Collagen Type II (Joint)

OBJECTIVE: To investigate the efficacy and safety of dietary supplements for patients with osteoarthritis. DESIGN: An intervention systematic review with random effects meta-analysis and meta-regression. DATA SOURCES: MEDLINE, EMBASE, Cochrane Register of Controlled Trials, Allied and Complementary Medicine and Cumulative Index to Nursing and Allied Health Literature were searched from inception to April 2017. STUDY ELIGIBILITY CRITERIA: Randomised controlled trials comparing oral supplements with placebo for hand, hip or knee osteoarthritis. RESULTS: Of 20 supplements investigated in 69 eligible studies, 7 (collagen hydrolysate, passion fruit peel extract, Curcuma longa extract, Boswellia serrata extract, curcumin, pycnogenol and L-carnitine) demonstrated large (effect size >0.80) and clinically important effects for pain reduction at short term. Another six (undenatured type II collagen, avocado soybean unsaponifiables, methylsulfonylmethane, diacerein, glucosamine and chondroitin) revealed statistically significant improvements on pain, but were of unclear clinical importance. Only green-lipped mussel extract and undenatured type II collagen had clinically important effects on pain at medium term. No supplements were identified with clinically important effects on pain reduction at long term. Similar results were found for physical function. Chondroitin demonstrated statistically significant, but not clinically important structural improvement (effect size -0.30, -0.42 to -0.17). There were no differences between supplements and placebo for safety outcomes, except for diacerein. The Grading of Recommendations Assessment, Development and Evaluation suggested a wide range of quality evidence from very low to high. CONCLUSIONS: The overall analysis including all trials showed that supplements provided moderate and clinically meaningful treatment effects on pain and function in patients with hand, hip or knee osteoarthritis at short term, although the quality of evidence was very low. Some supplements with a limited number of studies and participants suggested large treatment effects, while widely used supplements such as glucosamine and chondroitin were either i

The in vivo effect of platelet-rich plasma (PRP) on supraspinatus tendon morphology and subacromial bursa cell gene expression in degenerative rotator cuff tears remains unclear. This randomized controlled trial evaluated the effect of preoperative leukocyte-poor PRP (LP-PRP) subacromial injection on supraspinatus tendon histology and subacromial bursa gene expression. Sixteen patients with full-thickness supraspinatus tears were randomized to receive an ultrasound-guided LP-PRP injection (n = 8) or no injection (n = 8) six weeks before arthroscopic repair. Tendon biopsies were assessed using the modified Movin score. Gene expression of collagen type I, II and III, metalloproteinase 3 and 13, and interleukin 1β and 6 genes from subacromial bursa cells was quantified using quantitative real-time PCR. The results of the two groups were compared to determine any statistically significant difference regarding all the examined parameters. The PRP group demonstrated a significantly lower total modified Movin score than controls (6.5 vs. 12.1, p = 0.002), with lower scores for fiber structure, fiber arrangement, nuclear rounding, inflammation and cell density (all p < 0.003), while angiogenesis did not differ (p = 0.149), indicating an architecture closer to that of normal tendon. No statistically significant differences in gene expression were observed (all p > 0.05), although collagen II and metalloproteinase 3 and 13 showed biologically relevant downregulation [fold change 0.23 (95%CI 0.05-1.09), 0.24 (95%CI 0.002-26.10), and 0.26 (95%CI 0.02-2.76), respectively]. The LP-PRP injection was associated with improved supraspinatus tendon histological characteristics and biologically relevant reductions in selected bursal genes, in the setting of supraspinatus tendon tear.

Impact and resistance exercise have potent osteogenic effects and may positively affect cartilage through tissue deformation. These effects may be mediated through inhibitors of Wnt signaling, such as sclerostin and Dickkopf WNT signaling pathway inhibitor 1 (DKK1), which may also play a role in cartilage metabolism. This study evaluated the effect of acute bouts of impact and resistance exercise on biomarkers of bone turnover, signaling, and cartilage metabolism. Healthy young men completed impact or resistance exercise and a control trial in random order. Impact exercise involved 120 maximum-effort multidirectional jumps and hops. Resistance exercise involved 120 high load lower limb lifts. Jumps and lifts were interspersed with 1-3 s pauses. In control trial, participants rested in a supine position for same duration as exercise trial. Blood samples were taken before, immediately, and 24 h post-exercise/rest and analyzed for sclerostin, DKK1, C-terminal telopeptide of type I collagen (CTX-I), procollagen I N-terminal propeptide (PINP), procollagen II C-terminal propeptide (PIICP), and cartilage oligomeric matrix protein. Repeated measures ANOVA compared time points, trials, and their interaction. Participants were 26 men, mean (SD) age 23.4 (2.9) yr. Impact exercise increased PINP immediately post-exercise (by mean [95% CI] + 10.8[4.8, 17.2]%, p = .002) and 24 h later (+7.4 [0.0, 15.3]%, p = .05), whereas resistance exercise had no effect. A transient increase in sclerostin immediately post-exercise occurred in the impact exercise trial only (+36.3 [24.6, 49.3]%, p < .001). Both exercise modes transiently increased DKK1 immediately post-exercise (impact +32.4 [23.1, 42.4]%, p < .001; resistance +30.3 [22.8, 38.4]%, p < .001). Cartilage oligomeric matrix protein increased immediately after resistance exercise only (+36.2 [16.0, 59.8]%, p < .001). Neither form of exercise affected CTX-I. Impact and resistance exercise transiently increased Wnt signaling inhibitors. Resistance exercise increased a marker of cartilage turnover but did not affect markers of bone turnover. Impact exercise did not affect cartilage turnover markers. Increases in bone formation but no

