Loop technique for anterior cruciate ligament reconstruction combined with anterolateral structure reinforcement: technical description and clinical results.

PURPOSE: We describe a surgical technique for ACL reconstruction combined with anterolateral structure reinforcement and report early clinical follow-up results. METHODS: The semitendinosus and gracilis tendons are braided into 5 strands and the ACL femoral tunnel and tibial tunnel are created. The graft is passed through the tunnel with the use of a traction suture and the tibial end is fixed with absorbable interference screws at 30° of knee flexion. The ACL graft traction suture is used as an anterolateral reconstruction structure to pass through the proximal exit of the ACL femoral tunnel and then through the depth of the iliotibial bundle to the anterior to Gerdy's tubercle, a bony tunnel is created from the anterior to Gerdy's tubercle to the goose foot, and the traction suture is passed through this bony tunnel to form a Loop structure at 20° of knee flexion. Between March 2021 and May 2022 IKDC score, Lysholm score, and Tegner score were performed preoperatively and 6-12 months postoperatively in 24 consecutive patients who met the indications for this procedure and underwent surgery. The patient's maximum flexion angle, the circumference of the thigh, and the stress X-ray between the operated and healthy knee were measured. RESULTS: Patients showed significant improvement in IKDC score, Lysholm score and Tegner score at a mean follow-up of 7 months postoperatively compared to preoperatively. No significant increase in anterior tibial displacement was found between the patient's operated side and the healthy side. CONCLUSION: The Loop technique ACLR combined with ALSA can be used in patients with an ACL tear combined with a high degree of positive pivot shift. The patient's subjective perception was significantly improved from the preoperative period and knee stability was restored. LEVEL OF EVIDENCE: IV, therapeutic study.

Hyperactive lateral habenula mediates the comorbidity between rheumatoid arthritis and depression-like behaviors.

Rheumatoid arthritis (RA) patients have a high prevalence for depression. On the other hand, comorbid with depression is associated with worse prognosis for RA. However, little is known about the underlying mechanisms for the comorbidity between RA and depression. It remains to be elucidated which brain region is critically involved in the development of depression in RA, and whether alterations in the brain may affect pathological development of RA symptoms. Here, by combining clinical and animal model studies, we show that in RA patients, the level of depression is significantly correlated with the severity of RA disease activity and affects patients' quality of life. The collagen antibody-induced arthritis (CAIA) mouse model of RA also develops depression-like behaviors, accompanied by hyperactivity and alterations in gene expression reflecting cerebrovascular disruption in the lateral habenula (LHb), a brain region critical for processing negative valence. Importantly, inhibition of the LHb not only alleviates depression-like behaviors, but also results in rapid remission of RA symptoms and amelioration of RA-related pathological changes. Together, our study highlights a critical but previously overlooked contribution of hyperactive LHb to the comorbidity between RA and depression, suggesting that targeting LHb in conjunction with RA treatments may be a promising strategy for RA patients comorbid with depression.

A Mendelian randomization study on causal effects of leisure sedentary behaviour on the risk of rheumatoid arthritis.

BACKGROUND: The causal inference between leisure sedentary behaviour (LSB) and rheumatoid arthritis (RA) is still controversial because of potential residual confounding and reverse causality. METHODS: The present study used publicly available large-scale genome-wide association studies (GWAS) of LSB (television watching, computer use, and driving) and RA to perform a two-sample Mendelian randomization (MR) study to evaluate the causal effect of LSB on the risk of RA. We detected significant causal associations using the multiplicative random effects-inverse variance weighted (MRE-IVW) method, the maximum likelihood, robust adjusted profile scores, the weighted median, MR-Egger regression, and several complementary sensitivity analyses. Risk factor analysis was also conducted to further investigate potential mediators linking causal inference. RESULTS: Increased genetic liability to leisure television watching was significantly associated with a higher risk of RA (MRE-IVW method; OR = 2.46, 95% CI 1.77-3.41; p = 8.35 × 10-8 ). MR estimates indicated that prolonged leisure computer use was causally associated with a lower risk of RA (MRE-IVW method; OR = 0.23, 95% CI 0.12-0.46; p = 2.19 × 10-5 ). However, we found no evidence for a causal effect of leisure driving on the risk of RA (MRE-IVW method; OR = 0.59, 95% CI 0.10-3.41; p = 0.557). No pleiotropy was detected by the sensitivity analysis. CONCLUSIONS: This study supports a causal association between prolonged leisure television watching and an increased risk of RA. Additionally, prolonged computer use might be a protective factor for RA.

