HDAC4 represses ER stress induced chondrocyte apoptosis by inhibiting ATF4 and attenuates cartilage degeneration in an osteoarthritis rat model.

BACKGROUND: The present study evaluated whether the lack of histone deacetylase 4 (HDAC4) increases endoplasmic reticulum stress-induced chondrocyte apoptosis by releasing activating transcription factor 4 (ATF4) in human osteoarthritis (OA) cartilage degeneration. METHODS: Articular cartilage from the tibial plateau was obtained from patients with OA during total knee replacement. Cartilage extracted from severely damaged regions was classified as degraded cartilage, and cartilage extracted from a relatively smooth region was classified as preserved cartilage. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was used to detect chondrocyte apoptosis. HDAC4, ATF4, and C/EBP homologous protein (CHOP) expression levels were measured using immunohistochemistry staining and real-time quantitative PCR. Chondrocytes were transfected with HDAC4 or HDAC4 siRNA for 24 h and stimulated with 300 µM H2O2 for 12 h. The chondrocyte apoptosis was measured using flow cytometry. ATF4, CHOP, and caspase 12 expression levels were measured using real-time quantitative PCR and western blotting. Male Sprague-Dawley rats (n = 15) were randomly divided into three groups and transduced with different vectors: ACLT + Ad-GFP, ACLT + Ad-HDAC4-GFP, and sham + Ad-GFP. All rats received intra-articular injections 48 h after the operation and every three weeks thereafter. Cartilage damage was assessed using Safranin O staining and quantified using the Osteoarthritis Research Society International score. ATF4, CHOP, and collagen II expression were detected using immunohistochemistry, and chondrocyte apoptosis was detected using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. RESULTS: The chondrocyte apoptosis was higher in degraded cartilage than in preserved cartilage. HDAC4 expression was lower in degraded cartilage than in preserved cartilage. ATF4 and CHOP expression was increased in degraded cartilage. Upregulation of HDAC4 in chondrocytes decreased the expression of ATF4, while the expression of ATF4 was increased after downregulation of HDAC4. Upregulation of HDAC4 decreased the chondrocyte apoptosis under endoplasmic reticulum stress, and chondrocyte apoptosis was increased after downregulation of HDAC4. In a rat anterior cruciate ligament transection OA model, adenovirus-mediated transduction of HDAC4 was administered by intra-articular injection. We detected a stronger Safranin O staining with lower Osteoarthritis Research Society International scores, lower ATF4 and CHOP production, stronger collagen II expression, and lower chondrocyte apoptosis in rats treated with Ad-HDAC4. CONCLUSION: The lack of HDAC4 expression partially contributes to increased ATF4, CHOP, and endoplasmic reticulum stress-induced chondrocyte apoptosis in OA pathogenesis. HDAC4 attenuates cartilage damage by repressing ATF4-CHOP signaling-induced chondrocyte apoptosis in a rat model of OA.

TMT quantitative proteomics reveals key proteins relevant to microRNA-1-mediated regulation in osteoarthritis.