Osteoarthritis (OA) is a prevalent degenerative joint disease, often affecting the elderly, characterized by cartilage degradation and bone remodelling, leading to pain, stiffness, and impaired movement. This 12-week, randomized, double-blind, placebo-controlled pilot study investigated the efficacy of a formulation containing collagen type II, glucosamine hydrochloride and chondroitin sulfate, in alleviating knee OA symptoms in subjects with mild to moderate knee pain. Fifty-four participants were enrolled, with 52 completing the study. Participants were assessed using the Knee injury and Osteoarthritis Outcome Score (KOOS), performance-based physical function tests and global assessment tests. Results indicated significant improvements in the verum group compared to placebo. KOOS subscales showed improvements in symptoms (8.16%, p < 0.05), sport/recreation (25.25%, p < 0.01), and quality of life (27.66%, p < 0.001). Stiffness improved by 14.68% (p < 0.05) in the verum group. Both groups exhibited significant pain reduction (KOOS pain, p < 0.001 and p < 0.01 for verum and placebo, respectively). Performance-based measures, such as the Chair Stand test, improved significantly in both groups, though other metrics showed no significant differences. The verum group exhibited a linear improvement over 12 weeks, contrasting with the placebo group's initial response and subsequent plateau. SF-36 Physical Component scores improved in both groups (p < 0.05), but mental health scores remained unchanged. Global assessment favoured the verum group, with more participants reporting OA improvement and recommending the product (p < 0.01). Biomarkers hsCRP and COMP showed no significant changes, likely due to sample variability. While the study did not achieve its primary endpoint, the nutritional formulation demonstrated an excellent safety profile and encouraging improvements in patient-reported symptoms and quality of life, warranting larger confirmatory trials.Registration number: DRKS00029563 05/10/2022. © 2025. The Author(s).

INTRODUCTION: Current strategies for treating osteoarthritis (OA) are based on a multimodal approach that includes pharmacological and non-pharmacological methods. Undenatured chicken collagen type II (NK2) is considered safe and effective for maintaining joint health and can be used alone and combined with drugs for OA treatment. AIM: To further evaluate the efficacy of the combination of Artneo containing NK2 in patients with stage III knee OA compared with placebo in a multicenter, prospective, double-blind, placebo-controlled, randomized trial. MATERIALS AND METHODS: The study included 212 patients from 12 centers in the Russian Federation, of whom 50 had radiological stage III knee OA: 41 (82.0%) females and 9 (18.0%) males aged 44 to 75. Using the interactive web response system (IWRS), the study population was randomized into two groups: Group 1 (Artneo group) included 28 patients receiving the drug 1 capsule once a day for 180 days, Group 2 (placebo group) included 22 patients receiving placebo with drug-matched presentation and the same regimen as in Group 1. The effectiveness of therapy was assessed by the change of pain using the Visual Analog Scale, the WOMAC index, KOOS, the EQ-5D quality of life questionnaire, and the need for non-steroidal anti-inflammatory drugs. All patients had a complete blood count, urinalysis, blood chemistry, and ultrasonic examination of the target knee joint. RESULTS: A prospective, double-blind, placebo-controlled, randomized trial demonstrated that Artneo containing NK2 was significantly superior to placebo in all studied parameters, improved all clinical manifestations of OA: reduced pain and stiffness, improved joint function and quality of life, and had a good safety profile. CONCLUSION: Artneo showed high efficacy and safety in the general population of patients, including those with stage III knee OA. Publisher: Введение. Современные стратегии терапии остеоартрита (ОА) основаны на мультимодальном подходе, который включает фармакологические и нефармакологические методы. Неденатурированный куриный коллаген II типа (НК2) рассматривается как безопасное и эффективное средство для поддержания здоровья суставов, которое

BACKGROUND: Osteoarthritis is the prevailing form of inflammatory condition in joints of adults and the aging population, leading to long-term disability and chronic pain. Current therapeutic options have variable therapeutic efficacy and/or several side effects. METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted in 62 participants using a nutraceutical [standardized Boswellia serrata Roxb. gum resin (300 mg) and Apium graveolens L. seed extract (250 mg)], to determine its safety and efficacy for supporting cartilage health and reduction in knee osteoarthritis symptoms. All participants were assessed for physical function and pain with the help of WOMAC, VAS, Physicians' Global Assessment for the six-minute walk test/pain. Knee X-ray, KOOS questionnaire score, and FACIT-F score were assessed. Additionally, inflammatory, cartilage degeneration and regeneration biomarkers in serum and urine were evaluated at baseline and after 90 days of treatment. RESULTS: Oral administration of the nutraceutical resulted in prolonged symptomatic relief with reduced pain, stiffness, and swelling. Inflammatory (serum IL-7, IL-1, IL-6, hs-CRP, TNF-α, ESR) and cartilage degeneration biomarkers (serum CTX-II, COMP, MMP-3 and urinary CTX-II) were decreased in the nutraceutical group compared to baseline and placebo. Furthermore, serum N-propeptide of collagen IIA (PIIANP) and procollagen-type-C propeptide (PIICP) levels were increased in the nutraceutical group, suggesting collagen synthesis contributing to cartilage regeneration. At given doses for 90 days, there were no adverse effects based on the clinical examination, biochemical, hematological, and ECG analysis. CONCLUSIONS: Taken together, the combination of Boswellia and celery could be a safe and promising herbal nutraceutical option for managing osteoarthritis and cartilage health effectively. © 2025. The Author(s).

BACKGROUND: Menisci, one of the most important anatomical structures of the knee joint, plays a role in load transfer, stability, shock absorption, prevention of articular cartilage degeneration, and proprioception. Type I collagen, the main component of the meniscus, and type II collagen fibers play an important role in the stability of the knee joint. This study aimed to evaluate the effects of Naturagen® 4 Joint product containing type I, II, and III collagen on pain, quality of life, and physical functions in patients with meniscopathy. METHODS: This randomized, double-blind, placebo-controlled clinical study included 32 patients (collagen = 17 and placebo = 15) with meniscopathy. Patients completed the Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthrtis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS), Oxford Knee Score (OKS), Tampa Scale for Kinesiophobia (TSK), Short Form Health Survey (SF-12), Lower Extremity Functional Scale (LEFS), Foot Function Index (FFI), proprioceptive sensation, Timed Up and Go (TUG), 6-Minute Walking Test (6MWT), The Five Repetition Sit to Stand Test (5STS), Stair Climbing Test (SCT), Berg Balance Scale (BBS) and back and leg strength tests and scales were applied. All tests were repeated before and after eight weeks of collagen supplementation. RESULTS: The study showed that eight weeks of supplementation with various collagen types had statistically significant effects on pain, quality of life, kinesiophobia, and foot function scale scores in patients with meniscopathy (p < 0.05). Similarly, eight weeks of supplementation showed a statistically significant difference in leg strength (p = 0.057), but no significant difference was found in back strength, proprioception, balance, and various functional test results (p > 0.05). CONCLUSIONS: The results of the study showed that the eight-week collagen-based supplement had a positive effect on pain and quality of life levels and some functional test results in patients with meniscopathy. Longer-term studies and diversification of subject groups will help to understand better the effects of the product on