Mendelian randomization study on the causal effects of systemic lupus erythematosus on major depressive disorder.

The vast majority of epidemiological studies suggested a link between systemic lupus erythematosus (SLE) and major depressive disorder (MDD). However, the causality for SLE on the risk of MDD remained unknown due to confounding factors or reverse causality. Herein, we investigated the causality between SLE and MDD in those of European ancestry by a Mendelian randomization (MR) approach. Summary genetic data of cases with SLE/MDD were derived from independent largest public genome-wide association study. Forty-six single nucleotide polymorphisms associated with SLE were used as instrumental variables. The main causal inference was carried out using the MRE-IVW method. Additional, reverse-direction MR and multivariable MR analyses were further performed. Result indicated that SLE was causally associated with a lower risk of MDD (using the MRE-IVW method, odds ratio [OR] = 0.983, 95% confidence interval [CI] = 0.974-0.991, p = 1.18 × 10-4). Complementary analysis found no heterogeneity or horizontal pleiotropy. Multivariate MR analysis yielded consistent results (OR = 0.981; 95% CI = 0.969-0.993; p = 2.75 × 10-3). Reverse-direction MR analysis suggested non-causal relationship of MDD on the risk of SLE (using the IVW method, OR = 0.846, 95% CI = 0.345-2.072; p = 0.714). Thus, this is the first study providing evidence of potential causal links between SLE and MDD and further related research is needed.

A functional role of meningeal lymphatics in sex difference of stress susceptibility in mice.

Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to the peripheral immune system. Their potential role in depression-like behaviour has not been investigated. Here, we show in mice, sub-chronic variable stress as a model of depression-like behaviour impairs meningeal lymphatics in females but not in males. Manipulations of meningeal lymphatics regulate the sex difference in the susceptibility to stress-induced depression- and anxiety-like behaviors in mice, as well as alterations of the medial prefrontal cortex and the ventral tegmental area, brain regions critical for emotional regulation. Together, our findings suggest meningeal lymphatic impairment contributes to susceptibility to stress in mice, and that restoration of the meningeal lymphatics might have potential for modulation of depression-like behaviour.

The Role of 6-Minute Walk Test Guided by Impedance Cardiography in the Rehabilitation Following Knee Arthroplasty: A Randomized Controlled Trial.

Objective: To explore the effect of the 6-minute walk test (6MWT) guided by non-invasive cardiac output on the rehabilitation of patients with knee osteoarthritis following artificial total knee arthroplasty. Methods: About 66 patients with knee osteoarthritis planned to undergo artificial total knee arthroplasty were included from March 2019 to October 2019, and randomly assigned to the intervention group or control group. Under the guidance of a clinical rehabilitation physician, orthopedic physician, and cardiologist, a home rehabilitation exercise program based on 6MWT and non-invasive cardiac output was formulated for patients with knee osteoarthritis. The participants of the intervention group conducted full rehabilitation training supervision and guidance through the WeChat platform to ensure their rehabilitation pieces of training were completed safely and effectively. As for the control group, patients were just given rehabilitation training manuals at the time of discharge and completed the training by themselves. Results: At 6 months post-operatively, 6-minute walk distance (413.88 ± 44.61 vs. 375.00 ± 40.53 m, P < 0.05), active metabolic equivalent (4.13 ± 0.29 vs. 3.88 ± 0.27, P < 0.05), stroke volume after 6MWT (114.97 ± 12.05 vs. 98.38 ± 16.43 ml, P < 0.05), and cardiac output (11.92 ± 1.68 vs. 9.79 ± 1.82 l/min, P < 0.05) of the intervention group were significantly higher than those of the control group. The symptom evaluation scores of the intervention group were also better than those of the control group. Conclusions: The multidisciplinary post-operative rehabilitation exercise training program is beneficial to the recovery of lower limb function and the improvement of exercise capacity after knee replacement, and it also helps to improve the non-invasive hemodynamic indicators related to the cardiac function of the patient. Clinical Trial Registration: http://www.chictr.org.cn/index.aspx.

