High femoral anteversion in osteoarthritic knees, particularly for severe valgus deformity.

OBJECTIVE: Increased femoral anteversion (FA) has been correlated with less varus deformities in osteoarthritic (OA) knees, but the relationship between FA and the degree of valgus deformity in osteoarthritic (OA) knees is still largely unknown. We aimed to thoroughly analyze the distribution of FA in relation to varus or valgus deformities of the lower extremity in OA knees, and to further clarify the relationship between FA and trochlear morphology. METHODS: 235 lower extremities with OA knees were divided into five groups according to the mechanical tibiofemoral angle: excessive valgus (< - 10°), moderate valgus (- 10° to - 3°), neutral (- 3° to 3°), moderate varus (3° to 10°), and excessive varus (> 10°). FA (measured using the posterior condylar axis [pFA] and the transepicondylar axis [tFA]) was measured, and the relationships of FA to the mechanical tibiofemoral angle and femoral trochlear morphology were identified. RESULTS: Excessive FA (pFA ≥ 20°) was observed in 30.2% of all patients and in 58.8% of patients in the excessive valgus group. pFA showed a strong correlation with mechanical tibiofemoral angle (p = 0.018). Both the pFA and the tFA of patients in the excessive valgus group were greater than those in other four groups (all p ≤ 0.037). There were significant correlations between tFA and trochlear parameters, including the sulcus angle (SA), lateral trochlear slope (LTS), and medial trochlear slope (MTS) (all p ≤ 0.028). CONCLUSION: High FA is prevalent, particularly in severe valgus knees, and FA is significantly related to the femoral trochlear morphology in OA knees. With the aim of improving the patellofemoral prognosis and complications, high FA should be considered during total knee arthroplasty.

LncRNA NBR2 inhibits epithelial-mesenchymal transition by regulating Notch1 signaling in osteosarcoma cells.

Long noncoding RNAs (lncRNAs) have been identified to have increasingly important roles in tumorigenesis, and they may serve as novel biomarkers for cancer therapy. Recent studies have demonstrated that lncRNA NBR2 (neighbor of BRCA1 gene 2), a novel identified lncRNA, is decreased in several cancers; however, the role of NBR2 in the development of osteosarcoma has not been elucidated. In our study, we found that NBR2 expression was downregulated in osteosarcoma tissues, and osteosarcoma cases with lower NBR2 expression exhibited a shorter overall survival time compared with those with higher NBR2 expression. NBR2 overexpression inhibited osteosarcoma cell proliferation, invasion, and migration but did not increase apoptosis. Furthermore, RNA-binding protein immunoprecipitation assays confirmed that NBR2 directly binds to Notch1 protein. Furthermore, overexpression of Notch1 in NBR2-overexpressing osteosarcoma cells reversed the effects of NBR2 on cell proliferation, invasion, migration, and epithelial-mesenchymal transition. The in vivo results showed that NBR2 overexpression inhibited tumor growth in nude mice that were inoculated with osteosarcoma cells. NBR2 overexpression also suppressed the messenger RNA (mRNA) expression of Notch1, N-cadherin, and vimentin and increased the mRNA expression of E-cadherin in the tumor tissues. These data indicated that NBR2 served as a tumor suppressor gene in osteosarcoma and inhibited osteosarcoma cell proliferation, invasion, and migration. The current study provides a novel insight and treatment strategy for osteosarcoma.

Tangeretin Inhibits Oxidative Stress and Inflammation via Upregulating Nrf-2 Signaling Pathway in Collagen-Induced Arthritic Rats.

BACKGROUND/AIMS: Tangeretin (TAN), a major phytochemical in tangerine peels and an important Chinese herb, has multiple biological properties, especially antioxidative and anti-inflammatory effects. However, the mechanisms remain unclear. Based on these findings, the aim of the present study was to assess the antioxidant and anti-inflammatory properties of TAN in bovine type II collagen-induced arthritis rats. METHODS: TAN (50 mg/kg) was given orally once daily for 14 days. The effects of treatment were evaluated by biochemical assay (articular elastase, myeloperoxidase, end products of lipid peroxidation [MDA], antioxidant enzyme, such as superoxide dismutase, catalase, glutathione), nitric oxide, and inflammatory cytokines (interleukin-1ß [IL-1ß], -IL-10, tumor necrosis factor-alpha [TNF-α], interferon-γ [IFN-γ], and prostaglandin E2 [PGE2]). The protective effects of TAN against rheumatoid arthritis (RA) were evident from the decrease in arthritis scoring. Furthermore, the Nrf-2 signaling pathway was assessed to illustrate the molecular mechanism. RESULTS: TAN had therapeutic effects on RA by decreasing the oxidative stress damage and regulating inflammatory cytokine expression, including suppression of the accumulation of MDA products, decreasing the IL-1ß, TNF-α, IFN-γ, and PGE2 levels, enhancing the IL-10 and the activity of antioxidant enzymes, which was through upregulating Nrf-2 signaling pathway. CONCLUSION: TAN might have potential as a therapeutic agent for the treatment of RA.

