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Osteoarthritis (OA) is a degenerative joint disease and is the main cause of chronic pain and functional disability in adults. Articular cartilage is a hydrated soft tissue that is composed of normally quiescent chondrocytes at a low density, a dense network of collagen fibrils with a pore size of 60-200 nm, and aggrecan proteoglycans with high-density negative charge. Although certain drugs, nucleic acids, and proteins have the potential to slow the progression of OA and restore the joints, these treatments have not been clinically applied owing to the lack of an effective delivery system capable of breaking through the cartilage barrier. Recently, the development of nanotechnology for delivery systems renders new ideas and treatment methods viable in overcoming the limited penetration. In this review, we focus on current research on such applications of nanotechnology, including exosomes, protein-based cationic nanocarriers, cationic liposomes/solid lipid nanoparticles, amino acid-based nanocarriers, polyamide derivatives-based nanocarriers, manganese dioxide, and carbon nanotubes. Exosomes are the smallest known nanoscale extracellular vesicles, and they can quickly deliver nucleic acids or proteins to the required depth. Through electrostatic interactions, nanocarriers with appropriate balance in cationic property and particle size have a strong ability to penetrate cartilage. Although substantial preclinical evidence has been obtained, further optimization is necessary for clinical transformation. STATEMENT OF SIGNIFICANCE: The dense cartilage matrix with high-negative charge was associated with reduced therapeutic effect in osteoarthritis patients with deep pathological changes. However, a systematic review in nanodevices for deep cartilage penetration is still lacking. Current approaches to assure penetration of nanosystems into the depth of cartilage were reviewed, including nanoscale extracellular vesicles from different cell lines and nanocarriers with appropriate balance in cationic property and size particle. Moreover, nanodevices entering clinical trials and further optimization were also discussed, providing important guiding significance to future research.

The present study was designed to explore the relationship between thrombin and catabolic activity in chondrocytes. Primary rat chondrocytes were cultured for 24 h with rat serum (RS), rat plasma (RP), or rat plasma supplemented with thrombin (RPT). RNA-sequencing was then performed. Cell proliferation was analyzed by EdU uptake, CCK-8 assays and protein-protein interaction (PPI) network of proliferation-related genes. Heatmaps were used to visualize differences in gene expression. Gene Ontology (GO) enrichment analyses of up- and down-regulated differentially expressed genes were conducted. Molecular probes were used to label the endoplasmic reticulum in chondrocytes from three treatment groups. Immunofluorescence and Safranin O staining were used to assess type II collagen (Col2a1) expression and proteoglycan synthesis, whereas Lox expression was assessed by immunocytochemistry. The expression of enzymes involved in the synthesis and maturation of extracellular matrix (ECM) components and chemokines were measured by qPCR while matrix metalloproteinases (MMPs) levels were evaluated by Western blotting. Relevant nodules were selected through further PPI network analyses. A total of 727 and 1162 genes were up- and down-regulated based on the Venn diagrams comparison among groups. Thrombin was thus able to promote chondrocyte proliferation and a shift towards fibrotic morphology, while upregulating MMPs and chemokines linked to ECM degradation. In addition, thrombin decreased the enzyme expression involved in the synthesis and maturation of ECM.

To study role of TLR4/NF-κB pathway for early change of synovial membrane in knee osteoarthritis rats.Eighteen male SD rats weighted (200±20) g were randomly divided into 2 groups, namely control and model group, and 9 in each group. Knee OA model group was established by using modified Hulth method in model group. Control group was not treated. Synovial tissue and serum was extracted at 4 and 21 d after operation. Expression of CD14, TLR4, IL-1β, TNF-α, ADAMTS-4, MMP-13 were detected by real-time PCR respectively. NF-κB p65 protein was detected by Western-blot; serum concentrations of haluronic acid (HA), N-propeptide of type III procollagen(PIIINP) was detected by Elisa.Expression of CD14, ADAMTS-4, and NF-κB p65 in model group were higher than that of control group at 4 and 21 days after operation, while expression of TLR4, IL-1β, TNF-α and MMP-13 were higher than that of control group at 21 days after operation(NF-κB pathway could mediate occurrence of KOA by early activating and triggeringg synovial increasingly secreting inflammatory secretion CD14, TLR4, IL-1β, TNF-α, ADAMTS-4, MMP-13, PIIINP and HA.