Causal relationship between educational attainment and the risk of rheumatoid arthritis: a Mendelian randomization study.

BACKGROUND: Educational attainment is moderately heritable and inversely associated with the risk of rheumatoid arthritis. However, the causality from educational attainment on rheumatoid arthritis remained unknown. Here, we aimed to determine whether educational attainment is causally associated with rheumatoid arthritis (RA) by using Mendelian randomization (MR) approach. METHODS: Summary statistics data for RA were obtained from an available, published meta-analysis of genome-wide association studies (GWAS) that included 14,361 RA cases and 43,923 controls of European ancestry. The instrumental variables for educational attainment were obtained from a GWAS meta-analysis that included over 1 million individuals (N = 1,131,881) of European ancestry. MR analyses were mainly performed using the inverse-variance weighted (IVW) method. Sensitivity analyses were further performed to test the robustness of the association using the weighted median method, MR-Egger, Cochran Q test, "leave-one-out" analysis and MR-PRESSO test. RESULTS: A total of 387 SNPs were employed as instrumental variables in our MR analysis. Genetically predicted higher educational attainment was associated with a significantly lower risk of RA using the IVW method (odds ratio [OR] = 0.42, 95% confidence interval [CI]: 0.34-0.52; p = 1.78 × 10- 14). The weighted median method and MR Egger regression analysis yielded consistent results. The effect estimate remained robust after the outlier variants and SNPs (associated with the confounding factors) were excluded. "Leave-one-out" analysis confirmed the stability of our results. Additionally, the results suggested the absence of the horizontal pleiotropy. CONCLUSIONS: The MR analysis supported a potential inverse causative relationship between educational attainment and the risk of RA.

Causal Relationship Between Parathyroid Hormone and the Risk of Osteoarthritis: A Mendelian Randomization Study.

BACKGROUND: Previous studies have demonstrated an inverse association between parathyroid hormone (PTH) and the risk of osteoarthritis (OA). However, it remains unknown whether such association reflects causality. We aimed to apply a Mendelian randomization (MR) approach to investigate the causal association between PTH and OA. MATERIALS AND METHODS: We performed a two-sample MR analysis using summary statistics from 13 cohorts (PTH, N = 29,155) and a recent genome-wide association study meta-analysis (OA, N = 455,221) by the UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). MR analyses were carried out mainly using the inverse-variance-weighted method. Sensitivity analyses were performed to test the robustness of the associations using the weighted median method, the MR-Egger method, and "leave-one-out" analysis. Analyses were performed again to test whether the associations remained statistically significant after excluding any outlier variants that were detected using the MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) test. RESULTS: Five single-nucleotide polymorphisms (SNPs) were selected as instrumental variables at the genome-wide significance threshold (p < 5 × 10-8). The causal effect between PTH and OA was genetically predicted using the inverse-variance-weighted method (odds ratio = 0.67, 95% confidence interval: 0.50-0.90; p = 0.008). This result was borne out using the weighted median method (odds ratio = 0.73, 95% confidence interval: 0.60-0.90; p = 0.004). The causality remained robust after discarding the outlier variants as well as SNPs associated with confounding factors. CONCLUSION: MR analysis supported a potential causative relationship between decreased serum circulating PTH and a higher risk of hip and knee OA.

Involuntary, forced or voluntary exercise can ameliorate the cognitive deficits by enhancing levels of hippocampal NMDAR1, pAMPAR1 and pCaMKII in a model of vascular dementia.