Berberine inhibits the interleukin-1 beta-induced inflammatory response via MAPK downregulation in rat articular chondrocytes.

Osteoarthritis (OA) is one of the most chronic degenerative arthritic diseases, which gradually results in chondrocyte changes, articular cartilage degeneration, subchondral bone sclerosis, joint pain, swelling, and dysfunction. Berberine (BBR) has various confirmed biological activities, such as anti-inflammatory and antioxidant activities. However, the effect of BBR on the production of inflammation-associated proteins, including inducible nitric oxide synthase (iNOS), cyclooxygenase (Cox)-2, metalloproteinases (MMPs), Collagen II, TNF-α, and IL-6 via the MAPK (mitogen-activated protein kinases) pathway in IL-1ß-stimulated rat chondrocytes, has not yet been studied. Thus, the purpose of this study was to evaluate whether BBR would decrease the production of inflammation-associated proteins through the MAPK signal pathway. Rat chondrocytes were cultured and pretreated with BBR at different concentrations (0, 25, 50, and 100 µM) and then stimulated with or without IL-1ß (10 ng/mL). The mRNA expression of iNOS, COX-2, MMP-3, MMP-13, TNF-α, and IL-6 was measured by real-time polymerase chain reaction (RT-PCR), and the protein expression of iNOS, COX-2, Collagen II, MMP-3,MMP-13, and MAPKs were measured by Western blotting. The results showed that the expression of iNOS, COX-2, MMP-3, MMP-13, TNF-α, and IL-6 increased in the IL-1ß-treated group and BBR showed an ability to inhibit the elevated expression under the pretreatment. Furthermore, the IL-1ß-induced downregulation of Collagen II could be ameliorated by BBR. Moreover, the expression of MAPKs was significantly decreased by BBR. These results demonstrated that BBR had the anti-catabolic and anti-inflammation abilities that were through the MAPKs in IL-1ß-induced rat chondrocytes. These findings may provide a novel therapeutic choice for treatment of OA using BBR.

Arsenic trioxide induces autophagic cell death in osteosarcoma cells via the ROS-TFEB signaling pathway.

Osteosarcoma is a common primary malignant bone tumor, the cure rate of which has stagnated over the past 25-30 years. Autophagy modulation has been considered a potential therapeutic strategy for osteosarcoma, and previous study indicated that arsenic trioxide (ATO) exhibits significant anti-carcinogenic activity. However, the ability of ATO to induce autophagy and its role in osteosarcoma cell death remains unclear. In the present study, we showed that ATO increased autophagic flux in the human osteosarcoma cell line MG-63, as evidenced by the upregulation of LC3-II and downregulation of P62/SQSTM1. Moreover, the pharmacological or genetic blocking autophagy decreased ATO -induced cell death, indicating that ATO triggered autophagic cell death in MG-63 cells. Mechanistically, ATO induced TFEB(Ser142) dephosphorylation, activated TFEB nuclear translocation and increased TFEB reporter activity, which contributed to lysosomal biogenesis and the expression of autophagy-related genes and subsequently initiated autophagic cell death in MG-63 cells. Importantly, ATO triggered the generation of ROS in MG-63 cells. Furthermore, NAC, an ROS scavenger, abrogated the effects of ATO on TFEB-dependent autophagic cell death. Taken together, these data demonstrate that ATO induces osteosarcoma cell death via inducing excessive autophagy, which is mediated through the ROS-TFEB pathway. The present study provides a new anti-tumor mechanism of ATO treatment in osteosarcoma.

Coenzyme Q10 Prevents the Interleukin-1 Beta Induced Inflammatory Response via Inhibition of MAPK Signaling Pathways in Rat Articular Chondrocytes.

