes, and Christine A. Daley. “Dietary supplement for nutritionally promoting healthy joint function.” U.S. Patent No. 6,224,871. 1 May 2001.
BioPerine® has been found to enhance the gastrointestinal absorption of nutrients by at least 30% in a double-blind and in vivo studies. BioPerine® has been clinically tested with several nutrient groups, including fat-soluble vitamins (ß-carotene), water-soluble vitamins (vitamin B6, vitamin C), curcumin, coenzyme Q10. It was shown to significantly enhance the bioavailability of these supplemented nutrients through increased gastrointestinal absorption. Studied nutrients were measured by amounts present in the blood when administered with BioPerine® as compared to the control group receiving the above nutrients alone.
Source: Javaid, Nadia. “BioPerine, Absorption & Bioavailability.”
Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa) that has been associated with antioxidant, anti-inflammatory, anticancer, antiviral, and antibacterial activities as indicated by over 6,000 citations. In addition, over one hundred clinical studies have been carried out with curcumin. One of the major problems with curcumin is perceived to be the bioavailability. How curcumin should be delivered in vivo, how bioavailable is it, how well curcumin is absorbed and how it is metabolized, is the focus of this review. Various formulations of curcumin that are currently available are also discussed.
Piperine Besides these natural compounds have been also used to increase the bioavailability of curcumin. One of them is piperine, a major component of black pepper, known as inhibitor of hepatic and intestinal glucuronidation and is also shown to increase the bioavailability of curcumin. This effect of piperine on the pharmacokinetics of curcumin has been shown to be much greater in humans than in rats. In humans, curcumin bioavailability was increased by 2,000% at 45 minutes after co-administering curcumin orally with piperine, whereas in rats, it has been found that concomitant administration of piperine 20 mg/kg with curcumin 2 g/kg increased the serum concentration of curcumin by 154% for a short period of 1-2 hours post drug. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects [95].
Another study also showed that piperine (20 mg/kg orally) when administered with curcumin (2 g/kg orally) enhances the bioavailability of the latter up to 20-fold more in epileptic rats [111]. Enhanced bioavailability of curcumin was also evidenced by other researcher when curcumin was administered orally concomitant with piperine. Intestinal absorption of curcumin was also found relatively higher when administered concomitantly with piperine, and it stayed significantly longer in the body tissues [112]. In view of these findings, curcumin-piperine (Cu-Pi) nanoparticles has been prepared by various methods [113]. The bioavailability, cellular uptake and biological effects of this nanoparticles are being tested.
Source: Sahdeo Prasad, PhD, Amit K. Tyagi, PhD, and Bharat B. Aggarwal, PhD. “Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice” Cancer Research and Treatment (2014): 46(1): 2–18.