Osteoarthritis (OA) is the second-commonest arthritis, but pathogenic and regulatory mechanisms underlying OA remain incompletely understood. Here, we aimed to identify the mechanisms associated with microRNA-1 (miR-1) treatment of OA in rodent OA models using a proteomic approach. First, N = 18 Sprague Dawley (SD) rats underwent sham surgery (n = 6) or ACL transection (n = 12), followed at an interval of one week by randomization of the ACL transection group to intra-articular administration of either 50 µL placebo (control group) or miR-1 agomir, a mimic of endogenous miR-1 (experimental group). After allowing for eight weeks of remodeling, articular cartilage tissue was harvested and immunohistochemically stained for the presence of MMP-13. Second, N = 30 Col2a1-cre-ERT2 /GFPf1/fl -RFP-miR-1 transgenic mice were randomized to intra-articular administration of either placebo (control group, N = 15) or tamoxifen, an inducer of miR-1 expression (experimental group, N = 15), before undergoing surgical disruption of the medial meniscus (DMM) after an interval of five days. After allowing for eight weeks of remodeling, articular cartilage tissue was harvested and underwent differential proteomic analysis. Specifically, tandem mass tagging (TMT) quantitative proteomic analysis was employed to identify inter-group differentially-expressed proteins (DEP), and selected DEPs were validated using real-time quantitative polymerase chain reaction (RT-qPCR) technology. Immunohistochemically-detected MMP-13 expression was significantly lower in the experimental rat group, and proteomic analyses of mouse tissue homogenate demonstrated that of 3526 identified proteins, 345 were differentially expressed (relative up- and down-regulation) in the experimental group. Proteins Fn1, P4ha1, P4ha2, Acan, F2, Col3a1, Fga, Rps29, Rpl34, and Fgg were the *top ten most-connected proteins, implying that miR-1 may regulate an expression network involving these proteins. Of these ten proteins, three were selected for further validation by RT-qPCR: the transcript of Fn1, known to be associated with OA, exhibited relative upregulation in the experimental group, whereas the transcripts of P4ha1 and Acan exhibited relative downregulation. These proteins may thus represent key miR-1 targets during OA-regulatory mechanisms, and may provide additional insights regarding therapeutic mechanisms of miR-1 in context of OA.

HDAC4 mutant represses chondrocyte hypertrophy by locating in the nucleus and attenuates disease progression of posttraumatic osteoarthritis.

BACKGROUND: The aim of this study was to evaluate whether histone deacetylase 4 S246/467/632A mutant (m-HDAC4) has enhanced function at histone deacetylase 4 (HDAC4) to attenuate cartilage degeneration in a rat model of osteoarthritis (OA). METHODS: Chondrocytes were infected with Ad-m-HDAC4-GFP or Ad-HDAC4-GFP for 24 h, incubated with interleukin-1ß (IL-1ß 10 ng/mL) for 24 h, and then measured by RT-qPCR. Male Sprague-Dawley rats (n = 48) were randomly divided into four groups and transduced with different vectors: ACLT/Ad-GFP, ACLT/Ad-HDAC4-GFP, ACLT/Ad-m-HDAC4-GFP, and sham/Ad-GFP. All rats received intra-articular injections 48 h after the operation and every 3 weeks thereafter. Cartilage damage was assessed using radiography and Safranin O staining and quantified using the OARSI score. The hypertrophic and anabolic molecules were detected by immunohistochemistry and RT-qPCR. RESULTS: M-HDAC4 decreased the expression levels of Runx-2, Mmp-13, and Col 10a1, but increased the levels of Col 2a1 and ACAN more effectively than HDAC4 in the IL-1ß-induced chondrocyte OA model; upregulation of HDAC4 and m-HDAC4 in the rat OA model suppressed Runx-2 and MMP-13 production, and enhanced Col 2a1 and ACAN synthesis. Stronger Safranin O staining was detected in rats treated with m-HDAC4 than in those treated with HDAC4. The resulting OARSI scores were lower in the Ad-m-HDAC4 group (5.80 ± 0.45) than in the Ad-HDAC4 group (9.67 ± 1.83, P = 0.045). The OARSI scores were highest in rat knees that underwent ACLT treated with Ad-GFP control adenovirus vector (14.93 ± 2.14, P = 0.019 compared with Ad-HDAC4 group; P = 0.003 compared with Ad-m-HDAC4 group). Lower Runx-2 and MMP-13 production, and stronger Col 2a1 and ACAN synthesis were detected in rats treated with m-HDAC4 than in those treated with HDAC4. CONCLUSIONS: M-HDAC4 repressed chondrocyte hypertrophy and induced chondrocyte anabolism in the nucleus. M-HDAC4 was more effective in attenuating articular cartilage damage than HDAC4.

Proteomics and Bioinformatics Analysis of Cartilage in Post-Traumatic Osteoarthritis in a Mini-Pig Model of Anterior Cruciate Ligament Repair.