Objectives: To investigate the effect on vascular dementia of involuntary exercise induced by functional electrical stimulation and of forced and voluntary exercise, focusing on the recovery of cognitive function and using a rat model of dementia.Methods: A demential model was created in Wistar rats who were then given forced exercise, allowed voluntary exercise (wheel running) or had exercise induced through functional electrical stimulation. Their responses were quantified using a Morris water maze and by measuring long-term potentiation in the hippocampus. Immunohistochemical staining was used to evaluate neurogenesis in the hippocampus and Nissl staining was applied to visualize viable neuron loss in the DG sector. In addition, the levels of NMDAR1, AMPAR1, pAMPAR1, pCaMKII, CaMKII, Bcl-2 and Bax in the hippocampus were assessed by western blotting.Results: All of the exercise groups showed a recovery of cognitive performance and improved long-term potentiation. The three modes of exercise all increased the number of DCX immunopositive cells and reduced losses of intact-appearing neurons in the hippocampal DG zones roughly equally. All proved about equally effective in increasing the levels of NMDAR1, pAMPAR1 and pCaMKII and increasing the Bcl-2/Bax ratio to protect neurons from apoptosis.Conclusion: Exercise induced by electrical stimulation has beneficial effects comparable to those of other types of exercise for alleviating the cognitive deficits of vascular dementia.

Residual Mild Varus Alignment and Neutral Mechanical Alignment Have Similar Outcome after Total Knee Arthroplasty for Varus Osteoarthritis in Five-Year Follow-Up.

The effect of residual varus on survival rate and function in patients with varus knee osteoarthritis (OA) was considered an important issue for successful primary total knee arthroplasty (TKA). In this study, we compared the midterm clinical and functional outcomes in patients with different residual varus. A retrospective review of 175 patients (219 knees) with varus OA was > 3° for the hip-knee-ankle (HKA) who underwent primary TKA after exclusions and loss to follow-up from 237 patients (281 knees). The mean follow-up period was 5.2 ( ± 1.1) years. Patients were divided into four groups according to the first postoperative HKA angle from weight-bearing full-leg radiographs: "valgus" group (HKA angle > 0°, n = 44), "neutral" group (-3° ≤ HKA angle < 0°, n = 86), "mild varus" group (-6° ≤ HKA angle < -3°, n = 62), and "severe varus" group (HKA angle < -6°, n = 27). Survival analysis, Knee Society Score (KSS, including knee score and functional score), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were compared among the four groups. No knee required revision surgery during follow-up. For the KSS knee score and functional score at the last follow-up, the neutral and mild varus groups were better compared with the valgus and severe varus groups (p < 0.05), and there were no significant differences between the neutral and mild varus groups (p > 0.05). WOMAC scores of the neutral and mild varus groups were also better compared with the valgus and severe varus groups (p < 0.05), and there were no significant differences between the neutral and mild varus groups at the last follow-up. The postoperative HKA angle was significantly changed in valgus group between first and at the last follow-up when compared with the other three groups (p < 0.05). Leaving an HKA angle at < 6° varus had the same excellent functional outcome as neutral mechanical alignment after TKA for varus-type OA in the 5-year follow-up, using mechanically aligned technique. Caution is advised when leaving valgus or leaving severe varus after TKA.