OBJECTIVE To study the effects of three different laser treatments (650 nm alone, 10.6 μm alone and combined laser of 650 nm and 10.6 μm) on experimental osteoarthritis of the knees in C57 black mice. METHODS Sixty C57 black mice were divided randomly into 6 groups. Ten mice were assigned to a normal control group (no intervention) and the other 5 groups were subjected to a forced running regimen to induce osteoarthritis. One group was set as the model control group. The other 4 groups were given 90 s of a 650 nm laser, 90 s of a 10.6 μm laser, 90 s of a combined laser, or a sham treatment on acupoint Dubi (ST35) of the rear left leg 3 times per week for 4 weeks. The modified Mankin score was used to evaluate the degree of cartilage degradation. Immunohistochemical staining for heat shock protein (HSP) 70 was conducted. RESULTS Mankin scores of the model control group and the sham control group were significantly higher than that of the normal control group (P

To investigate regulation function of anodonta glucan HBP-A on chondrocytes through Wnt pathway in vitro.Rat chondrocytes were cultured and differentiated induced with IL-1beta (10 ng/ml) in vitro. Chondrocytes were divided into five groups:IL-13 group,IL-1beta + IWP-2 (5 microM,Wnt pathway inhibitor) group, IL-1beta + HBP-A (0.3 mg/ml) group and IL-1beta + IWP-2 + HBP-A group. Wnt-3a, beta-catenin (24 h,48 h,72 h) and MMP-13(72 h) genes expression were detected by Rt-PCR, while beta-catenin, MMP-13, Sox-9 and coll-II (48 h) protein expression were measured by Western-blot.After induction of IL-1beta, gene expression of Wnt-3a, beta-catenin and MMP-13 were increased,so were the protein expression of beta-catenin and MMP-13. In contrast,protein expression of Sox-9 and Coll-II were declined. Following addition of HBP-A, Wnt-3a, beta-catenin and MMP-13 were shown as induction of IL-1beta, but protein expression of Sox-9 and Coll-II were upgraded. Combining HBP-A with IWP-2 led to the lowest level in Wnt-3a, beta-catenin gene and beta-catenin protein expression and highest expression of Sox-9 protein.HBP-A could not only delay the differentiation of chondrocytes through downgrading the signal expression of Wnt/beta-catenin,but also adjust the expression of Wnt-3a, beta-catenin and Sox-9 when combinated with the Wnt inhibitor.

To observe the distribution features of tender points in knee of patients with knee osteoarthritis in order to provide evidences for the treatment and diagnosis.From November 2011 to December 2012,86 patients with knee osteoarthritis were recruited, including 21 males and 65 females, ranging in age from 45 to 85 years old, with an average of (59.98 +/- 8.23) years old. The course of disease ranged from 3 months to 15 years. The tender points and its distributions were determined by finger press carefully on their knees. Data of studying was analyzed by frequency statistics and Hierachical cluster analysis.The distribution of tender points in the knee osteoarthritis was mainly in the interior region and anterior area such as in apex of patella, adductor tubercle and et al. According to the results of hierachical cluster analysis, the tender points could be divided into two categories the first cluster was in the interior region of knee, the second cluster was in the lateral region.The findings demonstrated that cluster analysis statistical method can be used for classification of the distribution of tender points. The distribution features of tender points in knee osteoarthritis are related to the anatomic site in knee.

Rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs) proliferate abnormally and resist apoptosis. Bufalin inhibits cell proliferation and induces apoptosis in human cancer cells. In this study, we explored the effects of bufalin on interleukin-1beta (IL-1β)-induced proliferation and apoptosis of RAFLSs. The cell proliferation and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay and annexin V/propidium iodide staining, respectively. Bufalin dose-dependently inhibited IL-1β-induced RAFLS proliferation. Mechanistically, bufalin decreased the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB), both of which are involved in IL-1β-mediated RAFLS proliferation. Moreover, bufalin induced apoptosis and mitochondrial damage of RAFLSs, which was associated with Bcl-2 downregulation, Bax upregulation, mitochondrial cytochrome c release, and enhanced cleavages of caspase-3 and poly-(ADP-ribose) polymerase. Collectively, our results reveal that bufalin suppresses IL-1β-induced proliferation of RAFLSs through MAPK and NF-κB signaling pathways and induces RAFLS apoptosis via the mitochondria-dependent pathway.