BACKGROUND Although osteoarthritis (OA) is a degenerative disease that is increasingly common with age, the pathogenesis of post-traumatic OA (PTOA) is poorly understood. This study aimed to undertake proteomics and bioinformatics analysis of cartilage in PTOA in a mini-pig model of anterior cruciate ligament repair (ACLR). MATERIAL AND METHODS The mini-pig model of PTOA involved autologous orthotopic ACLR. Screening and identification of differentially expressed proteins in the knee joint cartilage in the OA cartilage group were compared with the control group using tandem mass tag (TMT)-labeling liquid chromatography with tandem mass spectrometry (LC-MS-MS). A protein expression level >1.2 fold-change represented protein upregulation and <0.83 fold-change represented protein down-regulation Bioinformatics analysis included Gene Ontology (GO) functional annotation and the Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis to determine the biological functions and pathways of proteins showing altered expression profiles associated with OA. RESULTS There were 2,950 proteins screened from the knee cartilage tissues of the OA model group using quantitative TMT-labeling LC-MS-MS. There were 491 proteins identified with altered expression profiles, 198 proteins were upregulated and 293 proteins were down-regulated in the OA cartilage group. GO function and KEGG pathway enrichment analysis of the 491 proteins identified their functions in cellular processes, metabolic processes, and biological regulation. CONCLUSIONS Proteomics and bioinformatics analysis of cartilage in PTOA in a mini-pig model of ACLR identified OA-related proteins.

Annexin A1 involved in the regulation of inflammation and cell signaling pathways.

With the deepening of research, proteomics has developed into a science covering the study of all the structural and functional characteristics of proteins and the dynamic change rules. The essence of various biological activities is revealed from the perspectives of the biological structure, functional activity and corresponding regulatory mechanism of proteins by proteomics. Among them, phospholipid-binding protein is one of the hotspots of proteomics, especially annexin A1, which is widely present in various tissues and cells of the body. It has the capability of binding to phospholipid membranes reversibly in a calcium ion dependent manner. In order to provide possible research ideas for researchers, who are interested in this protein, the biological effects of annexin A1, such as inflammatory regulation, cell signal transduction, cell proliferation, differentiation and apoptosis are described in this paper.

WITHDRAWN: Comparison of the accuracy between imageless navigation and manual freehand approaches for total hip arthroplasty: a systematic review and meta-analysis.

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A Novel Role for Protein Tyrosine Phosphatase 1B in Alleviating Chondrocyte Senescence.

Osteoarthritis (OA) is a kind of arthritis that impairs movement and causes joint discomfort. Recent research has demonstrated a connection between cellular senescence and the degenerative processes of OA chondrocytes. In yeast and human cells, protein tyrosine phosphatase 1B (PTP1B) knockdown prolongs longevity; however, the function of PTP1B in chondrocyte senescence has not been investigated. The goal of the current investigation was to evaluate PTP1B's contribution to human OA chondrocyte senescence. The function of PTP1B and cellular senescence in the onset of OA was investigated and confirmed by using a combination of bioinformatics techniques, clinical samples, and in vitro experimental procedures. The RNA sequencing data pertinent to the OA were obtained using the Gene Expression Omnibus database. Function enrichment analysis, protein-protein correlation analysis, the construction of the correlation regulatory network, and an investigation into possible connections between PTP1B and cellular senescence in OA were all carried out using various bioinformatic techniques. Compared with healthy cartilage, PTP1B expression was increased in OA cartilage. According to a Pearson correlation study, cellular senescence-related genes, including MAP2K1 and ABL1, were highly correlated with PTP1B expression levels in senescent chondrocytes. Furthermore, in vitro tests confirmed that PTP1B knockdown slowed cartilage degradation and prevented chondrocyte senescence in OA. In conclusion, we showed that PTP1B knockdown prevented the senescence of chondrocytes and prevented cartilage degradation in OA. These findings offer a fresh perspective on the pathophysiology of OA, opening up new avenues for OA clinical diagnosis and targeted treatment.