Platelet-Rich Plasma Vs Autologous Blood Vs Corticosteroid Injections in the Treatment of Lateral Epicondylitis: A Systematic Review, Pairwise and Network Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To compare the effectiveness of platelet-rich plasma (PRP), autologous blood (AB), and corticosteroid injections in patients with lateral epicondylitis. TYPE OF STUDY: Network meta-analysis. LITERATURE SURVEY: Randomized controlled trials (RCTs) that compared any two forms of injections among PRP, AB, and corticosteroid for the treatment of lateral epicondylitis were searched from inception to 30 November 2018, on PubMed, Embase, and Cochrane library. METHODOLOGY: Two researchers independently selected and assessed the quality of RCTs with the Cochrane Risk of Bias Tool. All relevant data from the included studies were extracted and heterogeneity was checked by Cochran's Q test and inconsistency statistic (I2 ). Publication bias was evaluated by constructing contour-enhanced funnel plots. Stata 15 software was applied for pairwise meta-analysis and network meta-analysis. To explore the efficacy between different follow-up periods, we considered the duration within 2 months to be short term, whereas 2 months or more was considered long term. SYNTHESIS: Twenty RCTs (n = 1271) were included in this network meta-analysis. According to ranking probabilities, corticosteroid ranked first for visual analog score (VAS) (surface under the cumulative ranking [SUCRA] = 90.7), modified Nirschl score (82.9), maximum grip strength (69.5), modified Mayo score (MMS) (77.9), and Patient-Related Tennis Elbow Evaluation (PRTEE) score (93.3) for the short-term period. For the long-term period, PRP ranked first for VAS (94.3), pressure pain threshold (99.8), Disabilities of Arm Shoulder and Hand (DASH) score (75.2), MMS (88.2), and the PRTEE score (81.8). CONCLUSION: PRP was associated with more improvement in pain intensity and function in the long term than were the comparators. However, in the short term, corticosteroids were associated with the most improvement.

Single-cell RNA-seq analysis identifies meniscus progenitors and reveals the progression of meniscus degeneration.

OBJECTIVES: The heterogeneity of meniscus cells and the mechanism of meniscus degeneration is not well understood. Here, single-cell RNA sequencing (scRNA-seq) was used to identify various meniscus cell subsets and investigate the mechanism of meniscus degeneration. METHODS: scRNA-seq was used to identify cell subsets and their gene signatures in healthy human and degenerated meniscus cells to determine their differentiation relationships and characterise the diversity within specific cell types. Colony-forming, multi-differentiation assays and a mice meniscus injury model were used to identify meniscus progenitor cells. We investigated the role of degenerated meniscus progenitor (DegP) cell clusters during meniscus degeneration using computational analysis and experimental verification. RESULTS: We identified seven clusters in healthy human meniscus, including five empirically defined populations and two novel populations. Pseudotime analysis showed endothelial cells and fibrochondrocyte progenitors (FCP) existed at the pseudospace trajectory start. Melanoma cell adhesion molecule ((MCAM)/CD146) was highly expressed in two clusters. CD146+ meniscus cells differentiated into osteoblasts and adipocytes and formed colonies. We identified changes in the proportions of degenerated meniscus cell clusters and found a cluster specific to degenerative meniscus with progenitor cell characteristics. The reconstruction of four progenitor cell clusters indicated that FCP differentiation into DegP was an aberrant process. Interleukin 1ß stimulation in healthy human meniscus cells increased CD318+ cells, while TGFß1 attenuated the increase in CD318+ cells in degenerated meniscus cells. CONCLUSIONS: The identification of meniscus progenitor cells provided new insights into cell-based meniscus tissue engineering, demonstrating a novel mechanism of meniscus degeneration, which contributes to the development of a novel therapeutic strategy.

Best bone of acetabulum for cup component placement in Crowe types I to III dysplastic hips: a computer simulation study.

BACKGROUND: During cup implantation, vertical height of the cup center (V-HCC) should be precisely controlled to achieve sufficient bone-cup coverage (BCC). Our study aimed to investigate the acetabular bone stock and the quantitative relationship between V-HCC and BCC in Crowe types I to III hips. METHODS: From November 2013 to March 2016, pelvic models of 51 patients (61 hips) with hip dysplasia were retrospectively reconstructed using a computer software. Acetabular height and doom thickness were measured on the mid-acetabular coronal cross section. V-HCC was defined as the vertical distance of cup rotational center to the interteardrop line (ITL). In the cup implantation simulation, the cup was placed at the initial preset position, with a V-HCC of 15 mm, and moved proximally by 3-mm increments. At each level, the BCC was automatically calculated by computer. Analysis of variance and Kruskal-Wallis test were used to compare the differences between groups. RESULTS: There were no significant between-group differences in maximum thickness of the acetabular doom; however, peak bone stock values were obtained at heights of 41.63 ±â€Š5.14 mm (Crowe type I), 47.58 ±â€Š4.10 mm (Crowe type II), and 55.78 ±â€Š3.64 mm (Crowe type III) above the ITL. At 15 mm of V-HCC, median BCC was 78% (75-83%) (Crowe type I), 74% (66-71%) (Crowe type II), and 61% (57-68%) (Crowe type III). To achieve 80% of the BCC, the median V-HCC was 16.27 (15.00-16.93) mm, 18.19 (15.01-21.53) mm, and 24.13 (21.02-28.70) mm for Crowe types I, II, and III hips, respectively. CONCLUSION: During acetabular reconstruction, slightly superior placement with V-HCC <25 mm retained sufficient bone coverage in Crowe I to III hips.