Preclinical Research Osteoarthritis (OA) is a widely prevalent degenerative joint disease that severely impairs the health of the elderly population resulting in a heavy economic burden worldwide. Coenzyme Q10 (CoQ10) has shown anti-inflammatory effects in some diseases. The present study aimed to investigate if CoQ10 would suppress catabolic responses of interleukin (IL)-1ß-induced chondrocytes. Rat chondrocytes were cultured and pretreated with CoQ10, and then stimulated with or without IL-1ß (10 ng/ml). The expression and production of matrix metalloproteinase (MMP)-3, MMP-9, and MMP13 were determined using real-time PCR and Western blotting. CoQ10 suppressed MMP-3, MMP-9, and MMP13 production induced by IL-1ß, and markedly inhibited IL-1ß-induced MAPK pathways in rat chondrocytes. The present study provides insight into potential mechanisms by which CoQ10 protects against degeneration of cartilage in patients with OA, which may lead to new approaches for the treatment of OA.Drug Dev Res 78 : 403-410, 2017. © 2017 Wiley Periodicals, Inc.

Pristimerin Inhibits Prostate Cancer Bone Metastasis by Targeting PC-3 Stem Cell Characteristics and VEGF-Induced Vasculogenesis of BM-EPCs.

BACKGROUND/AIMS: Prostate cancer (PCa) is one of the most common malignant cancers and a major leading cause of cancer deaths in men. Cancer stem-like cells are shown to be highly tumorigenic, pro-angiogenic and can significantly contribute to tumor new vessel formation and bone marrow derived-EPCs (BM-EPCs) are shown to recruit to the angiogenic switch in tumor growth and metastatic progression, suggesting the importance of targeting cancer stem cells (CSCs) and EPCs for novel tumor therapies. Pristimerin, an active component isolated from Celastraceae and Hippocrateaceae, has shown anti-tumor effects in some cell lines in previous studies. However, the effect and mechanism of Pristimerin on CSCs and EPCs in PCa bone metastasis are not well studied. METHODS: The effect of Pristimerin on PC-3 stem cell characteristics and metastasis were detected by spheroid formation, CD133 and CD44 protein expression, matrix-gel invasive assay and colony-formation assay in vitro, VEGF and pro-inflammatory cytokines expression by ELISA assay, and tumor tumorigenicity by X-ray and MR in NOD-SCID mice model in vivo. In addition, we also detected the effect of Pristimerin on VEGF-induced vasculogenesis and protein expression of BM-EPCs. RESULTS: Pristimerin could significantly inhibit spheroid formation and protein expression of CD133 and CD44, reduce VEGF and pro-inflammation cytokines expression of PC-3 cell, and prevent the xenografted PC-3 tumor growth in the bone of nude mice. The present data also showed that Pristimerin significantly inhibited VEGF-induced vasculogenesis of BM-EPCs by suppressing the EPCs functions including proliferation, adhesion, migration, tube formation and inactivation the phosphorylation of VEGFR-2, Akt and eNOS. CONCLUSION: These data provide evidence that Pristimerin has strong potential for development as a novel agent against prostate bone metastasis by suppressing PC-3 stem cell characteristics and VEGF-induced vasculogenesis of BM-EPCs.

Efficacy and Safety of Tranexamic Acid in Bilateral Total Knee Replacement: A Meta-Analysis and Systematic Review.

BACKGROUND Tranexamic acid (TXA) has been well documented to reduce blood loss and transfusion requirements in patients undergoing unilateral total knee arthroplasty (TKA). However, the efficacy and safety of TXA in simultaneous bilateral TKA have not been clearly defined. The aim of our study was to systematically review the existing evidence regarding the role of TXA in patients undergoing simultaneous bilateral TKA. MATERIAL AND METHODS A systematic search of all studies published through June 2014 was performed using Medline, EMBASE, OVID, and other databases. All studies that compared the efficacy and safety of TXA administration in simultaneous bilateral TKA patients were identified. The data from the included trials were extracted and analyzed regarding blood loss and transfusion rates. The evidence quality levels of the selected articles were evaluated using a grading system. RESULTS Six studies were included, in which a total of 245 patients received TXA and 271 patients were controls. Overall, the results demonstrated that the use of TXA significantly reduced total blood loss by a mean of 371.1 ml (95% confidence interval (CI)=-412.12 to -330.09; p<0.001) and reduced the number of patients requiring blood transfusion (risk ratio (RR)=0.16; 95% CI=0.10 to 0.28; p<0.001). No significant differences in adverse effects such as deep vein thrombosis (DVT) or pulmonary embolism (PE) were noted in any group. CONCLUSIONS The intravenous use of TXA in patients undergoing simultaneous bilateral TKA is effective and safe and results in significantly reduced estimated blood loss and transfusion rates. No significant difference was observed in the incidence of side effects. Due to the limitations in the evidence quality of current meta-analyses, well-conducted, larger, high-quality randomized controlled trials (RCTs) are required.