Effective biomarkers for clinical usage of osteoarthritis are still limited. It was confirmed that C-terminal crosslinking telopeptide of type I collagen (CTX- II) was a specific marker reflecting degradation of articular cartilage. Detection of CTX- II could promptly reflect level of cartilage injury and degradation ,diagnose OA,predict its progress,monitor effects of drug treatment, thus, reflect the condition of osteoarthritis patient indirectly. Application of CTX- II focused mainly on in the early stage of OA and need together to detect with other biomarkers,in order to more accurately reflection of the pathological changes of OA,but the specific clinical significance of CTX- II results still need to improve further.

Background: To evaluate the diagnostic utility of conventional ultrasonography and real time ultrasound elastography in differentiating degenerating cystic thyroid nodules mimicking malignancy from papillary thyroid carcinoma. Methods: We retrospectively analyzed conventional ultrasonographic and elastographic characteristics of 19 degenerating cystic thyroid nodules mimicking malignancy in 19 patients, with 30 surgically confirmed PTCs as controls. Based on size, the nodules had been grouped into less than 10mm (group A) and greater than 10 mm (group B). We evaluated conventional parameters and elasticity pattern. Color-scaled elastograms were graded as to stiffness of nodules using an elasticity pattern from I (soft) to IV (stiff). Results: Degenerating cystic thyroid nodules were similar to PTCs in conventional ultrasonographic findings, but the former frequently showed oval to round in shape (group A, 69.2% vs 18.8%, P=0.017; group B, 66.7% vs 7.14%, P=0.017) and punctuate hyperechoic foci (group A, 61.5% vs 0, P

To explore the diagnostic value of whole-organ magnetic resonance imaging score (WORMS) in knee osteoarthritis (KOA).From November 2009 to January 2011,70 patients with KOA combined with knee effusion among outpatient and inpatient were analyzed retrospectively. Among the patients, 12 patients were male, 58 patients were female,ranging in age from 46 to 75 years,with a mean age of (59.66 +/- 9.93) years. The clinical symptoms were evaluated by WOMAC, the imaging of KOA was assessed by K-L score and WORMS, and COMP and CTX- II were measured respectively by ELISA. The correlation analyses and multiple linear regression analysis were studied to determine associations among biomarkers, clinical variables and radiographic findings of knee joints.The average scores of WOMAC and WORMS were (57.50 +/- 8.20) and (64.54 +/- 16.45) respectively. The median of CTX- II nd COMP were 2.42 ng/ml and 4.56 ng/ml respectively. Grouped by less than the lowest quartile and more than the highest quartile of WORMS, COMP was significantly different (Z=2.04, P=0.039), but there was no significant difference in CTX-II (Z=0.79, P=0.427). WORMS were positively correlated with WOMAC and K-L score (r=0.777, P0.01; r=0.716, P0.01; respectively); WOMAC was also positively correlated with K-L score (r=0.692, P0.01). WORMS's cartilage, osteophytes and synovitis were positively correlated with WOMAC, K-L score and COMP respectively (r=0.771, P0.01; r=0.509, P0.01; r=0.917, P0.01). It was determined by stepwise regression that the KOA was mainly affected by WORMS, K-L score (P=0.015, P=0.025 respectively) when WOMAC as a dependent variable, age, gender, K-L score, WORMS, COMP and CTX- II as independent variables (F=20.327, P0.01).WORMS has a better reference value for diagnosis of KOA. The expression of COMP is high in the synovial fluid when WORMS at the high point. The clinical symptoms of knee osteoarthritis are mainly affected by WORMS and K-L score.

Osteoarthritis (OA) is the most prevalent of joint diseases,and its pathology is characterized by the degeneration of cartilage, sclerosis of subchondral bone, and osteophyte formation. Localization of the early lesions of OA has not been clarified, but many researchers have focused on cartilage and have considered that changes in subchondral bone occur subsequently to the degeneration of cartilage. However, a low bone mineral density, particularly in the knee joint with OA, high bone turnover, and efficacy of bone resorption inhibitors for OA have recently been reported, suggesting that subchondral bone plays an important role in the pathogenesis of OA. This review aims to make a conclusion about advancement in research of subchondral bone in osteoarthritis.

The Wnt signaling exists in every kinds of species and regulates a variety of biological processes including cell fate, proliferation and function, immunity, stress, apoptosis and so on. During the researching, Wnt signaling also plays an important role in chondrocyte differentiation and maturation. So it has been the new spot in pathogenesis of osteoarthritis study.