MicroRNA-320c inhibits development of osteoarthritis through downregulation of canonical Wnt signaling pathway.

AIMS: Osteoarthritis (OA) is a leading cause of deformity in aging people. Emerging evidence suggests that microRNAs and Wnt signaling pathway are associated with its pathogenesis. We aimed to determine whether microRNA-320c inhibits the development of osteoarthritis by suppressing Wnt signaling pathway. MATERIALS AND METHODS: MiR-320c and ß-catenin expression was assessed in human adipose derived stem cells (hADSCs) model of chondrogenesis and in normal and OA primary human chondrocytes. OA chondrocytes were transfected with miR-320c or its antisense inhibitor and ß-catenin siRNA respectively. Direct interaction between miR-320c and ß-catenin mRNA as well as activity of ß-catenin/TCF complex were confirmed by luciferase reporter assay. Mmu-miR-320-3p agomir was intra-articularly injected in collagenase-induced OA mouse model. OA progression was evaluated histologically and immunohistochemically. KEY FINDINGS: MiR-320c was decreased and ß-catenin was increased in OA chondrocytes and late stage of hADSCs chondrogenesis. Overexpression of miR-320c and knockdown of ß-catenin had similar effects that the cartilage-specific genes were elevated and hypertrophy-related genes were down-regulated in OA chondrocytes. Luciferase reporter assay confirm that miR-320c regulated the expression of ß-catenin by directly targeting 3'UTR of ß-catenin mRNA and decreased the relative transcriptional activity of the ß-catenin/TCF complex. Injection of mmu-miR-320-3p attenuated OA progression in the OA mouse model. SIGNIFICANCE: Our results supports that miR-320c can inhibits the degeneration of osteoarthritis chondrocytes via suppressing the canonical Wnt signaling pathway and indicates the potential of miR-320c as a novel therapeutic agent for osteoarthritis treatment.

Value of Computed Tomography-Based Three-Dimensional Pre-operative Planning in Cup Placement in Total Hip Arthroplasty With Dysplastic Acetabulum.

Objects: To investigate the value of CT-based 3D templating software for pre-operative planning in patients with acetabular dysplasia undergoing total hip arthroplasty (THA) with a minimum follow-up of 2 years. Methods: We performed a retrospective review of a single surgeon's cohort of patients with Crowe I to III developmental dysplastic hip (49 hips in 41 patients) who underwent cementless primary THA and were available for follow-up at a mean of 2.7 years after THA. We analyzed the accuracy of cup size prediction, the reliability of pre- and post-operative cup orientation and position of reconstructed rotation center using CT-based 3D templating software. Post-operative Harris Hip Score and lower limb discrepancy was obtained at the last follow-up. Results: The sizes of 71% of the cup components (35/49) were estimated exactly, and 100% of the cup size estimates were accurate to within one-cup size. There was good reproducibility of pre- and post-operative position of reconstructed rotation center (correlation coefficient r = 0.396 for vertical position, p = 0.005; r = 0.326 for horizontal position, p = 0.024). There was no substantial agreement between the planned acetabular orientation and that measured post-operatively (correlation coefficient -0.174 for inclination and 0.045 for anteversion). There were 44 (90%) excellent or good results according to HHS. Seven patients (14%) reported lower limb discrepancy. Conclusions: Pre-operative CT-based 3D templating made it possible to predict accurate cup size and achieve reproducible cup position in patients with dysplastic acetabulum. The reproducibility of cup orientation could not be demonstrated in this study.