Relationship between the tibial mechanical axis and bony anatomical landmarks of the calf and foot as measured on radiographs obtained with a new laser-calibrated position.

OBJECTIVE: To investigate relationship between the tibial mechanical axis and bony landmarks of the calf and foot by developing a new laser-calibrated position for radiography of the lower limb. MATERIALS AND METHODS: A total of 120 volunteers were randomly divided into two groups. All subjects were marked with skin projection of the hypothetical axis of the calf on the frontal and sagittal planes. Radiographs of weight-bearing full-length lower-limb were obtained by the laser-calibrated positioning in the experimental group, and by the use of conventional technique in the control group. To consider the rotation of the calf, radiological features of the knee and ankle were investigated. The relationship between the tibial mechanical axis and the bony landmarks of the calf and foot were also measured. RESULTS: Anteroposterior view depicted a tangential projection on the superior/inferior tibiofibular syndesmosis and between lateral malleolus and talus in ankle mortise in the experimental group. Bony overlap on the superior/inferior tibiofibular syndesmosis and between lateral malleolus and talus was seen in control group. On the tangential projection, it also presented a clear wheel-like contour of the medial femoral condyle, but a partial overlap between medial femoral condyle and tibial plateau. The femoral joint angle between the connecting line at the lowest point of the medial and lateral femoral condyles and the tibial mechanical axis was 83.6° ± 2.49° in the experimental group and 85.3° ± 2.18° in the control group (P < 0.001). The tibial tubercle-axis distance from the center of the medial and middle one-third of the tibial tubercle to the tibial mechanical axis was 1.5 mm in the experimental group and 3.7 mm in the control group (P < 0.05). The malleoli-axis distance from the midpoint of the bimalleolar line joining the tips of the medial and lateral malleoli to the tibial mechanical axis was 1.9 mm in the experimental group and 6.9 mm in the control group (P < 0.001). Lateral view showed no difference between the tibial mechanical axis and the fibular reference line within two groups. CONCLUSION: In the new radiographic position, our data indicate that the hypothetical tibial mechanical axis and fibular reference line, obtained by marking the specified anatomic landmarks of the calf and foot, are located more closely to the tibial mechanical axis by correcting the rotation of the calf and foot during the radiography. On anteroposterior view, the tibial mechanical axis was approximately 2 mm medial to the center of the ankle. This indicates that the hypothetical tibial mechanical axis marked on the skin could be referred to guide the tibial osteotomy in total knee arthroplasty.

Relationships between position of patellar ridge high point and morphology of resected surface for patellar resurfacing in total knee arthroplasty.

Background: Reproducing the native patellar ridge high point while maximizing osseous coverage is important for the success of patellar replacement, but it cannot always be achieved simultaneously. This study aimed to thoroughly investigate the relationships and their influencing factors between the positions of the high point of patellar ridge (HPPR) and the morphology of the patellar resected surface. Methods: Four hundred seventy-three patients (265 men, 208 women) aged 18 to 50 years with knee injuries before arthroscopy were retrospectively collected for this cross-sectional study. Computed tomography (CT) and magnetic resonance imaging (MRI) were used to construct 3D computer models of the patella and patellar cartilage. The morphometric characteristics of the patellar cut after virtual resection and the HPPR position relative to the patellar cut centre were measured and analyzed. Results: The medial displacements of the HPPR were positively correlated with Wiberg's classification and index (all P<0.001). The mean values of HPPR's medial displacements were 0.15 of the medial width of patellar cut, and 93.2% of all patella ranged from 0 to 0.3. When the implant's apex were placed at 0.15 of the medial width of patellar cut medialized, the proportion of implant placement errors within 1 mm of the native high point was 12% more in female patella (P=0.01), and 7% more in all patella (P=0.03) than 3 mm medialized. Conclusions: Wiberg's system can roughly predicted the medial-lateral position of the HPPR. The HPPR was mainly medially located at the 0.15 of the medial patellar width approximately, and 15% medialized of the implant's apex can better reproduce the native patellar high point than 3 mm medialized. The current results provide basic data for patellar implant selection, preoperative planning, and implant design to reproduce the native patellar high point better while maximizing osseous coverage for patellar resurfacing.