[Meta-analysis of the role of fibular fixation in tibiofibular fractures].

OBJECTIVE: To compare the role and importance of fibular fixation in tibiofibular fractures by Meta-analysis. METHODS: The literature related to the comparison of the efficacy of fixation of the fibula with or without fixation on the treatment of tibiofibular fractures was searched through the databases of China Knowledge Network, Wipu, Wanfang, The Cochrane Library, Web of science and Pubmed, and statistical analysis was performed using RevMan 5.3 software. The rates of malrotation, rotational deformity, internal/external deformity, anterior/posterior deformity, non-union, infection, secondary surgery and operative time were compared between the fibula fixation and non-fixation groups. RESULTS: A total of 11 publications were included, six randomised controlled trials and five case-control trials, eight of which were of high quality. A total of 813 cases were included, of which 383 were treated with fibula fixation and 430 with unfixed fibulae.Meta-analysis results showed that fixation of the fibulae in the treatment of tibiofibular fractures reduced the rates of postoperative rotational deformity[RR=0.22, 95%CI(0.10, 0.45), P<0.000 1] and internal/external deformity[RR=0.34, 95%CI(0.14, 0.84), P=0.02] and promoted fracture healing [RR=0.76, 95%CI(0.58, 0.99), P=0.04]. In contrast, the rates of poor reduction [RR=0.48, 95% CI(0.10, 2.33), P=0.36], anterior/posterior deformity[RR=1.50, 95%CI(0.76, 2.96), P=0.24], infection[RR=1.43, 95%CI(0.76, 2.72), P=0.27], secondary surgery[RR=1.32, 95%CI(0.82, 2.11), P=0.25], and operative time[MD=10.21, 95%CI(-17.79, 38.21), P=0.47] were not statistically significant (P>0.05) for comparison. CONCLUSION: Simultaneous fixation of the tibia and fibula is clinically more effective in the treatment of tibiofibular fractures.

TSP-1 increases autophagy level in cartilage by upregulating HSP27 which delays progression of osteoarthritis.

This study aimed to determine whether Thrombospondin-1 (TSP-1) can be used as a biomarker to diagnose early osteoarthritis (OA) and whether it has a chondroprotective effect against OA. We examined TSP-1 expression in cartilage, synovial fluid, and serum at different time points after anterior cruciate ligament transection (ACLT) surgery in rats. Subsequently, TSP-1 was overexpressed or silenced to detect its effects on extracellular matrix (ECM) homeostasis, autophagy level, proliferation and apoptosis in chondrocytes. Adenovirus encoding TSP-1 was injected into the knee joints of ACLT rats to test its effect against OA. Combined with proteomic analysis, the molecular mechanism of TSP-1 in cartilage degeneration was explored. Intra-articular injection of an adenovirus carrying the TSP-1 sequence showed chondroprotective effects against OA. Moreover, TSP-1 expression decreases with OA progression and can effectively promote cartilage proliferation, inhibit apoptosis, and helps to sustain the balance between ECM anabolism and catabolism. Overexpression of TSP-1 also can increase autophagy by upregulating Heat Shock Protein 27 (HSP27, hspb1), thereby enhancing its effect as a stimulator of autophagy. TSP-1 is a hopeful strategy for OA treatment.

Bibliometric study and visualization of cellular senescence associated with osteoarthritis from 2009 to 2023.