OBJECTIVES: The aim of this study was to assess the effect of Naturagen® 4 Joint product, containing type 1, 2, and 3 collagen, on pain associated with osteoarthritis (OA) and to evaluate its effects on quality of life and physical functioning. PATIENTS AND METHODS: This double-blind, randomized, placebo-controlled clinical study included a total of 31 patients (8 males, 23 females; mean age: 53.5±9.1 years; range, 35 to 65 years) with Grade 2-3 OA according to the Kellgren-Lawrence (KL) classification system between June 2023 and November 2023. The patients were divided into two groups: a collagen group (n=16) and a placebo group (n=15). The Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS-PS), Oxford Knee Score (OKS), Tampa Scale for Kinesiophobia (TSK), Short Form Health Survey (SF-12), Foot Function Index (FFI), Timed Up and Go (TUG), 6-Min Walking Test (6MWT), Five Repetition Sit to Stand Test (5STS), Stair Climbing Test (SCT), and Berg Balance Scale (BBS) were used. All tests were performed before and after eight weeks of collagen supplementation. RESULTS: Eight weeks of collagen supplementation yielded notable enhancements across all osteoarthritis-related pain and quality of life scales evaluated, including VAS, WOMAC, KOOS-PS, OKS, TSK, SF-12, and FFI scores (p<0.05). In functional evaluations, there were significant positive effects of collagen use in BBS and 6MWT results (p<0.05). In TUG, 5STS, and SCT tests, no significant difference was found between the groups (p>0.05). CONCLUSION: Our study results suggest that the eight-week collagen-based supplement exerts a favorable effect on pain and quality of life levels, as well as some functional test results.

BACKGROUND AND OBJECTIVE: Boswellia serrata Roxb. ex Colebr. (Family: Burseraceae; Genus: Boswellia) gum resin (Salai guggul) has profound therapeutic value in Ayurvedic and Unani medicines in alleviating several chronic inflammatory illnesses, including arthritis, asthma, skin and blood diseases, fever, etc. SN13108F (Aflapin®) is a proprietary, standardized Boswellia serrata gum resin extract. This 180-day randomized, placebo-controlled clinical study aimed to evaluate cartilage morphology using magnetic resonance imaging (MRI), pain and joint function and long-term safety in the SN13108F-supplemented volunteers with knee osteoarthritis (KOA). MATERIALS AND METHODS: Eighty adult male and female subjects with the Kellgren-Lawrence grade II - III KOA were supplemented with SN13108F (100 mg/day) or a matched placebo for 180 consecutive days. RESULTS: SN13108F reduced (p < 0.001; vs. baseline and placebo) Western Ontario and McMaster Universities Osteoarthritis Index, Visual Analogue Scale, Lequesne's Functional Index scores, improved six-minute walk test, and stair climb test. Post-trial MRI assessments of the tibiofemoral joints revealed that the cartilage volume, thickness, and joint space width were increased (p < 0.001; vs. placebo), and levels of high-sensitivity C-reactive protein, matrix metalloproteinase-3, Fibulin-3, type II collagen degradation peptide in serum, and cross-linked C-terminal telopeptide of type II collagen in urine were significantly reduced (p < 0.001; vs. baseline and placebo) in the SN13108F-supplemented subjects. Hematology, complete serum biochemistry, urine analysis, and the participants' vital signs did not alter between the groups. CONCLUSION: SN13108F supplementation is safe, and it mitigates joint pain and improves musculoskeletal function and cartilage morphology in KOA.

BACKGROUND: Non-pharmacological treatments based on collagen as a dietary supplement are emerging as a new area of interest to support preventive or therapeutic effects in patients with osteoarthritis (OA). AIM: In a multicenter, prospective, double-blind, placebo-controlled, randomized study, to evaluate the effectiveness and safety of the use of the Artneo complex containing undenatured chicken collagen type II in patients with OA of the knee joints. MATERIALS AND METHODS: The study enrolled 212 outpatients from 12 centers in the Russian Federation with knee OA, stages II and III according to the Kellgren-Lawrence classification. The participants included 171 women (80.7%) and 41 men (19.3%), with an average age of 60.2±9.0 years (range: 40 to 75 years). The study population was randomly allocated in equal proportions into two groups using an interactive web response system (IWRS). Group 1 (Artneo) consisted of 106 patients who took one capsule of the drug once daily for 180 days. Group 2 (Placebo) also had 106 patients, with the dosage form and regimen identical to Group 1. During the treatment period, the following outcomes were assessed: WOMAC index, KOOS, pain according to VAS, quality of life using the EQ-5D questionnaire, and the need for NSAIDs. All patients underwent a clinical blood test, general urine analysis, biochemical blood test, and ultrasound examination of the affected knee joint. RESULTS: In a prospective, double-blind, placebo-controlled, randomized study, it was demonstrated that the Artneo combination, containing undenatured chicken collagen type II, has a positive effect on all clinical manifestations of OA: it effectively reduces pain, stiffness, and improves the functional state of joints and quality of life. It has a good safety profile and is superior to placebo in all parameters studied. CONCLUSION: The results of the study confirm the good effectiveness and safety of the Artneo combination in patients with OA of the knee joints. Publisher: Обоснование. Немедикаментозные методы лечения, основанные на приеме коллагена в качестве биологически активной добавки, позиционируют как новый объект интереса для поддержки профилактического ил

