How much of the superolateral femoral neck should be removed in intramedullary nail fixation for intertrochanteric fracture?

The objective of this study was to measure how much of the superolateral femoral neck should be removed to reduce the incidence of wedge effect. Simulating surgery: Computed Tomography images of 131 intertrochanteric fracture patients were included, three-dimensionally reconstructed, virtually reduced and implanted with Proximal Femoral Nail Antirotation blade-Ⅱ(PFNA-Ⅱ) nail. The antero-posterior length and media-lateral width of the intersection between superolateral femoral neck and PFNA-Ⅱ nail were measured. Retrospective study: The pre- and postoperative CT of 30 patients were collected. The average varus angle of the neck-shaft angle and the correlation between the angles and the difference in the actual and estimated width of the fragments removed were measured. Models of 108 patient were selected for analysis. The average antero-posterior length and media-lateral width were 14.46 mm (14.00-14.93 mm) and 9.33 mm (8.79-9.87 mm), respectively. The AO/OTA classification was not significantly associated with the outcome, but the gender was. In the retrospective study, the mean value of the varus angles was -4.58° (SE = 6.85°), and the difference of width was strongly positively correlated with the varus angle with a correlation coefficient of 0.698. Results obtained in this study can improve the understanding of this region and help surgeons to make appropriate preoperative planning to reduce the incidence of wedge effect. Retrospective study provided effective proof of the reliability of this study.

Regulatory mechanism of the six-method massage antipyretic process on lipopolysaccharide-induced fever in juvenile rabbits: A targeted metabolomics approach.

Objective: To investigate the mechanism of the six-method massage antipyretic process (SMAP) and its influence on the body's metabolic state. Methods: The random number table method was used to divide 24 New Zealand 2-month-old rabbits with qualified basal body temperature into a control group, model group and massage group (n = 8 per group). The model group and massage groups were injected with 0.5 µg/ml lipopolysaccharide (1 ml/kg) into the auricular vein, and the control group was injected with the same amount of normal saline at the same temperature. One hour after modelling, the massage group was given SMAP (opening Tianmen, pushing Kangong, rubbing Taiyang, rubbing Erhougaogu, clearing the Tianheshui and pushing the spine). The change of anal temperature 5 h after moulding was recorded to clarify the antipyretic effect. Results: After modelling, the rectal temperature of the juvenile rabbits in the three groups increased. The rectal temperature of the model group was higher than that of the control group 5 h after modelling, and the rectal temperature of the massage group was lower than that of the model group (P < 0.05). The antipyretic mechanism is related to the regulation of the synthesis of phenylalanine, tyrosine and tryptophan, as well as the pentose phosphate pathway. Compared with the model group, the plasma interleukin (IL)-1, IL-6, interferon-gamma, toll-like receptor 4, nuclear factor κB, the mechanistic target of rapamycin complex 1, indoleamine 2,3-dioxygenase 1, aryl hydrocarbon receptor, liver aspartate transaminase (AST), alanine transaminase (ALT) and l-glutamate dehydrogenase (L-GLDH) expression in the massage group were significantly decreased (P < 0.05). Compared with the model group, the massage group had significantly reduced AST, ALT and L-GLDH expression in plasma (P < 0.05). Conclusion: The mechanism of SMAP therapy is related to regulating the expression of peripheral inflammatory factors and metabolic pathways.

Selective 1,2-Hydroarylation(Alkenylation) of gem-Difluoroalkenes to Access (-CF2 H) Motifs.

An emerging class of C-C coupling transformations that furnish drug-like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem-difluoroalkenes without additional electronic activation remains largely unsuccessful. This owes partly to poor reactivity and the propensity of difluoroalkenes to undergo defluorinative side reactions. Here, we report a nickel catalytic system that promotes efficient 1,2-selective hydroarylation and hydroalkenylation, suppressing defluorination and providing straightforward access to a diverse assortment of prized organofluorides bearing difluoromethyl-substituted carbon centers. In contrast to radical-based pathways and reactions triggered by hydrometallation via a nickel-hydride complex, our experimental and computational studies support a mechanism in which a catalytically active nickel-bromide species promotes selective carbonickelation with difluoroalkenes followed by alkoxide exchange and hydride transfer, effectively overcoming the difluoroalkene's intrinsic electronic bias.

GDF15 is a major determinant of ketogenic diet-induced weight loss.

A ketogenic diet (KD) has been promoted as an obesity management diet, yet its underlying mechanism remains elusive. Here we show that KD reduces energy intake and body weight in humans, pigs, and mice, accompanied by elevated circulating growth differentiation factor 15 (GDF15). In GDF15- or its receptor GFRAL-deficient mice, these effects of KD disappeared, demonstrating an essential role of GDF15-GFRAL signaling in KD-mediated weight loss. Gdf15 mRNA level increases in hepatocytes upon KD feeding, and knockdown of Gdf15 by AAV8 abrogated the obesity management effect of KD in mice, corroborating a hepatic origin of GDF15 production. We show that KD activates hepatic PPARγ, which directly binds to the regulatory region of Gdf15, increasing its transcription and production. Hepatic Pparγ-knockout mice show low levels of plasma GDF15 and significantly diminished obesity management effects of KD, which could be restored by either hepatic Gdf15 overexpression or recombinant GDF15 administration. Collectively, our study reveals a previously unexplored GDF15-dependent mechanism underlying KD-mediated obesity management.