BACKGROUND: Osteoarthritis is a common degenerative joint disease that is highly prevalent in the elderly population. Along with the occurrence of sports injuries, osteoarthritis is gradually showing a younger trend. Osteoarthritis has many causative factors, and its pathogenesis is currently unknown. Cellular senescence is a stable form of cell cycle arrest exhibited by cells in response to external stimuli and plays a role in a variety of diseases. And it is only in the last decade or so that cellular senescence has gradually become cross-linked with osteoarthritis. However, there is no comprehensive bibliometric analysis in this field. The aim of this study is to present the current status and research hotspots of cellular senescence in the field of osteoarthritis, and to predict the future trends of cellular senescence in osteoarthritis research from a bibliometric perspective. METHODS: This study included 298 records of cellular senescence associated with osteoarthritis from 2009 to 2023, with data from the Web of Science Core Collection database. CiteSpace, Scimago Graphica software, VOSviewer, and the R package "bibliometrix" software were used to analyze regions, institutions, journals, authors, and keywords to predict recent trends in cellular senescence related to osteoarthritis research. RESULTS: The number of publications related to cellular senescence associated with osteoarthritis is increasing year by year. China and the United States contribute more than 70% of the publications and are the mainstay of research in this field. Central South University is the most active institution with the largest number of publications. International Journal of Molecular Sciences is the most popular journal in the field with the largest number of publications, while Osteoarthritis and Cartilage is the most cited journal. Loeser, Richard F. is not only the most prolific author, but also the most frequently cited author, contributing greatly to the field. CONCLUSION: In the last decade or so, this is the first bibliometric study that systematically describes the current status and development trend of research on cellular senescence associated with osteoarthritis. The study comprehensively and systematically summarizes and concludes the research hotspots and development trends, providing valuable references for researchers in this field.

Intra-articular injection of miRNA-1 agomir, a novel chemically modified miRNA agonists alleviates osteoarthritis (OA) progression by downregulating Indian hedgehog in rats.

Our objective in this study is to determine whether intra-articular injection of miRNA-1 can attenuate the progression of OA in rats by down regulating Ihh. Knee chondrocytes were isolated from male Sprague-Dawley rats aged 2-3 days. Second-generation chondrocytes were transfected with miR-1 mimic and empty vector with lipo3000 for 6 h and then stimulated with 10 ng/mL IL-1ß for 24 h. OA-related and cartilage matrix genes were quantified using real-time quantitative polymerase chain reaction (RT-qPCR). Two-month-old male Sprague-Dawley rats were divided into three groups (n = 30?): sham operation group + 50 µL saline, anterior cruciate ligament transection (ACLT) group + 50 µL miR-1 agomir (concentration), and control group ACLT + 50 µL miR-1 agomir. Treatment was started one week after the operation. All animals were euthanized eight weeks after the operation. X-rays and micro-CT were used to detect imaging changes in the knee joints. FMT was used to monitor joint inflammation in vivo. Safranin O staining was used to detect morphological changes in articular cartilage. Immunohistochemistry was used to detect Col2, Col10, metalloproteinase-13 (MMP-13). RT-qPCR was used to detect gene changes includingmiR-1, Col2, Col10, MMP-13, Ihh, Smo, Gli1, Gli2, and Gli3. Overexpression of miR-1 in IL-1ß-stimulated chondrocytes reduced the levels of Ihh, MMP-13, and Col10 but increased the levels of Col2 and aggrecan. Intra-articular injection of miR-1 agomir reduced osteophyte formation, inflammation, and prevented cartilage damage. RT-qPCR results indicated that the miR-1 agomir increased articular cartilage anabolism and inhibited cartilage catabonism. miR-1 can attenuate the progression of OA by downregulating Ihh.

[Preliminary clinical experience on radiofrequency catheter ablation of right-sided accessory pathway guided by Ensite-NavX navigation].

OBJECTIVE: To explore the feasibility and methodology of radiofrequency catheter ablation (RFCA) guided by 3D navigation system (Ensite-NavX) for right atrioventricular accessory pathway. METHOD: Thirty-three cases of right accessory pathway atrioventricular reentrant tachycardia including 16 cases in right free wall, 3 in right middle septum, 14 in right posterior septum; 23 cases of dominant accessory pathway and 10 cases of concealed were treated by RFCA guided by NavX navigation. NavX navigation modeling method or spatial localization method was exploited to locate target positioning. RESULT: All patients were successfully ablated without serious complications. Among them, 25 cases were operated without exposure to X-ray, 7 patients were exposed for several seconds to verify catheter position, 1 case in right free wall was ablated under X-ray combined with Swartz sheath ablation. CONCLUSION: Nonfluoroscopy or less fluoroscopy RFCA for right atrioventricular accessory pathway with Ensite-NavX is safe and feasible, modeling or spatial orientation method are helpful to locate the ablation target positioning.

