FOXM1 activates JAK1/STAT3 pathway in human osteoarthritis cartilage cell inflammatory reaction.

Osteoarthritis (OA), the most prevalent form of arthritis disease, is characterized by destruction of articular cartilage, osteophyte development, and sclerosis of subchondral bone. Transcription factors Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and Forkhead box M1 (FOXM1) are key mediators of this inflammatory reaction. In this study, we investigated the interaction between JAK1/STAT3 and FOXM1 in OA. Inflammation is related to the cartilage damage, and lipopolysaccharides (LPS) are a major pro-inflammatory inducer, so LPS was utilized to stimulate chondrocytes and establish a cell-based OA model. We found LPS treatment caused a generation of inflammatory cell factors (IL-1ß, IL-6, and TNF-α), and upregulation of inducible nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), prostaglandin E2 (PGE2) and other inflammatory mediators. Cell viability of chondrocytes was impaired with LPS stimulation, along with an upregulation of JAK1 expression, and phosphorylation and nuclear accumulation of STAT3. The administration of STAT3 inhibitor WP1066, which abated activation and nuclear location of STAT3, depleted the effect of LPS on inflammation and cell death. Co-immunoprecipitation showed that STAT3 was able to bind to FOXM1, and deactivation of STAT3 resulted in the downregulation of FOXM1. Moreover, FOXM1 silencing inhibited the generation of inflammatory cytokines induced by LPS, and the attenuation of cell survival. These findings indicated that the interaction between JAK1/STAT3 and FOXM1 may play a key role in OA pathogenic studies, and suggest the JAK1/STAT3 pathway may be a potential target for OA therapy.

Pharmacological basis for use of madecassoside in gouty arthritis: anti-inflammatory, anti-hyperuricemic, and NLRP3 inhibition.

Objectives: Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints, which is associated with the rise of serum urate content. This study aims to investigate the therapeutic effect of Madecassoside on gouty arthritis and hyperuricemia. Methods: DBA/1 mice were intradermally injected with MSU to stimulate joint inflammation or intraperitoneally injected with MSU to trigger peritonitis. Moreover, ICR mice were exposed to potassium oxonate to stimulate hyperuricemia. Results: Madecassoside repressed MSU-triggered pad swelling, joint 99mTc uptake, and joint inflammation in DBA/1 mice with gouty arthritis. Neutrophil infiltration and IL-1ß & IL-6 & MCP-1 secretion was also alleviated in lavage fluids from DBA/1 mice with peritonitis due to Madecassoside treatment. Furthermore, Madecassoside decreased MSU-induced neutrophil cytosolic factor 1, caspase-1 and NLRP3 expression in mice with peritoneal inflammation. In hyperuricemic mice, Madecassoside improved renal dysfunction. Serum uric acid, BUN, and creatinine were down-regulated by Madecassoside. Conclusion: These findings indicate that Madecassoside has potential to ameliorate inflammation in both acute gouty arthritis model and peritonitis model, probably via regulating IL-1ß and NLRP3 expression. Practical point: Madecassoside also exhibited a urate-lowering effect and a renal protective effect in hyperuricemic mice.

Knockdown of FOXM1 attenuates inflammatory response in human osteoarthritis chondrocytes.

Osteoarthritis (OA) is the most common inflammatory joint disease that is mainly characterized by articular cartilage destruction. Forkhead box M1 (FOXM1) is a transcription factor that acts as a critical mediator of inflammatory response. However, the role of FOXM1 in OA has not been investigated. Interleukin (IL)-1ß is a major proinflammatory cytokine, which is associated with cartilage destruction in the pathophysiology of OA. In the present study, we used IL-1ß to stimulate chondrocytes for the establishment of OA in vitro model. We found that FOXM1 was up-regulated in IL-1ß-induced chondrocytes. Knockdown of FOXM1 attenuated IL-1ß-caused decrease in cell viability. Knockdown of FOXM1 suppressed the IL-1ß-induced production of inflammatory cytokines including tumor necrosis factor (TNF)-α, and IL-6. Besides, several inflammatory mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthases (iNOS), and cyclooxygenase-2 (COX-2) were also repressed by knockdown of FOXM1. FOXM1 silencing also inhibited the production of matrix metalloproteinases (MMPs) including MMP-3 and MMP-13. Furthermore, we found that knockdown of FOXM1 blocked the IL-1ß-induced NF-κB activation in chondrocytes. These findings indicated that FOXM1 might play an important role in the pathogenesis of OA, suggesting that FOXM1 might be a potential therapeutic target for the treatment of OA.

A randomized controlled trial: preoperative home-based combined Tai Chi and Strength Training (TCST) to improve balance and aerobic capacity in patients with total hip arthroplasty (THA).