Sonoelastography for Testicular Tumor Identification: A Systematic Review and Meta-Analysis of Diagnostic Test Accuracy.

The objective of this review was to summarize the applications of sonoelastography in testicular tumor identification and inquire about their test performances. Two authors independently searched English journal articles and full conference papers from CINAHL, Embase, IEEE Xplore®, PubMed, Scopus, and Web of Science from inception and organized them into a PIRO (patient, index test, reference test, outcome) framework. Eleven studies (n = 11) were eligible for data synthesis, nine of which (n = 9) utilized strain elastography and two (n = 2) employed shear-wave elastography. Meta-analyses were performed on the distinction between neoplasm (tumor) and non-neoplasm (non-tumor) from four study arms and between malignancy and benignity from seven study arms. The pooled sensitivity of classifying malignancy and benignity was 86.0% (95%CI, 79.7% to 90.6%). There was substantial heterogeneity in the classification of neoplasm and non-neoplasm and in the specificity of classifying malignancy and benignity, which could not be addressed by the subgroup analysis of sonoelastography techniques. Heterogeneity might be associated with the high risk of bias and applicability concern, including a wide spectrum of testicular pathologies and verification bias in the reference tests. Key technical obstacles in the index test were manual compression in strain elastography, qualitative observation of non-standardized color codes, and locating the Regions of Interest (ROI), in addition to decisions in feature extractions. Future research may focus on multiparametric sonoelastography using deep learning models and ensemble learning. A decision model on the benefits-risks of surgical exploration (reference test) could also be developed to direct the test-and-treat strategy for testicular tumors.

Positive medial cortical support versus anatomical reduction for trochanteric hip fractures: Finite element analysis and biomechanical testing.

BACKGROUND AND OBJECTIVES: The anatomical reduction (AR) is usually considered the best option for fractures. Nevertheless, in unstable trochanteric hip fractures (UTHF), previous clinical reports found that the positive medial cortical support (PMCS, an over-reduction technique) attained higher mechanical stability, but this challenging clinical finding still needs experimental validation. METHODS: This study constructed in-silico and biomechanical PMCS and AR models, with the use of the most clinically-representative geometry design of fracture models, the multi-directional design in FE analysis, and the subject-specific (osteoporotic) bone material properties, to make the models better mimic the actual condition in clinical settings. Then multiple performance variables (von-Mises stress, strain, integral axial stiffness, displacement, structural changes, etc.) were assessed to uncover details of integral and regional stability. RESULTS: Among in-silico comparison, PMCS models showed significantly lower maximum displacement than AR models, and the maximum von Mises stress of implants (MVMS-I) was significantly lower in PMCS models than in AR models (highest MVMS-I in -30°-A3-AR of 1055.80 ± 93.37 MPa). Besides, PMCS models had significantly lower maximum von Mises stress along fracture surfaces (MVMS-F) (highest MVMS-F in 30°-A2-AR of 416.40 ± 38.01 MPa). Among biomechanical testing comparison, PMCS models showed significantly lower axial displacement. Significantly lower change of neck-shaft angle (CNSA) was observed in A2-PMCS models. A fair amount of AR models converted into the obvious negative medial cortical support (NMCS) condition, whereas all PMCS models kept the PMCS condition. The results were also validated through comparison to previous clinical data. CONCLUSIONS: The PMCS is superior to the AR in the UTHF surgery. The current study opens up the second thought of the role of over-reduction technique in bone surgery.

A new posterosuperior screw placement strategy to avoid in-out-in screws in femoral neck fractures.

Objective: The inverted triangle configuration of the three cannulated screws is the classic fixation method most commonly performed for undisplaced femoral neck fractures in young and geriatric patients. However, the posterosuperior screw has a high incidence of cortical breach, known as an in-out-in (IOI) screw. In this study, we present a novel posterosuperior screw placement strategy to prevent the screw from becoming IOI. Methods: Using computed tomography data and image-processing software, 91 undisplaced femoral neck fractures were reconstructed. The anteroposterior (AP), lateral, and axial radiographs were simulated. To simulate the intraoperative screw placement process, participants used three screw insertion angles (0°, 10°, and 20°) to place the screw on the AP and lateral views of the radiograph according to the three established strategies. On the AP radiograph, a screw was placed abutting (strategy 1), 3.25 mm away from (strategy 2), or 6.5 mm away from (strategy 3) the superior border of the femoral neck. On the lateral radiograph, all the screws were placed abutting the posterior border of the femoral neck. Axial radiographs were used to evaluate the screw position. Results: In strategy 1, all the placed screws were IOI regardless of the screw insertion angle. In strategy 2, 48.3% (44/91) of IOI screws occurred at a 0° screw insertion angle, 41.7% (38/91) of IOI screws occurred at a 10° screw insertion angle, and 42.9% (39/91) of IOI screws occurred at a 20° screw insertion angle situation. In strategy 3, no IOI screw occurred, and the screw insertion angles did not affect the safety and accuracy of screw placement. Conclusions: Screws placed according to strategy 3 are safe. The reliability of this screw placement strategy is unaffected by a screw insertion angle of less than 20 degrees.