To understand the information of female patients with knee osteoarthritis regarding muscle force, constitution parameter.Thirty-seven cases diagnosed as knee osteoarthritis and 37 controls were examined by MES. T-test was used to analysis two groups differences of muscle force, constitution parameter, et al.Compared between affected limbs and controls limbs in patients revealed that the lower limb muscle distribution index of the affected limbs was higher than the control limbs (P0.05), but comparison in functional status the lower limb muscle force, muscle functional index and muscle force of unit volume of the affected limbs were lower than the control limbs (P0.05). Compared between patients group and control group the muscle force of both lower limbs, muscle functional index and muscle force of unit volume were lower than control group (P0.001).The utility muscle force of lower limbs of female patients with knee osteoarthritis is weaker than healthy female. Muscle function disorder instead of muscle atrophy is the key cause of the weakness.

This article summarizes relevant clinical studies on muscle status and osteoarthritis. Evidence from many researches have implied the importance of muscle weakness, decreased muscle strength and muscle function as pathological factor in the process of osteoarthritis, and muscle should also be an effective target for the treatment of osteoarthritis. Further study need to be conducted from the angle of muscle to explore the mechanism of osteoarthritis and to develop new drugs.

s / Osteoarthritis and Cartilage 22 (2014) S57–S489 S423 in the degeneration of the joint cartilage and pain. The rats showing pain-related behaviors were selected for the evaluation of TG-C for its individual cell type (1. hChonJ; 2. hChonJb#7; or 3. TG-C (hChonJ and hChonJb#7)) for pain and cartilage regeneration. At twoweekspost MIA administration, the individual cells were injected into the osteoarthritic knee cavity. The effect of the cells on the mechanical allodynia was evaluated by von Frey filament test in blinded fashion. After completing the test, the knees were harvested for histological analysis. Results: In MIA model, the reduction of pain was observed in hChonJ#7 treated and TG-C treated groups from day 15 post injection but not in hChonJ alone or in untreated group. The magnitude of pain reduction in hChonJ#7 treated group was comparable to that of TG-C treated group up to day 28. However, TG-C showed longer and greater pain reduction thereafter up to 8 weeks, indicating synergy between hChonJ and hChonJ#7 cells. The histological analysis showed that the integrity of cartilage was severely damaged by MIA treatment. However, hChonJ#7 cell treatment improved the damaged cartilage, in addition, TG-C treatment showed even greater improvement in the regeneration of the cartilage. Conclusions: This study showed that TG-C treatment could reduce pain and regenerate damaged cartilage in a rat MIA osteoarthritis model and contributes to the understanding of the effect of TG-C on the improvement of clinical outcomes observed in phase 2b trials. 763 TRADITIONAL CHINESE HERBAL MEDICATED BATH THERAPIES FOR OSTEOARTHRITIS B. Chen y, M. Chung z, H. Zhan y, Y. Cao y, C. Wang z. y Shuguang Hosp. Affiliated to Shanghai Univ. of Traditional Chinese Med., Shanghai, China; z Tufts Med. Ctr., Boston, MA, USA Table 1 Effect of traditional Chinese herbal medicated bath therapy on knee osteoarthritis Author year N Age Bath therapy (formula, water temperature, dose) Control intervention Li, 2011 204 63 14 Herbs: 9-30g each, 30 min, twice a day. Loxoprofen, 60 mg, 3/day Zhang, 2012 96 58 14 Herbs: 6-15g each, 30 min, twice a day, Hyaluronate injection, 2ml/wk Hyaluronate injectio 1 2ml/1 wk Du, 2012 60 63 9 Herbs: 12-15g each, 40-45 C, 20-30 min, 2x/day. Diclofenac topical c 2#/ day. Chen, 2013 60 57 10 Herbs: 5-30g each, 35-60 C, 30 min, 1-2x/day Diclofenac diethylam 2/day Zhang, 2011 90 58 8 Herbs: 5-15g each, 20 min, once or twice a day Diclofenac sodium, 75 mg/day Wu, 2011 98 55 8 Herbs: 20g each, 40 min, every other day Acupuncture. Meloxicam, 7.5 mg/ Huang, 2011 120 58 31 Herbs: 9-18g each, 20 min, twice a day. Oral herbal medicine Hyaluronate injecti