MiR-1 is a critical regulator of chondrocyte proliferation and hypertrophy by inhibiting Indian hedgehog pathway during postnatal endochondral ossification in miR-1 overexpression transgenic mice.

Endochondral bone formation from the growth plate plays a critical role in vertebrate limb development and skeletal homeostasis. Although miR-1 is mainly expressed in the hypertrophic region of the growth plate during this process, its role in the endochondral bone formation is unknown. To elucidate the role of miR-1 in cartilage development, chondrocyte-specific transgenic mice with high expression of miR-1 were generated (Col2a1-Cre-ERT2-GFPfl/fl-RFP-miR-1). Transgenic mice showed short limbs and delayed formation of secondary ossification centers. In the tibia growth plate of miR-1-overexpressing transgenic mice, the chondrocytes in the proliferative zone were disorganized and their proliferation decreased, and the ColX, MMP-13 and Indian Hedgehog (IHH) in chondrocytes showed a downward trend, resulting in decreased terminal differentiation in the hypertrophic zone. In addition, the apoptosis index caspase-3 also showed a downward trend in the tibia growth plate. It was concluded that miR-1 overexpression affects chondrocyte proliferation, hypertrophic differentiation, and apoptosis, thereby delaying the formation of secondary ossification centers and leading to short limbs. It was also verified that miR-1 affects endochondral ossification through the IHH pathway. The above results suggest that miR-1 overexpression can affect endochondral osteogenesis by inhibiting chondrocyte proliferation, hypertrophic differentiation, and apoptosis, thus causing limb hypoplasia in mice. This work gives potential for new therapeutic directions and insights for the treatment of dwarf-related diseases.

[Comparison of cryoablation and radiofrequency ablation for treating atrioventricular nodal reentrant tachycardia].

OBJECTIVE: To compare the efficacy and safety between cryoablation (Cryo) and radiofrequency (RF) ablation for treating patients with atrioventricular nodal reentrant tachycardia (AVNRT). METHODS: Patients with AVNRT (n = 304) were divided into Cryo group (n = 67) and RF group (n = 237). The procedure success rate, complete slow pathway block rate, atrioventricular block rate and relapse rate were compared between two groups. RESULTS: There was no statistically difference between 2 groups in the success rate (Cryo group 98.5% vs RF group 97.0%, P = 0.820), complete slow pathway block rate (Cryo group 98.5% vs RF group 91.6%, P = 0.088), atrioventricular block rate (Cryo group 0 vs RF group 2.5%, P = 0.413), relapse rate (Cryo group 0 vs RF group 1.7%, P = 0.643). But Cryo group had more advantage than RF group. CONCLUSION: Efficacy and safety were comparable between cryoablation and radiofrequency ablation for treating patients with AVNRT.

MicroRNA-1 promotes cartilage matrix synthesis and regulates chondrocyte differentiation via post-transcriptional suppression of Ihh expression.