AIM: To evaluate the efficacy of Artneo (AN) in comparison with a combination of glucosamine hydrochloride and chondroitin sulfate (GC) in patients with osteoarthritis (OA) of the knee joint (KJ). MATERIALS AND METHODS: 70 patients with stages I-III of primary knee OA were randomized into 2 groups. Participants in the 1st (n=35) took AN 1 caps/day, in the 2nd (n=35) GC according to the standard regimen. After 7, 30, 90, 180 days, the Lequesne index (severity of OA), pain when moving according to VAS, WOMAC score were assessed, after 1, 3, 6 months - quality of life SF-36 and morning stiffness, after 6 months - MRI with T2 mapping, laboratory safety indicators. RESULTS: Over the course of 6 months of use, an improvement in the WOMAC index and a decrease in pain were observed without intergroup differences, and a greater decrease in stiffness in the AN group. After 3 months, the severity of OA decreased from moderate to mild in the AN group and was significantly lower compared to the GC group; quality of life (physical component of SF-36) was higher in the AN group. After 6 months, there was an improvement in cartilage ultrastructure (T2 relaxation time) in both groups and a more pronounced reduction of the synovitis area (MRI) in the AN group (2.95 and 1.37 times in the AN and GC group, respectively). There were no clinically significant adverse reactions observed in both groups. CONCLUSION: The use of AN in patients with stage I-III primary knee OA was not inferior in efficacy to the combination of GC. Further studies with greater statistical power (sample size) and follow-up period are warranted including in real clinical practice. Publisher: Цель. Оценить эффективность Артнео (АН) в сравнении с комбинацией глюкозамина гидрохлорида и хондроитина сульфата (ГХ) у больных остеоартритом (ОА) коленного сустава (КС). Материалы и методы. В исследовании 70 пациентов с I–III стадиями первичного ОА КС рандомизированы на 2 группы. В 1-й (n=35) группе участники принимали АН по 1 капсуле в сутки, во 2-й (n=35) – ГХ по стандартной схеме. Через 7, 30, 90, 180 дней оценивали индекс Лекена (тяжесть ОА), боль при движении по Визуальной аналоговой шкале, индекс WOMAC, через 1, 3

The current work aimed to examine the properties of oral supplementation of niacinamide and undenatured type II collagen (UCII) on the inflammation and joint pain behavior of rats with osteoarthritis (OA). Forty-nine Wistar rats were allocated into seven groups; control (no MIA), MIA as a non-supplemental group with monosodium iodoacetate (MIA)-induced knee osteoarthritis, MIA + undenatured type II collagen (UCII) at 4 mg/kg BW, MIA + Niacinamide at 40 mg/kg BW (NA40), MIA + Niacinamide at 200 mg/kg BW (NA200), MIA + UCII + NA40 and MIA + UCII + NA200. Serum IL-1β, IL-6, TNF-α, COMP, and CRP increased in rats with OA and decreased in UCII and NA groups (p < 0.05). Rats with osteoarthritis had greater serum MDA and knee joint MMP-3, NF-κB, and TGβ protein levels and decreased in treated groups with UCII and NA (p < 0.05). The rats with OA also bore elevated joint diameters with joint pain behavior measured as decreased the stride lengths, the paw areas, and the paw widths, and increased the Kellgren-Lawrence and the Mankin scores (p < 0.05) and decreased in UCII treated groups. These results suggest the combinations with the UCII + NA supplementation as being most effective and reduce the inflammation responses for most OA symptoms in rats. © 2021. The Author(s).

BACKGROUND: Osteoarthritis (OA) is a common worldwide disease induced by a wide range of biochemical processes, mainly inflammation and degradation of collagen. The aim of this study, was to describe the effect of a multistrain probiotic (PB) and chondroitin sulfate (CS), administered separately or in combination, on the expression of Ptgs2, Tgfb1 and Col2a1 during monoiodoacetate-induced OA in male rats. METHODS: OA was induced in male rats by injecting monoiodoacetate in right hind knee. Therapeutic groups received 3 mg/kg of CS for 28 days and/or 1.4 g/kg of multistrain PB for 14 days. Knee cartilage were taken 30 days after monoiodoacetate injection. RNA was extracted and the expression of Ptgs2, Tgfb1 and Col2a1 were analyzed using SYBR Green 1-step real-time quantitative polymerase chain reaction. RESULTS: Induction of OA caused an upregulation in Ptgs2, Tgfb1 expression, and downregulation of Col2a1. Separate administration of PB and CS reduced Ptgs2 and Tgfb1 expressions. Their combined administration significantly decreased the expression of these pro-inflammatory cytokines, comparable to controls. Expression of Col2a1 showed similar behavior, with upregulation in therapeutic group with separate administration and the cumulative effects in case of co-administration. CONCLUSIONS: The multistrain PB diet may offer a perspective to improve the standard treatment of OA and, necessitates further investigation with clinical trials.

Liver fibrosis is a common pathological response to chronic hepatic injury. STAT3 is actively involved in the fibrogenesis and angiogenesis seen in liver fibrosis. S3I-201 (NSC 74859) is a chemical inhibitor of STAT3 activity, which blocks the dimerization of STAT3, STAT3-DNA binding and transcription activity. This study evaluated the effects of S3I-201 against liver fibrosis. S3I-201 inhibited the proliferation, migration, and actin filament formation in primary human hepatic stellate cells (HSCs), as well as the expression of α-SMA, collagen I and TIMP1 in both primary HSC and in a CCl4-induced fibrosis mouse model. S3I-201 induced both apoptosis and cell cycle arrest in the HSC cell line (LX-2). S3I-201 inhibited the expression of fibrogenesis factors TGFβ1 and TGFβRII, as well as the downstream phosphorylation of Smad2, Smad3, Akt and ERK induced by TGFβ1. In addition to fibrogenesis, both in vitro and in vivo assays showed that S3I-201 inhibited angiogenesis through expression suppression of VEGF and VEGFR2. Moreover, S3I-201 also had a synergistic effect with sorafenib, an FDA approved liver cancer drug, in the proliferation, apoptosis, angiogenesis and fibrogenesis of HSC. S3I-201 suppressed liver fibrosis through multiple mechanisms, and combined with sorafenib, S3I-201 could be a potentially effective antifibrotic agent.