OBJECTIVES: To investigate the effect of a 12-week balance training program, combined TCST, on balance activity and aerobic capacity in patients with hip osteoarthritis. METHODS: Single-blind randomized grouping cohort study was conducted at our hospital from December 2008 to December 2011. A total of 81 patients aged from 60 to 69 years old diagnosed with end-stage hip osteoarthritis were recruited. They were randomly divided into two groups: training group (TG) and control group (CG). Participants in TG should do the TCST program under family's supervision for 12 weeks. Parameters including WOMAC score, 6 min walk test, stand up, walk test, situation of the hip mobility were compared between TG and CG by one-way ANOVA. RESULTS: There was no significant difference of baseline characteristics between these two groups (P>0.05). Participants in TG could complete 87.1% of movements of TCST. After training, the distance of 6-min walk was obviously increased from 409.59±51.31 m to 478.10±52.46 m (P<0.01), and the time for up and go was significantly shorten from 18.53±3.90 s to 14.61±2.60 s (P<0.01), and self-reported functional status scores evaluated by WOMAC was improved from 40.97±5.65 to 36.28±5.11 (P<0.01). However, there were no significant changes in pain WOMAC and side hip motion. CONCLUSION: The 12-week TCST program have good adherence, and can effectively improve balance and aerobic capacity status in patients with end-stage osteoarthritis, while this training can not effectively alleviate the pain and improve hip motion of patients. Hence, further THA is necessary to solve the problems. PRACTICE: Patients with osteoarthritis can do this training program under family's supervision. IMPLICATIONS: Providing a good advice on rehabilitation for patients preparing to do THA.

Hot beverage and food intake and esophageal cancer in southern China.

AIM: Hot beverage and food intake may be associated with increased risks of esophageal cancer. In this study, we analyzed data from two hospital based case-control studies to examine this question. METHODS: A structured questionnaire was used to collect data on potential risk factors of esophageal cancer from 213 cases and 213 controls in southern of China from Jan. 2007 to Dec. 2010. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional multivariable adjusted logistic regression, adjusting for confounders. RESULTS: Those who consumed hot and very hot beverages demonstrated significantly increased risk of esophageal cancer (OR=4.13, 95% CI: 2.13-8.05; OR=8.55, 95% CI: 3.67-20.9, respectively), related to increasing temperature. A high frequency of barbecued and fried food was also revealed to elevate risk of esophageal cancer (OR=3.44, 95% CI: 1.12-8.34, p for trend 0.034; OR=2.39, 95% CI: 1.25-6.32, p for trend 0.035). Furthermore, we found evidence for an association with a fast eating habit in our Chinese (OR=4.76, 95% CI: 2.12-7.74). CONCLUSION: This study found hot beverage and high-temperature cooking methods might greatly increase the risk of esophageal cancer. Further studies in Chinese populations with larger sample size are warranted.

[Long-term follow-up results of synovectomy for rheumatoid knee].

OBJECTIVE: To continuously observe the long-term effects of synovectomy for improving joint damage and quality-of-life in patients with the rheumatoid knee. METHODS: Twenty-one consecutive patients with rheumatoid arthritis (RA) involving 24 knees underwent open synovectomy from November 1988 to January 1997 between November 1988 and January 1997. The changes in radiographic damage were assessed with Larsen score on plain films before and 6 months after surgery with subsequent annual assessment for 8 years, and the functional recovery of the patients was also evaluated with Health Assessment Questionnaire (HAQ) at the same time. RESULTS: The radiographic joint damage and juxta-articular osteoporosis or bone erosion was ameliorated after surgery in all the patients. Larsen score began to decrease 6 months after the operation, and the best effects were achieved at one year and maintained for at least 5 years after the operation, but then followed by recurrence of joint lesions. HAQ scores were improved after the surgery with the best effects observed 6 months after the operation lasting for over 2 years. HAQ score gradually decreased 4 years after the operation till reaching the preoperative scores. CONCLUSION: Synovectomy in the patients with rheumatoid knee not only reverses progressive joint damage, but also improves juxta-articular bone erosions and the patients' quality of life. However, radiographic joint damage and functional deterioration may recur due to hyperplasia of the inflammatory synovium in the long term after operation, suggesting that the inflammatory synovium participates in local joint damage with bone erosions and systemic pathologic process of RA.

[Induced differentiation of human peripheral blood CD68+ mononuclear cells into osteoclasts in vitro].

OBJECTIVE: To establish a method for obtaining highly purified primary human osteoclast precursors for the biochemical and molecular biological research. METHODS: CD68(+) mono/macrophages were separated from peripheral blood mononuclear cells (PBMCs) of healthy donors by means of immunomagnetic cell sorting for subsequent analysis with flow cytometry. The isolated cells were incubated on coverslips or bone slices in the presence of dexamethasone(10(-8) mol/L), macrophage colony-stimulating factor (25 microg/L ) and soluble receptor activator of nuclear factor (NF)-kappaB ligand (s-RANKL, 16 microg/L). Calcitonin receptor (CR) immunocytochemistry and tartrate-resistant acid phosphatase (TRAP) histochemistry were employed. The bone slices were also studied by scanning electron microscopy (SEM). RESULTS: Fluorescence-activated cytometric analysis showed that 93.06%+/-0.61% n=4 of the selected cells were CD68(+) cells. After 7 days of culture of the CD68(+) cells, VR+, TRAP+ multinucleated giant cells appeared, and resorption lacunae could be observed by SEM. CONCLUSION: Highly purified CD68(+) cells can be obtained from human PBMCs as the osteoclast precursors, and mature osteoclasts can be induced from CD68(+) mono/macrophages by RANKL.