[Digital study on the relationship between position of patellar high point and shape of osteotomy surface in Chinese].

Objective: To measure the position of patellar high point and the shape of the osteotomy surface, and to analyze their relationship, distribution, and gender differences. Methods: A total of 127 patients who needed anterior cruciate ligament reconstruction or meniscus repair due to trauma between September 2020 and September 2021 were selected as the research subjects. There were 71 males and 56 females, with an average age of 30.5 years (range, 19-43 years). There were significant differences in height and body weight between male and female patients ( P<0.05), but no significant difference in age and body mass index ( P>0.05). The three-dimensional model of the patella was reconstructed in Mimics software based on the CT images of the knee joint, and then imported into Geomagic Studio software for virtual osteotomy of the patella. The horizontal axis and vertical axis of the osteotomy surface represented the total width (W) and total height (H) of the osteotomy surface, respectively. Then the osteotomy surface was divided into four quadrants with the two axes: inner proximal, inner distal, outer proximal, and outer distal, and the inner width (W1), proximal height (H1), outer width (W2), and distal height (H2) were measured. The midpoint of the patellar ridge was selected as the patellar high point, and the point projected onto the osteotomy surface was defined as the optimal point for patellar prosthesis positioning (OPPP). The distances of OPPP on the horizontal axis (L1) and vertical axis (L2) relative to the center of the osteotomy surface were measured and L1/W1 and L2/H1 were also calculated; the quadrant distribution of OPPP was recorded. The patients were grouped according to gender, and the morphological parameters of the osteotomy surface (W, W1, W2, H, H1, H2) and the parameters related to the position of the OPPP (L1, L2, L1/W1, L2/H1) were analyzed between groups. Results: The width and height of each osteotomy surface of the patella in males were significantly larger than those in females ( P<0.05). As for the relationship between OPPP and osteotomy surface, the L1 of both male and female patients was 1-7 mm, and there was no significant difference in the distribution between the two groups ( χ 2=8.068, P=0.149); L1/W1 in both male and female patients was mainly 1/10-3/10. The L2 of male patients was 0-5 mm, and that of female patients was -1-4 mm; the difference in distribution between the two groups was significant ( χ 2=15.500, P=0.006); L2/H1 in both male and female patients was mainly 0-1/5. The OPPP of male patients was mainly distributed in the inner proximal (98.59%) and outer proximal (1.41%) quadrants, while the female patients were distributed in the inner proximal (91.07%), inner distal (7.14%), and outer proximal (1.79%) quadrants. There was significant difference in the OPPP quadrant distribution between the two groups ( χ 2=5.186, P=0.036). Conclusion: The OPPP points are widely distributed but mainly concentrated on around 1/5 of the medial patella surface and around 1/10 of the superior patella surface. A small portion of females' OPPP were inferior while all males' OPPP were superior to the center of the patella.

Improved angle accuracy of tibial plateau osteotomy for total knee arthroplasty using tibial mechanical axis skin-mapping.

Background: The tibial crest is often used as an anatomic landmark for tibial plateau osteotomy (TPO) in total knee arthroplasty (TKA), but it is not very accurate. This study aimed to investigate errors in using the tibial crest as a marker and present a simple approach to improve the angle accuracy of TPO by mapping the tibial mechanical axis (TMA), determined preoperatively, according to the tibial crest on the skin overlying the tibia. Methods: We evaluated 50 healthy young volunteers and 100 pre-TKA osteoarthritic knees. The middle tibial crest lines (MTCLs) were marked on the shank tibial skin and covered with Kirschner wires. All participants underwent two sets of anteroposterior (AP) standing radiographs of the lower extremity, with the feet in neutral and external rotation positions. The MTCL-TMA angles were measured and compared. The TMA was mapped onto the tibial skin according to the MTCL-TMA angle prior to TKA and used for TPO. Postoperative outcomes were determined by the angle between the vertical tibial component axis (TCA) and the TMA. Results: The MTCL had no evident relationship with the TMA. A few MTCLs were parallel to the TMA. External rotation of the foot significantly changed the MTCL-TMA relationship. The angle accuracy of the TPO as guided by TMA skin-mapping was 0.83 ± 0.76°. No postoperative errors exceeded 3°. Conclusion: The MTCL was not equivalent to the TMA. The TPO error can be reduced by preoperatively marking the TMA on the tibial skin according to the MTCL.