Cross-linked hyaluronic acid hydrogel (cHA gel) and dexamethasone (Dex) have been used to treat knee osteoarthritis (OA) in clinical practice owing to their chondroprotective and anti-inflammatory effects, respectively. The aim of the present study was to compare the treatment effects of the cHA gel pre-mixed with/without Dex in a surgery-induced osteoarthritis model in rats. Anterior cruciate ligament transection (ACLT) surgery was performed on the right knee of rats to induce OA. Male 2-month-old Sprague-Dawley rats were randomly divided into five groups (n = 10/per group): (1) ACLT + saline; (2) ACLT + cHA gel; (3) ACLT + cHA-Dex (0.2 mg/mL) gel; (4) ACLT + cHA-Dex (0.5 mg/mL) gel; (5) Sham + saline. Intra-joint injections were performed four weeks after ACLT in the right knee. All animals were euthanized at 12 weeks post-surgery. Cartilage damage and changes in the synovial membrane were assessed by micro X-ray, Indian ink articular surface staining, Safranin-O/Fast Green staining, immunohistochemistry, hematoxylin and eosin staining of the synovial membrane, and quantitative reverse transcription-polymerase chain reaction for changes in gene expression. Micro X-ray revealed that the knee joint treated with the cHA-Dex gel was wider than those treated with cHA gel alone or saline. The cHA-Dex gel group had less Indian ink staining (indicator of cartilage fibrillation) than the cHA gel or saline injection groups. Safranin-O/Fast Green staining indicated that increased proteoglycan staining and less cartilage damage were found in the cHA-Dex gel group compared with the cHA gel or saline injection groups. Quantification of histology findings from saline, cHA gel, cHA-Dex (0.2 mg/mL) gel, cHA-Dex (0.5 mg/mL) gel, and sham groups were 5.84 ± 0.29, 4.50 ± 0.87, 3.00 ± 1.00, 2.00 ± 0.48, and 0.30 ± 0.58 (p < 0.05), respectively. A strong staining of type II collagen was found in both the cHA-Dex gel groups compared with saline group or cHA alone group. Similar result was found for the mRNA level of aggrecan and opposite result for type X collagen. Hematoxylin and eosin staining in the synovial membrane showed less synovial lining cell layers and reduced inflammator

In a mouse arthritis model, we investigated whether interleukin-6 receptor (IL-6R) blockade would enhance the anti-arthritic effect of glucocorticoids (GCs). DBA/1J mice were immunized with type II collagen (CII), and were treated with prednisolone (PSL) and/or anti-mouse IL-6R antibody (MR16-1). Also, the effects of IL-6 on gene expression and the nuclear translocation of glucocorticoid receptors (GRs) were examined in cultured cells treated with dexamethasone (DEX). PSL reduced the arthritis score dose-dependently in the collagen-induced arthritis (CIA) mouse model. The arthritis score in the PSL (3 mg/kg) + MR16-1 group was lower than in the PSL (3 mg/kg) group, and at the same level as in the PSL (6 mg/kg) group. Lumbar vertebra bone mineral density (BMD) was decreased significantly in CIA mice and was higher in the PSL (3 mg/kg) + MR16-1 group than in the PSL (6 mg/kg) group. In the in-vitro synovial cells, IL-6 pretreatment attenuated the inhibitory effect of DEX on cyclooxygenase (COX)-2 expression and inhibited the nuclear translocation of GR induced by DEX. In contrast, in MC3T3-E1 osteoblastic cells, IL-6 pretreatment exacerbated the decrease in expression of osteocalcin and the increase in expression of receptor activator of nuclear factor kappa-B ligand (RANKL) by DEX. We demonstrated that IL-6 signalling blockade by an anti-IL-6R antibody can augment the anti-arthritic effect of GCs and inhibit the bone loss they cause. © 2015 British Society for Immunology.

Nimesulide is a COX-2 inhibitor used for symptomatic relief of rheumatoid arthritis. Leflunomide is an anti-pyrimidine used to manage the progression of rheumatoid arthritis. Herein we studied the influence of nimesulide and leflunomide combination in terms of disease symptoms and progression using collagen-induced arthritis model in mice, as a model for rheumatoid arthritis. Collagen induced arthritis was induced by immunization with type II collagen. Assessment of joint stiffness and articular hyperalgesia were evaluated using a locomotor activity cage and the Hargreaves method, respectively. Disease progression was assessed via arthritic index scoring, X-ray imaging, myeloperoxidase enzyme activity and histopathologic examination. Nimesulide induced only transient symptomatic alleviation on the top of decreased leucocytic infiltration compared to arthritis group. However, nimesulide alone failed to induce any significant improvement in the radiological or pathological disease progression. Leflunomide alone moderately alleviates the symptoms of arthritis and moderately retarded the radiological and pathological disease progression. Combination of nimesulide and leflunomide significantly improved symptomatic (analgesia and joint stiffness) and arthritic disease progression (radiological, pathological and Myeloperoxidase enzyme activity) in collagen induced arthritis animal model.

OBJECTIVE: To analyze the combination therapy of Sinomenine (SIN) and Methotrexate (MTX) in rheumatoid arthritis (RA), we herein demonstrated the combination effect of SIN and MTX on collagen-induced arthritis (CIA) in rats through their modulation on osteoclast-related cytokines. METHODS: CIA was induced by the immunization of type II collagen (CII) in SD rats. SIN and MTX were administrated alone or in combination after the onset of arthritis. Arthritis index and histological analysis were used to evaluate the effect of treatments. Effects of SIN and MTX on expression of receptor activator of NF-κB ligand (RANKL) and osteopontin (OPN) in synovial tissues were assayed by immunohistochemistry. RANKL, osteoprotegerin (OPG), IL-6, IL-17 and matrix metalloproteinases (MMPs) in rat serum were measured by ELISA. The expression of osteoclast-related cytokines in fibroblast-like synoviocytes (FLS) from RA patients was assayed by RT-PCR. RESULTS: SIN and MTX combination additively reduced the inflammatory symptoms and joint damage in CIA. Combination of SIN and MTX significantly repressed synovial RANKL and OPN production. SIN and MTX exhibited complementary and synergistic effect upon down-regulating RANKL, IL-6, IL-17 and MMPs in rat serum. SIN and MTX also modulated the expression of RANKL and OPG in RA-FLS. CONCLUSION: SIN and MTX have additive effects, decreasing inflammation and joint damage in CIA rats by modulating osteoclast-related cytokines. These results are indicative of the combined effect of SIN and MTX for anti-arthritic treatment in RA.