CDK6 and miR-320c Co-Regulate Chondrocyte Catabolism Through NF-κB Signaling Pathways.

BACKGROUND/AIMS: Cyclin-dependent kinase 6 (CDK6) regulates inflammatory response and cell differentiation. This study sought to determine whether CDK6 and miR-320c co-regulate chondrogenesis and inflammation. METHODS: Utilizing quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC), CDK6 and miR-320c expression were assessed in a micromass culture of human bone mesenchymal stem cells that underwent chondrogenesis in vitro as well as in chondrocytes from E16.5 mouse forelimbs. Normal chondrocytes were transfected with miR-320c mimic, miR-320c inhibitor, or CDK6-siRNA. Luciferase reporter assay results confirmed that miR-320c directly targets CDK6 by interacting with the 3'-untranslated region (3'-UTR) of its mRNA. qRT-PCR, Western blotting, and Cell Counting Kit-8 were subsequently used to evaluate the effects of miR-320c overexpression and CDK6 inhibition on inflammatory factor expression, as well as to investigate the effects of NF-kB and MAPK signaling pathway activation on IL-1ß-induced chondrocyte inflammation. RESULTS: Our results show that miR-320c expression increased during the middle stage and decreased during the late stage of hBMSC chondrogenic differentiation. In contrast, CDK6 expression decreased during the middle stage and increased during the late stage of hBMSC chondrogenic differentiation. Moreover, CDK6 expression increased in severe OA cartilage and in hypertrophic chondrocytes of mouse forelimbs at E16.5. Results of the luciferase reporter assay showed that miR-320c modulated CDK6 expression by binding to the 3'-UTR of its mRNA. miR-320c overexpression and CDK6 inhibition repressed IL-1ß-induced expression of inflammatory factors and regulated the NF-kB signaling pathway. CONCLUSION: CDK6 and miR-320c co-regulate hBMSC chondrogenesis and IL-1ß-induced chondrocyte inflammation through the NF-kB signaling pathway, suggesting that miR-320c and CDK6 inhibitors can be used to repress catabolism in human chondrocytes.

Exosomal miR-95-5p regulates chondrogenesis and cartilage degradation via histone deacetylase 2/8.

MicroRNAs play critical roles in the pathogenesis of osteoarthritis, the most common chronic degenerative joint disease. Exosomes derived from miR-95-5p-overexpressing primary chondrocytes (AC-miR-95-5p) may be effective in treating osteoarthritis. Increased expression of HDAC2/8 occurs in the tissues and chondrocyte-secreted exosomes of patients with osteoarthritis and mediates cartilage-specific gene expression in chondrocytes. We have been suggested that exosomes derived from AC-miR-95-5p (AC-miR-95-5p-Exos) would enhance chondrogenesis and prevent the development of osteoarthritis by directly targeting HDAC2/8. Our in vitro experiments showed that miR-95-5p expression was significantly lower in osteoarthritic chondrocyte-secreted exosomes than in normal cartilage. Treatment with AC-miR-95-5p-Exos promoted cartilage development and cartilage matrix expression in mesenchymal stem cells induced to undergo chondrogenesis and chondrocytes, respectively. In contrast, co-culture with exosomes derived from chondrocytes transfected with an antisense inhibitor of miR-95-5p (AC-anti-miR-95-5p-Exos) prevented chondrogenic differentiation and reduced cartilage matrix synthesis by enhancing the expression of HDAC2/8. MiR-95-5p suppressed the activity of reporter constructs containing the 3'-untranslated region of HDAC2/8, inhibited HDAC2/8 expression and promoted cartilage matrix expression. Our results suggest that AC-miR-95-5p-Exos regulate cartilage development and homoeostasis by directly targeting HDAC2/8. Thus, AC-miR-95-5p-Exos may act as an HDAC2/8 inhibitor and exhibit potential as a disease-modifying osteoarthritis drug.