Circular RNA circ_0000423 regulates cartilage ECM synthesis via circ_0000423/miRNA-27b-3p/MMP-13 axis in osteoarthritis.

Circular RNA (circRNA) is related to many human diseases including osteoarthritis (OA). Our research purpose was to show that functional circRNAs have a role in the pathogenesis of OA, while also identifying potential circRNA that bind to miRNA-27b-3p. Microarray analysis was used to evaluate the expression of CircRNA in OA and normal cartilage. The role and functional mechanism of Circ_0000423 up-regulation were detected in OA and verified in vitro and in vivo. RNA transfection, qRT-PCR, Western blot analysis, immunofluorescence, and dual-luciferase assays were used to investigate the interaction between Circ_0000423 and miRNA-27b-3p in vitro. The roles of Circ_0000423 were discussed in vivo. Our results discovered 11 down-regulated circRNAs and 101 up-regulated circRNAs between control and OA tissues, and confirmed that Circ_0000423 an increase significantly in OA tissues by evaluating the different circRNAs expressions. Meanwhile, luciferase analysis confirmed Circ_0000423 can be directly targeted by miRNA-27b-3p and act as a miRNA-27b-3p sponge. Circ_0000423 can influence MMP-13 and collagen II expression by targeting miRNA-27b-3p expression as ceRNA in OA. Furthermore, AAV-shRNA-Circ 0000423 intra-articular injection slows the progression of OA by decreasing articular cartilage destruction and erosion, joint surface fibrosis, osteophyte formation, MMP-13 expression, and increasing collagen II expression in the articular cartilage of ACLT-induced OA mice model. These findings confirmed that the Circ_0000423-miRNA-27b-3p-MMP-13 axis could affect the pathogenesis of OA which might lead to a novel target for diagnostic molecular biological indicators and potential OA treatments.

Medium Activity Prevents Periprosthetic Bone Mass Loss in the Medial Metaphyseal Region of the Tibia after Posterior-Stabilized TKA: A 5-Year Follow-up Study of 110 Knees.

OBJECTIVE: The bone mass around the prosthesis plays an important role in the stability of the prosthesis. This study aimed to assess the effect of postoperative activity on bone mineral density (BMD) in the proximal tibia 5 years after total knee arthroplasty (TKA). To provide a scientific guidance for postoperative functional exercise. METHODS: 110 patients underwent unilateral primary TKA were divided into three groups based on the University of California Los Angeles (UCLA) activity scale: low activity group (LA group, UCLA = 4, 5); medium activity group (MA group, UCLA = 6, 7); and high activity group (HA group, UCLA = 8, 9). The primary observation was a comparison of the BMD and BMD change percentage (ΔBMD (%)) in the periprosthetic tibia among the LA, MA and HA groups at 1 year, 3 years and 5 years. The secondary observations were radiographic evaluation (prosthetic stability, periprosthetic fractures, aseptic loosening and periprosthetic joint infection) and clinical evaluation (Knee Society Score (KSS), visual analogue score scores and range of motion (ROM)). A one-way ANOVA was used to compare the clinical scores and BMD among the three groups. RESULTS: The BMD of medial region decreased by 10.80%, 12.64%, 13.61% at 1, 3, and 5 years respectively; these were 5.72%, 6.26%, 7.83% in lateral region and 1.42%, 1.78%, 3.28% in diaphyseal region. For medial metaphyseal region, the BMD of the MA group was significantly greater than that of the LA and HA groups at 1 and 3 years (108.9 ± 5.2 vs. 106.1 ± 6.69 vs. 105.4 ± 5.2 and 108.5 ± 6.0 vs. 101.2 ± 6.76 vs. 103.0 ± 6.8, P < 0.01 and P < 0.001), and the BMD changes (ΔBMD (%)) in the MA group were significantly smaller than those in the LA and HA groups (8.75 ± 5.36 vs. 11.92 ± 5.49 vs. 12.70 ± 5.21 and 9.11 ± 5.11 vs. 16.04 ± 4.79 vs. 14.82 ± 4.26, P < 0.01 and P < 0.001). Regarding secondary observations, all of the prostheses were assessed as stable, without periprosthetic fractures, aseptic loosening and periprosthetic joint infection. Regarding KSS scores, there was no significant difference among the three groups. However, the VAS and ROM of the HA group were better than those of the MA and LA groups (1.65 ± 0.79 vs. 2.63 ± 0.77 vs. 3.00 ± 1.17, p < 0.001, and 111.90 ± 9.17 vs. 110.20 ± 6.78 vs. 102.90 ± 8.48, P < 0.001). CONCLUSION: Medium activity prevented periprosthetic bone loss in the medial metaphyseal region of the tibia after posterior-stabilized TKA, and moderate-intensity exercise is recommended for patients after TKA to reduce periprosthetic bone loss.