Methotrexate is a disease modifying anti-rheumatic drug that is widely used for the treatment of rheumatoid arthritis. Nimesulide is a non-steroidal anti-inflammatory drug which is frequently used as adjuvant therapy for symptomatic alleviation of rheumatoid arthritis. In this study, we have evaluated the potential influence of nimesulide on the disease modifying anti-rheumatic properties of methotrexate using the collagen-induced arthritis model. Mice were immunized with collagen type II for the induction of arthritis and treated with methotrexate (2.5mg/kg) twice a week, nimesulide (20mg/kg) every other day or a combination of both drugs. Treatment started one week after the onset of arthritis until day 40. An arthritic index was used to compare the severity of arthritis between different treatments. In addition, articular hyperalgesia, joint stiffness, radiological deterioration and intra-articular leucocytic infiltration were evaluated. Methotrexate alone showed modest but significant analgesic and anti-inflammatory effects, and the effects of nimesulide were comparable. On the other hand, nimesulide significantly improved the disease modifying anti-rheumatic profile of methotrexate in terms of arthritic index and joint mobility. Furthermore, although nimesulide failed to show any radiological evidence of articular protection, it significantly improved methotrexate-induced joint protection as judged by X-ray analysis. Copyright 2010 Elsevier B.V. All rights reserved.

Benazepril, an angiotensin-converting enzyme inhibitor, and candesartan, an angiotensin receptor blocker, are common drugs for treating hypertension. This study aimed to investigate the enhanced attenuation of myocardial fibrosis in spontaneously hypertensive rats (SHRs) possibly induced by joint treatment with benazepril and candesartan and the possible involvement of transforming growth factor beta1 (TGF-beta1)-Smad signaling pathway. SHRs were treated with benazepril at 10 mg.kg.d, candesartan at 4 mg.kg.d, and a combination of 2 drugs at half dose, respectively, for 12 weeks. Echocardiography and histology indicated that joint treatment with 2 drugs more significantly inhibited myocardial fibrosis in SHRs than either monotherapy, as evidenced by the changes in cardiac structural parameters, ultrasonic integrated backscatters, collagen volume fraction, and perivascular collagen area. The collagen analyses further revealed that significant decreases in total collagen concentration, the ratio of collagen type I to type III, and collagen cross-linking were found after the enhanced attenuation of myocardial fibrosis. Western blot analysis showed that the protein expression of TGF-beta1 and Smad3 was significantly decreased after joint treatment with 2 drugs. We conclude that synergistic attenuation of myocardial fibrosis in SHRs is produced by combined use of benazepril and candesartan possibly through the modulation of TGF-beta/Smad signaling proteins.

OBJECTIVE: To elucidate the pathophysiologic links between prostaglandin E(2) (PGE(2)) and osteoarthritis (OA) by characterizing the catabolic effects of PGE(2) and its unique receptors in human adult articular chondrocytes. METHODS: Human adult articular chondrocytes were cultured in monolayer or alginate beads with and without PGE(2) and/or agonists of EP receptors, antagonists of EP receptors, and cytokines. Cell survival, proliferation, and total proteoglycan synthesis and accumulation were measured in alginate beads. Chondrocyte-related gene expression and phosphatidylinositol 3-kinase/Akt signaling were assessed by real-time reverse transcription-polymerase chain reaction and Western blotting, respectively, using a monolayer cell culture model. RESULTS: Stimulation of human articular chondrocytes with PGE(2) through the EP2 receptor suppressed proteoglycan accumulation and synthesis, suppressed aggrecan gene expression, did not appreciably affect expression of matrix-degrading enzymes, and decreased the type II collagen:type I collagen ratio. EP2 and EP4 receptors were expressed at higher levels in knee cartilage than in ankle cartilage and in a grade-dependent manner. PGE(2) titration combined with interleukin-1 (IL-1) synergistically accelerated expression of pain-associated molecules such as inducible nitric oxide synthase and IL-6. Finally, stimulation with exogenous PGE(2) or an EP2 receptor-specific agonist inhibited activation of Akt that was induced by insulin-like growth factor 1. CONCLUSION: PGE(2) exerts an antianabolic effect on human adult articular cartilage in vitro, and EP2 and EP4 receptor antagonists may represent effective therapeutic agents for the treatment of OA.

BACKGROUND: Knee osteoarthritis (KOA) is the most common form of degenerative arthritis. We used Phellinus linteus (PL), which has been well-known anti-inflammatory function. In this study, we will evaluate if PL extract improves symptoms with KOA. METHODS: This study will be an 8-week single-center randomized controlled double-blind clinical trial. Total of 24 subjects with KOA will be enrolled and they will be divided into 3 groups, PL 1,000 mg, PL 1,500 mg and placebo. Subjects will be followed up every 4 weeks with efficacy and safety at the 2nd and 3rd visits. All subjects should maintain a dosage schedule for this protocol. The primary outcome will be assessed with the Korean version of the Western Ontario and McMasters Universities. And the secondary outcomes will be measured using the visual analog scale, quality of life scale (EQ-5D-3L), ESR, C-reactive protein, and C-telopeptide of type-II collagen. Statistical analysis will be performed on the principle of full analysis set. DISCUSSION: This study has inclusion and exclusion criteria and a well-controlled intervention. This clinical trial is the first step to assess the efficacy and safety of PL in patients with KOA. This study will make an important contribution to the literature and aid follow-up research into the use of PL in KOA.

Articular cartilage and the osteochondral unit have limited intrinsic healing capacity, creating a need for advanced tissue engineering solutions. This systematic review critically evaluates the development and performance of carrageenan (CG)-based biomaterials for cartilage and osteochondral regeneration. Using a structured search of PubMed, Scopus, and Web of Science (2002-2025), we identified and analyzed 140 relevant studies that met predefined inclusion criteria: (1) use of κ-, ι-, or λ-carrageenan in scaffold fabrication, (2) in vitro or in vivo assessment of chondrogenic or osteochondral repair, and (3) reporting of mechanical, biological, or degradation data. Our analysis reveals that the sulfate-rich backbone and ion-sensitive gelation of CG provide a versatile platform for designing biomimetic scaffolds. We provide a comparative assessment of major scaffold classes-including ionic hydrogels, covalent hybrids, polyelectrolyte complexes, pHoto-crosslinkable networks, and multiphasic composites-highlighting distinct trade-offs in mechanical strength, degradation profiles, and bioactivity. CG-based systems consistently support chondrocyte viability (>90%) and enhance the expression of cartilage-specific markers (collagen II, aggrecan, SOX9). However, significant variability exists in reported performance metrics, which often depends on CG type, crosslinking method, and composite formulation. Despite promising preclinical outcomes, key barriers to clinical translation persist. These include limited long-term mechanical stability under physiological loading, insufficient control over degradation kinetics, and a lack of standardized in vivo models for osteochondral defect repair. We conclude that while CG-based hydrogels represent a compelling biomaterial strategy for cartilage regeneration, future progress depends on the rational integration of advanced fabrication techniques, standardized characterization protocols, and targeted immunomodulatory design to address these translational hurdles.