Indian hedgehog signaling molecule (Ihh) is known to play critical roles in chondrogenesis and cartilage development. However, it remains largely unknown how Ihh is regulated during the process. Previous studies suggest that Ihh plays an important regulatory role in the growth and development of articular cartilage, but whether it is regulated by miRNAs is unclear. The present study aimed to investigate the effects of miR­1 on chondrocyte differentiation and matrix synthesis, and to determine whether miR­1 can regulate the Ihh signaling pathway. In the present study, the expression level of miR­1 was altered via transfection of the miR­1 mimic or inhibitor in mouse thorax chondrocytes, and the impact on chondrocyte phenotypes and Ihh expression was examined. Overexpression of miR­1 promoted the expression of the matrix synthesis­associated molecules collagen (Col)­II and aggrecan, two key components in cartilage matrix. Conversely, overexpression of miR­1 significantly downregulated the expression of chondrocyte differentiation markers Col­X and matrix metallopeptidase 13. Moreover, overexpression of miR­1 dose­dependently inhibited endogenous Ihh expression, and an association was observed between miR­1 and Ihh expression. The 3' untranslated region (UTR) of Ihh from various species contains two miR­1 binding sites. Luciferase reporter assays indicated that miR­1 post­transcriptionally suppressed Ihh expression, which was dependent on the binding of miR­1 to one of the two putative binding sites of the Ihh 3'UTR. Furthermore, via inhibition of Ihh expression, miR­1 decreased the expression of molecules downstream of Ihh in the Hedgehog signaling pathway in mouse thorax chondrocytes. This study provided new insight into the molecular mechanisms of miR­1 in regulating chondrocyte phenotypes via targeting the Ihh pathway.

MicroRNA­1 regulates the development of osteoarthritis in a Col2a1­Cre­ERT2/GFPfl/fl­RFP­miR­1 mouse model of osteoarthritis through the downregulation of Indian hedgehog expression.

The present study assessed the effects of microRNA­1 (miR­1) on the development of osteoarthritis using human tissues and a Col2a1­Cre­ERT2/GFPfl/fl­RFP­miR­1 mouse model of osteoarthritis. Human cartilage tissues (n=20) were collected for reverse transcription­quantitative polymerase chain reaction (RT­qPCR), histological analysis and immunohistochemistry experiments. A transgenic mouse model of osteoarthritis was established by subjecting Col2a1­Cre­ERT2/GFPfl/fl­RFP­miR­1 transgenic mice to anterior cruciate ligament transection (ACLT). Mice were subjected to radiography and in vivo fluorescence molecular tomography (FMT), while mouse tissues were collected for histological analysis, RT­qPCR and Safranin O staining. It was found that the miR­1 level was downregulated, whereas the levels of Indian hedgehog (Ihh), as well as those of its downstream genes were upregulated in human osteoarthritic cartilage. In the transgenic mice, treatment with tamoxifen induced miR­1, as well as collagen, type II (Col2a1) and Aggrecan (Acan) expression; however, it decreased Ihh, glioma­associated oncogene homolog (Gli)1, Gli2, Gli3, smoothened homolog (Smo), matrix metalloproteinase (MMP)­13 and collagen type X (Col10) expression. Safranin O staining revealed cartilage surface damage in the non­tamoxifen + ACLT group, compared with that in the tamoxifen + ACLT group. Histologically, an intact cartilage surface and less fibrosis were observed in the tamoxifen + ACLT group. Immunohistochemistry revealed that the protein expression of Ihh, Col10, and MMP­13 was significantly higher in the joint tissues of the non­tamoxifen + ACLT group than in those of the tamoxifen + ACLT group. However, Col2a1 expression was lower in the joint tissues of the non­tamoxifen + ACLT group than in those of the tamoxifen + ACLT group. The results of RT­qPCR and FMT further confirmed these findings. On the whole, the findings of the present study demonstrate that miR­1 expression protects against osteoarthritis­induced cartilage damage and gene expression by inhibiting Ihh signaling.

Adenovirus-mediated transduction with Histone Deacetylase 4 ameliorates disease progression in an osteoarthritis rat model.