miR-125a-5p Regulates Osteogenic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells under Oxidative Stress.

Adipose-derived mesenchymal stem cells (ADSCs) are a well-recognized multilineage stem cell with vital clinical feasibility for tissue regeneration. Extensive evidence indicates that oxidative stress and microRNAs (miRNAs/miRs) play an important role in the osteoinduction of adipose-derived mesenchymal stem cells. In this study, we investigated the mechanism of miR-125a-5p in regulating the osteogenesis of human adipose-derived mesenchymal stem cells (hADSCs) under oxidative stress. The expression of miR-125a-5p lessened gradually during the osteogenic differentiation of hADSCs. Relative to the negative group, the expression levels of runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osteocalcin (OCN), and osterix in the miR-125a-5p group were marked lower than those in the miR-125a-5p inhibitor group. The levels of p16, p21, p53, miR-125a-5p, and ROS during osteoinduction of hADSCs were assessed in vitro under oxidative stress and were observed to be upregulated. Further experiments showed that oxidative stress and miR-125a-5p together suppressed the expression of VEGF during osteogenic differentiation of hADSCs and that the inhibition of miR-125a-5p reversed the effect of oxidative stress. In short, our study indicated that miR-125a-5p is induced under oxidative stress and inhibits the expression of VEGF, leading to the reduction of osteogenic differentiation of hADSCs. Our outcomes showed that miR-125a-5p could be a potential clinical target for bone repairing.

Urinary miRNAs as biomarkers for idiopathic osteonecrosis of femoral head: A multicentre study.

OBJECTIVES: Urinary microRNAs (miRNAs) have shown great diagnostic and prognostic values for multiple diseases. The profile of urinary miRNAs in patients with idiopathic osteonecrosis of femoral head (ONFH) is currently unclear. METHODS: We first randomly chose ten patients with each Association Research Circulation Osseous (ARCO) stage (I, II, III and IV) and ten healthy participants from the entire cohorts for initial screening. The miRNA polymerase chain reaction (PCR) array was then performed to identify the differentially abundant miRNAs in urine of these participants. We then verified the findings in the entire cohort. Clinical features including age, gender, bone mass index (BMI), lesion size and stages were recorded. We then analysed the association between the level of urinary miRNAs and clinical features. RESULTS: Our data indicated that there were 13 differentially abundant miRNAs among all groups. Urinary miR-150 demonstrated the highest diagnostic value among all candidates. Urinary miR-185 and miR-133a increased by ARCO staging. The levels of urinary miR-4824 abruptly decreased after femoral head collapse (ARCO stage III and IV). Urinary miR-144 was the only marker that correlated with lesion size. CONCLUSIONS: The levels of urinary miRNAs are valuable biomarkers for idiopathic ONFH. Given the noninvasive nature of this test, it is potentially useful for diagnosis and monitoring of idiopathic ONFH progression. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This article gives novel methods for ONFH diagnosis and progression monitoring in a convenient and non-invasive way.

Circ_HECW2 regulates LPS-induced apoptosis of chondrocytes via miR-93 methylation.

INTRODUCTION: Circ_HECW2 plays a key role in lipopolysaccharide (LPS)-induced signal transduction, which is critical in osteoarthritis (OA). Thus, we analyzed the role of Circ_HECW2 in osteoarthritis. METHODS: The expression of Circ_HECW2 and miR-93 was examined using reverse-transcription polymerase chain reaction. Cell apoptosis was evaluated using Annexin V-FITC Apoptosis Detection Kit. RESULTS: Circ_HECW2 and miR-93 were inversely correlated, with Circ_HECW2 upregulated and miR-93 downregulated in OA and LPS-induced chondrocytes. Circ_HECW2 overexpression inhibited miR-93 expression and increased methylation of miR-93 coding gene. Cell apoptosis analysis showed that Circ_HECW2 overexpression increased LPS-induced chondrocyte apoptosis, while MiR-93 overexpression reversed the effects of Circ_HECW2 on chondrocyte apoptosis. CONCLUSION: In summary, our data revealed that the Circ_HECW2 is highly expressed in OA and might inhibit miR-93 expression through methylation to affect LPS-induced chondrocyte apoptosis.