Tripterygium polyglycosides (TG), Triptolide (TP), and Celastrol (CEL), which are extracts from Tripterygium wilfordii Hook F (TwHF), are renowned for their anti-inflammatory and immunomodulatory properties in the treatment of rheumatoid arthritis (RA). However, a comprehensive systematic review and meta-analysis of preclinical evidence supporting the use of Tripterygium wilfordii extracts for RA has not yet been conducted. This study aimed to conduct a systematic review and meta-analysis to evaluate the therapeutic effects and potential underlying mechanisms of Tripterygium wilfordii extracts in CIA model of RA. Six electronic databases, including PubMed, Embase, Web of Science, Cochrane Library, Scopus, and Ovid, were searched from their inception to June 2024. The methodological quality was assessed via SYRCLE's risk of bias tool. Statistical analyses were performed using Stata 18.0 software and Review Manager 5.4.1 software. This study included 32 articles involving 568 animals. The results revealed that Tripterygium wilfordii extracts significantly reduced joint manifestations (arthritis index, paw swelling degree, and paw thickness); histopathological changes in joints (histopathological score, cartilage damage, bone destruction, synovial hyperplasia, pannus formation, and inflammatory cell infiltration); levels of related cytokines (TNF-α, IL-1β, IL-6, IL-23, IFN-γ, and IL-17); anti-type II collagen antibodies; and T-cell subsets (CD4+ T cells, Th1 cells, and Th17 cells). Moreover, Tripterygium wilfordii extracts significantly increased the levels of relevant cytokines (IL-10, IL-4, and TGF-β) and the number of Treg cells compared with those in the control group. However, animal species and sex, extract category and dosage, and treatment duration were identified as important factors influencing the above results. Tripterygium wilfordii extracts (TG, TP and CEL) exhibit promising therapeutic effects and mechanisms in the treatment of RA. But the effect characteristics and mechanisms vary among different Tripterygium wilfordii extracts. These specific effects and mechanisms also vary depending on the treatment duration and dosage. © 2025. The Author(s).

OBJECTIVE: Intervertebral disc degeneration (IDD) is a major cause of chronic lower back pain, with current treatment options offering limited efficacy. Exosome-loaded hydrogels have emerged as a promising therapeutic approach due to their biocompatibility and regenerative potential, making them a focus of research for IDD treatment. This study systematically evaluates and performs a meta-analysis of the effectiveness of exosome-loaded hydrogels in preclinical models of IDD. METHODS: A comprehensive literature search was conducted across four major databases (PubMed, Embase, Cochrane, Web of Science), including animal studies that met predefined criteria. Data extraction and quality assessment were independently performed by two authors. Treatment effects were quantified using standardized mean differences (SMD) with 95% confidence intervals (CI). Outcome measures included disc height index (DHI), magnetic resonance imaging (MRI) grade, histological grade, IDD-related immunohistochemical (IHC) markers (e.g., collagen type II (COL2), matrix metalloproteinase 13 (MMP13)), and aging-related markers (e.g., p16Ink4a-positive cells, p21CIP1A-positive cells). RESULTS: Treatment with exosome-loaded hydrogels significantly enhanced DHI scores at 4 (p = 0.002) and 8 weeks (p < 0.0001), and decreased MRI scores at 8 (p < 0.00001) and 12 weeks (p < 0.0001), and histological assessments. Furthermore, the treatment group exhibited increased COL2 expression at 8 (p = 0.0002) and 12 weeks (p = 0.002), decreased MMP13 levels at 8 (p = 0.0001) and 12 weeks (p = 0.0009), and a reduction in aging markers (p16Ink4a, p21CIP1A, all p < 0.05), suggesting that exosome-loaded hydrogels facilitate intervertebral disc repair through the modulation of molecular pathways. Sensitivity analysis confirmed the robustness of the findings. CONCLUSIONS: Exosome-loaded hydrogels show potential for improving the structure and function of intervertebral discs in IDD treatment, potentially slowing degeneration by inhibiting matrix degradation and cellular aging. Further investigation is required to elucidate the underlying mechanisms and to assess the safety and efficacy of these hydrogels for clinical

OBJECTIVE: To evaluate the efficacy of fibroblast growth factor-18 (FGF-18) augmentation for improving articular cartilage healing following surgical repair in preclinical (in vivo) animal models. DESIGN: A systematic review was performed evaluating the efficacy of FGF-18 augmentation with cartilage surgery compared with cartilage surgery without FGF-18 augmentation in living animal models. Eligible intervention groups were FGF-18 treatment in conjunction with orthopedic procedures, including microfracture, osteochondral auto/allograft transplantation, and cellular-based repair. Outcome variables were: International Cartilage Repair Society (ICRS) score, modified O'Driscoll histology score, tissue infill score, qualitative histology, and adverse events. Descriptive statistics were recorded and summarized for each included study. RESULTS: In total, 493 studies were identified and 4 studies were included in the final analysis. All studies were randomized controlled trials evaluating in vivo use of recombinant human FGF-18 (rhFGF-18). Animal models included ovine (n = 3) and equine (n = 1), with rhFGF-18 use following microfracture (n = 3) or osteochondral defect repair (n = 1). The rhFGF-18 was delivered via intra-articular injection (n = 2), collagen membrane scaffold (n = 1), or both (n = 1). All studies reported significant, positive improvements in cartilage defect repair with rhFGF-18 compared with controls based on ICRS score (n = 4), modified O'Driscoll score (n = 4), tissue infill (n = 3), and expression of collagen type II (n = 4) (P < 0.05). No adverse events were reported with the intra-articular administration of this growth factor, indicating short-term safety and efficacy of rhFGF-18 in vivo. CONCLUSION: This systematic review provides evidence that rhFGF-18 significantly improves cartilage healing at 6 months postoperatively following microfracture or osteochondral defect repair in preclinical randomized controlled trials.