MicroRNA-193b-3p regulates chondrogenesis and chondrocyte metabolism by targeting HDAC3.

Histone deacetylase 3 (HDAC3) plays a pivotal role in the repression of cartilage-specific gene expression in human chondrocytes. The aim of this study was to determine whether microRNA-193b-3p (miR-193b-3p) regulates the expression of HDAC3 during chondrogenesis and chondrocyte metabolism. Methods: miR-193b-3p expression was assessed in a human mesenchymal stem cell (hMSC) model of chondrogenesis, in interleukin-1ß (IL-1ß)-treated primary human chondrocytes (PHCs), and in non-degraded and degraded cartilage. hMSCs and PHCs were transfected with miR-193b-3p or its antisense inhibitor. A direct interaction between miR-193b-3p and its putative binding site in the 3'-untranslated region (3'-UTR) of HDAC3 mRNA was confirmed by performing luciferase reporter assays. Chondrocytes were transfected with miR-193b-3p before performing a chromatin immunoprecipitation assay with an anti-acetylated histone H3 antibody. To investigate miR-193b-3p-transfected PHCs in vivo, they were seeded in tricalcium phosphate-collagen-hyaluronate (TCP-COL-HA) scaffolds, which were then implanted in nude mice. In addition, plasma exosomal miR-193b-3p in samples from normal controls and patients with osteoarthritis (OA) were measured. Results: miR-193b-3p expression was elevated in chondrogenic and hypertrophic hMSCs, while expression was significantly reduced in degraded cartilage compared to non-degraded cartilage. In addition, miR-193b-3p suppressed the activity of reporter constructs containing the 3'-UTR of HDAC3, inhibited HDAC3 expression, and promoted histone H3 acetylation in the COL2A1, AGGRECAN, COMP, and SOX9 promoters. Treatment with the HDAC inhibitor trichostatin A (TSA) increased cartilage-specific gene expression and enhanced hMSCs chondrogenesis. TSA also increased AGGRECAN expression and decreased MMP13 expression in IL-1ß-treated PHCs. Further, 8 weeks after implanting PHC-seeded TCP-COL-HA scaffolds subcutaneously in nude mice, we found that miR-193b overexpression strongly enhanced in vivo cartilage formation compared to that found under control conditions. We also found that patients with OA had lower plasma exosomal miR-193b levels than control subjects. Conclusions: These findings indicate that miR-193b-3p directly targets HDAC3, promotes H3 acetylation, and regulates hMSC chondrogenesis and metabolism in PHCs.

Better Prognosis of Senile Patients with Intertrochanteric Femoral Fracture by Treatment with Open Reduction Internal Fixation than by Hip Arthroplasty.

PURPOSE: To compare the postoperative survival and mortality rates in intertrochanteric femoral fracture (IFF) patients who underwent either open reduction internal fixation (ORIF) or hip arthroplasty. METHODS: Clinical data from senior patients who had IFF and underwent ORIF or hip arthroplasty were analyzed retrospectively. Survival curves were compared between groups with Kaplan-Meier method and log-rank test. Significant independent prognostic factors were identified by Cox multivariate regression analysis. RESULTS: All patients recovered fully post-surgery. Although 31 patients died during the follow-up period (ORIF, mean 45.4 months; arthroplasty, mean 51.6 months), mortality rate did not differ significantly between the groups. The 1-yr and 2-yr survival rate estimates for the ORIF group were 92.2%, and 86%, respectively; they were 85% and 74% for the arthroplasty group. Average survival lengths for ORIF and arthroplasty groups were 88 and 67 months, respectively. The effect of surgical approaches on survival differed significantly (log-rank test c2 = 6.402, p = 0.011). Multivariate Cox regression model indicated that surgical choice (p = 0.036) was a significant independent risk factor for the prognosis of senile IFF, even with adjustment for age (p = 0.002). CONCLUSION: The overall postoperative prognosis was superior in senile IFF patients treated with ORIF.