PSMA-Targeting Reduction-Cleavable Hyperbranched Polyamide-Amine Gene Delivery System to Treat the Bone Metastases of Prostate Cancer.

OBJECTIVE: This study aimed to develop aptamer-anchored hyperbranched poly(amido amine) (HPAA) for the systemic delivery of miRNA-133a-3p and to evaluate its therapeutic potential against bone metastasis of prostate cancer in vivo and in vitro. METHODS: A glutathione (GSH)-responsive cationic HPAA was prepared by the Michael addition reaction. Furthermore, HPAA-PEG was produced by PEGylation, and then the aptamer targeted to prostate-specific membrane antigen (PSMA) was conjugated to the HPAA-PEG. The obtained HPAA-PEG-APT could form nanocomplexes with miRNA-133a-3p through electrostatic adsorption. RESULTS: The results of immunocytochemistry indicated that the complexes could target PSMA-expressing LNCaP cells. The ability of HPAA-PEG-APT to facilitate the delivery of miRNA-133a-3p into LNCaP cells was proven, and HPAA-PEG-APT/miRNA-133a-3p demonstrated enhanced antitumor activity, lower cytotoxicity and better biocompatibility in vitro. Moreover, in a mouse tibial injection tumor model, the intravenous injection of the HPAA-PEG-APT/miRNA-133a-3p complex significantly inhibited cancer growth and extended the survival time. CONCLUSION: This study provided an aptamer-anchored HPAA-loaded gene system to deliver miRNA-133a-3p for better therapeutic efficacy of bone metastasis of prostate cancer.

Exosome-transmitted circular RNA hsa_circ_0051443 suppresses hepatocellular carcinoma progression.

Extracellular communication in the tumor microenvironment is critical. Results of qRT-PCR show that circ-0051443 is significantly lower in the plasma exosomes and tissues from patients with hepatocellular carcinoma (HCC) than healthy controls. Compared with the producer cells, circ-0051443 is mainly packaged into exosomes. A receiver operating characteristic curve (ROC) shows that the patients with HCC can be distinguished from the controls by exosomal circ-0051443. The role of exosomal circ-0051443 in HCC was determined by animal and cell analyses. Circ-0051443 is transmitted from normal cells to HCC cells via exosomes and suppresses the malignant biological behaviors by promoting cell apoptosis and arresting the cell cycle. Exosomal circ-0051443 decreases the weight and volume of the xenograft tumors in nude mice via BAK1 upregulation in these tumors. BAK1 expression is mediated by exosomal circ-0051443 through competitive bound to miR-331-3p. Therefore, exosomal circ-0051443 can serve as a predictor and potential therapeutic target for HCC.

Ectopic Expression of miR-532-3p Suppresses Bone Metastasis of Prostate Cancer Cells via Inactivating NF-κB Signaling.

miR-532-3p is a widely documented microRNA (miRNA) involved in multifaceted processes of cancer tumorigenesis and metastasis. However, the clinical significance and biological functions of miR-532-3p in bone metastasis of prostate cancer (PCa) remain largely unknown. Herein, we report that miR-532-3p was downregulated in PCa tissues with bone metastasis, and downexpression of miR-532-3p was significantly associated with Gleason grade and serum prostate-specific antigen (PSA) levels and predicted poor bone metastasis-free survival in PCa patients. Upregulating miR-532-3p inhibited invasion and migration abilities of PCa cells in vitro, while silencing miR-532-3p yielded an opposite effect on invasion and migration abilities of PCa cells. Importantly, upregulating miR-532-3p repressed bone metastasis of PCa cells in vivo. Our results further demonstrated that overexpression of miR-532-3p inhibited activation of nuclear facto κB (NF-κB) signaling via simultaneously targeting tumor necrosis factor receptor-associated factor 1 (TRAF1), TRAF2, and TRAF4, which further promoted invasion, migration, and bone metastasis of PCa cells. Therefore, our findings reveal a novel mechanism contributing to the sustained activity of NF-κB signaling underlying the bone metastasis of PCa.