BACKGROUND: Postmenopausal women are one of the most vulnerable groups to osteoporosis. Romosozumab is a newly monoclonal drug that inhibits the activity of sclerostin. Since it has been on the market for only 3 years, there is a lack of systematic analysis on postmenopausal women and the efficacy is not clear. In this study, we compared randomized controlled trials to assess the effects of blosozumab versus placebo in perimenopausal and postmenopausal women. METHODS: This meta-analysis has been registered in the PROSPERO registry (number CRD42020145839). The PubMed, Cochrane Library, ClinicalKey, and Embase databases were searched from inception date to July 01, 2021. We used the keywords "osteoporosis", "decreased bone mass", and "blosozumab" to retrieve studies on the relationship between blosozumab and osteoporosis in each database. The inclusion criteria were: (I) randomized controlled trials (RCTs) comparing the treatment of osteoporosis with blosozumab and a placebo or without treatment, (II) studies on postmenopausal women aged over 50 years, and (III) studies providing bone mineral density data. The quality of all randomized controlled trials included in this study was independently assessed by two researchers according to the Cochrane risk manual and was divided into high, medium and low quality. The main results analyzed were bone mineral density (BMD) and T-score. Our results mainly include BMD and procollagen type I N-terminal propeptide (P1NP), C-terminal telopeptide of type I collagen (CTX), bone-specific alkaline phosphatase (BSAP), and osteocalcin (OC). RESULTS: Three RCTs with 105 patients were selected from 157 retrieved articles. Due to high heterogeneity [BMD: Tau2=2.79; Chi2=11.70, degrees of freedom (df) =1 (P=0.0006); I2=91%], we could not perform statistical analysis of BMD. The results of BMD were then evaluated systematically. Three RCT studies were included in the evaluation. Compared with that of the placebo, blosozumab increased levels of the BMD biomarker osteocalcin [mean deviation (MD) 12.55; 95% confidence interval (CI), 8.18, 16.91; P<0.00001]. None of the 3 RCTs presented a risk of bias during the meta-analysis. CONCLUSIONS: T

Comment in Int J Rheum Dis. 2023 Jun;26(6):1198-1200. doi: 10.1111/1756-185X.14642. Int J Rheum Dis. 2023 Jun;26(6):1201. doi: 10.1111/1756-185X.14639. Rheumatoid arthritis (RA) and osteoarthritis (OA) both are chronic diseases affecting joints. Immune response against collagen in both diseases may have a role in the initiation and progression of the disease. There is a hypothesis that suppression of immune response vs collagen could be a therapeutic approach in RA and OA. Exposure of gut immune system to collagen is a way to suppress immune response against collagen in the joints. So, the current systematic review is aimed to evaluate the effects of collagen supplementation in OA and RA patients. In the current systematic review, online electronic databases including PubMed/MEDLINE, Web of Sciences and Scopus were searched and finally 19 articles were included. The enrolled articles evaluated the effects of collagen supplementation on treatment of OA (n = 9) and RA (n = 10). Intact (n = 4) and hydrolyzed (n = 5) collagen were used to treat OA. All of the studies on RA used intact and type II collagen in their intervention. The last trials on collagen supplementation in RA and OA patients were performed in 2011 and 2016, respectively. High adverse effects of collagen supplementation and its low efficiency compared to routine treatments were reported by several included studies. Also, risk of bias assessment showed that most of the studies had poor quality. Therefore, it is not possible to definitely decide on the beneficial or detrimental effects of collagen supplementation on OA and RA patients. Further studies are needed to reach a final decision. © 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

OBJECTIVE: Biomarkers in osteoarthritis (OA) could serve as objective clinical indicators for various disease parameters, and act as surrogate endpoints in clinical trials for disease-modifying drugs. The aim of this systematic review was to produce a comprehensive list of candidate molecular biomarkers for knee OA after the 2013 ESCEO review and discern whether any have been studied in sufficient detail for use in clinical settings. DESIGN: MEDLINE and Embase databases were searched between August 2013 and May 2018 using the keywords "knee osteoarthritis," "osteoarthritis," and "biomarker." Studies were screened by title, abstract, and full text. Human studies on knee OA that were published in the English language were included. Excluded were studies on genetic/imaging/cellular markers, studies on participants with secondary OA, and publications that were review/abstract-only. Study quality and bias were assessed. Statistically significant data regarding the relationship between a biomarker and a disease parameter were extracted. RESULTS: A total of 80 studies were included in the final review and 89 statistically significant individual molecular biomarkers were identified. C-telopeptide of type II collagen (CTXII) was shown to predict progression of knee OA in urine and serum in multiple studies. Synovial fluid vascular endothelial growth factor concentration was reported by 2 studies to be predictive of knee OA progression. CONCLUSION: Despite the clear need for biomarkers of OA, the lack of coordination in current research has led to incompatible results. As such, there is yet to be a suitable biomarker to be used in a clinical setting.

OBJECTIVE: To investigate the impact of exercise therapy on molecular biomarkers related to cartilage and inflammation in individuals at risk of, or with established, knee osteoarthritis by conducting a systematic review of randomized controlled trials (RCTs). METHODS: We conducted a literature search up to September 2017 in 5 major databases with no restriction on publication year or language. Data were extracted from the first available follow-up time point, and we performed a narrative synthesis for the effect of exercise therapy on molecular biomarkers related to cartilage and inflammation. A subset of studies reporting sufficient data was combined in a meta-analysis, using an adjusted random-effects model. RESULTS: Twelve RCTs involving 57 study comparisons at 4 to 24 weeks following an exercise-therapy intervention were included. Exercise therapy decreased molecular biomarkers in 17 study comparisons (30%), had no effect in 36 (63%), and increased molecular biomarkers in 4 study comparisons (7%). Meta-analyses of 9 biomarkers showed that exercise therapy was associated with nonsignificant reductions of the C-reactive protein level, C-terminal crosslinking telopeptide of type II collagen, tumor necrosis factor (TNF), soluble TNF receptors 1 and 2, C2C neoepitope of type II collagen, and cartilage oligomeric matrix protein, compared to nonexercising control groups, and exercise therapy had no effect on interleukin-6 and soluble interleukin-6 receptor. CONCLUSION: Exercise therapy is not harmful, because it does not increase the concentration of molecular biomarkers related to cartilage turnover and inflammation, implicated in osteoarthritis progression. The overall quality of evidence was downgraded to low because of the limited number of RCTs available. © 2018, American College of Rheumatology.