BACKGROUND: Downregulation of histone deacetylase-4 (HDAC4) contributes to cartilage degeneration in osteoarthritis (OA) because it promotes upregulation of runt-related transcription factor-2 (Runx-2) and osteoarthritis-related genes. The effect of HDAC4 upregulation on cartilage damage in OA remains unknown. METHODS: Rat chondrocytes were infected with Ad-GFP or Ad-HDAC4-GFP for 48 h, stimulated with interleukin-1ß (IL-1ß, 10 ng/mL) for 24 h, and then harvested for RT-qPCR. Male Sprague-Dawley rats in 3 groups were given anterior cruciate ligament transection (ACLT) or sham operation, and knee injections with different adenovirus (Ad) vectors at 48 h after surgery and every 3 weeks thereafter: ACLT+Ad-GFP (n = 17); ACLT+Ad-HDAC4-GFP (n = 20); and sham+Ad-GFP (n = 15). Three ACLT-Ad-HDAC4-GFP rats were sacrificed at different times to examine the expression of HDAC4. Two ACLT-Ad-GFP rats and two ACLT-Ad-HDAC4-GFP rats were euthanized at week-2; articular cartilage was harvested and expression of HDAC4 was determined by RT-qPCR. All other rats were euthanized at week-8. Cartilage damage and OA progression was assessed using radiography, fluorescence molecular tomography (FMT), histology, immunohistochemistry (IHC), ELISA, and RT-qPCR. RESULTS: Overexpression of HDAC4 in chondrocytes stimulated by IL-1ß reduced the levels of Runx-2, MMP-13, and Collagen X, but increased the levels of Collagen II and Aggrecan. Upregulation of HDAC4 reduced osteophyte formation and cartilage damage, and increased articular cartilage anabolism. CONCLUSION: HDAC4 attenuated articular cartilage damage by repression of Runx-2, MMP-13, and collagen X and induction of collagen II and ACAN in this rat model of OA. Upregulation of HDAC4 may provide chondroprotection in OA patients.

Cholesterol pericarditis associated with rheumatoid arthritis: A rare case report.

BACKGROUND: Cholesterol pericarditis (CP) is a special type of pericarditis. It is characterized by chronic pericardial effusion with high cholesterol concentration and with or without the formation of crystals in pericardial effusion. METHODS: In this case report, we described a 74-year-old male with massive pericardial effusion. He presented with no symptoms. However, he had 8-year history of rheumatoid arthritis medicated with methotrexate, celecoxib, and prednisone, and 5-year history of hypertension medicated with amlodipine besylate. On admission, transthoracic echocardiography revealed a large pericardial effusion. RESULTS: We performed pericardiocentesis for this patient and a lot of cholesterol crystals were found in pericardial effusion under the microscope. A successful operation of thoracoscopic pericardiectomy was proceeded, and the diagnosis was confirmed by surgical pathology. The patient was well recovered and discharged on the tenth day after surgery. It could be predicted that pericardiectomy under video-assisted thoracoscope could be a promising therapy for CP. CONCLUSION: Rheumatoid arthritis may cause CP with no symptoms. Pericardiectomy could be a promising therapy for CP.

Association of blood pressure level with nonalcoholic fatty liver disease in nonhypertensive population: Normal is not the new normal.

The functional crosstalk between nonalcoholic fatty liver disease (NAFLD) and hypertension has been reported by some literatures; however, in nonhypertensive individuals, there is no article describes the characteristic of NAFLD. In this study, we aimed to determine the strength of the association between NAFLD with normal blood pressure (BP) in nonhypertensive individuals. This cross-sectional study was conducted in the sixth Affiliated Hospital of Wenzhou Medical University, from October 2007 to December 2011. In brief, 24,200 subjects were enrolled to participate in the survey. Among those subjects, there were 5305 enrolled subjects, those with filling the diagnostic criteria for NAFLD (21.9%; 4803 males and 502 females). Nonhypertension was identified in 17,403 (71.9%; 8179 males and 9224 females). The PR% of NAFLD for the systolic blood pressure (SBP) in quartiles 1 to 4 was 10.83, 12.55, 20.38, and 19.97. SBP, diastolic blood pressure (DBP), sex, age, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, fasting plasma glucose, uric acid, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol are closely associated with the risk for NAFLD. SBP (odds ratio [OR]: 1.092, 95% confidence interval [CI]: 1.030-1.158; P < 0.05) and DBP (OR: 1.157, 95%CI: 1.094-1.223; P < 0.05) were found to be independent risk factors for NAFLD. Our analysis indicates that BP is significantly associated with NAFLD in nonhypertensive individuals; SBP and DBP are found to be independent risk factors for NAFLD.