Separate vertical wiring plus bilateral anchor girdle suturing fixation for the fractures of the inferior pole of the patella.

BACKGROUND: The fixation of inferior pole fractures of the patella (IPFPs) is still a great challenge for surgeons. MATERIALS AND METHODS: We introduced a new fixation method for IPFP fixation, that is, separate vertical wiring plus bilateral anchor girdle suturing fixation (SVW-BSAG). Three finite element models including the anterior tension band wiring (ATBW) model, separate vertical wiring (SVW) model and SVW-BSAG model, were built to evaluate the fixation strength of different fixation methods. A total of 41 consecutive patients with IPFP injury were enrolled in this retrospective study, including 23 patients in the ATBW group and 18 patients in the SVW-BSAG group. The operation time, radiation exposure, full weight-bearing time, Bostman score, extension lag versus contralateral healthy leg, Insall-Salvati ratio, and radiograph outcomes were employed to assess and compare the ATBW group and SVW-BSAG group. RESULTS: The finite element analysis confirmed that the SVW-BSAG fixation method was as reliable as the ATBW fixation method in terms of fixed strength. Through retrospective analysis, we found that there was no significant difference between the SVW-BSAG and ATBW groups in age, sex, BMI, fracture side, fracture type, or follow-up time. There were no significant differences between the two groups in the Insall-Salvati ratio, 6-month Bostman score, and fixation failure. Compared with the ATBW group, the SVW-BSAG group showed advantages in intraoperative radiation exposure, full weight-bearing time, and extension lag versus the contralateral healthy leg. CONCLUSION: The finite element analysis and clinical results showed that SVW-BSAG fixation methods are a reliable and valuable for IPFP treatment.

[Comparison of effect between internal fixation and total hip replacement in the treatment of displaced femoral neck fracture in middle age patients].

OBJECTIVE: To analyze and compare the clinical efficacy of internal fixation and total hip replacement in the treatment of displaced femoral neck fracture from 55 to 65 years. METHODS: From September 2016 to August 2020, 86 patients with Garden type Ⅲ or Ⅳ femoral neck fracture were divided into two groups according to different surgical methods. Among them, 38 patients were treated with lag screws for internal fixation, there were 26 males and 12 females, aged 55 to 64 years old with an average of(60.2±3.1) years;the other 48 patients were treated with total hip replacement, including 28 males and 20 females, aged from 57 to 65 years old with an average of(61.3±3.8) years. The time from injury to operation ranged from 1 to 3 days. The reoperation rate, incidence of deep infection, Harris score of hip joint function, visual analogue scale(VAS) of pain and patients reported outcome scores(European five-dimensional Health Questionnaire, EQ-5D) were compared between two groups. RESULTS: All patients were followed up for 24 to 54 months with an average of (35.8±10.3) months. There was significant difference in reoperation rate between two groups (P<0.05). There was no significant difference on the incidence of deep infection, hip Harris score and VAS between two groups(P>0.05) . The postoperative EQ-5D score of patients with internal fixation was lower than that of total hip replacement, and the difference was statistically significant(P<0.05). CONCLUSION: Both the surgery of internal fixation and total hip replacement have similar effect in short-and medium term among the patients aged 55 to 65 years old. However, for the reoperation rate, the group of internal fixation was higher than that of total hip replacement. For the subjective functional score of patients, the group of internal fixation was lower than that of total hip replacement.

Endocrine Tumor Classification via Machine-Learning-Based Elastography: A Systematic Scoping Review.

Elastography complements traditional medical imaging modalities by mapping tissue stiffness to identify tumors in the endocrine system, and machine learning models can further improve diagnostic accuracy and reliability. Our objective in this review was to summarize the applications and performance of machine-learning-based elastography on the classification of endocrine tumors. Two authors independently searched electronic databases, including PubMed, Scopus, Web of Science, IEEEXpress, CINAHL, and EMBASE. Eleven (n = 11) articles were eligible for the review, of which eight (n = 8) focused on thyroid tumors and three (n = 3) considered pancreatic tumors. In all thyroid studies, the researchers used shear-wave ultrasound elastography, whereas the pancreas researchers applied strain elastography with endoscopy. Traditional machine learning approaches or the deep feature extractors were used to extract the predetermined features, followed by classifiers. The applied deep learning approaches included the convolutional neural network (CNN) and multilayer perceptron (MLP). Some researchers considered the mixed or sequential training of B-mode and elastographic ultrasound data or fusing data from different image segmentation techniques in machine learning models. All reviewed methods achieved an accuracy of ≥80%, but only three were ≥90% accurate. The most accurate thyroid classification (94.70%) was achieved by applying sequential training CNN; the most accurate pancreas classification (98.26%) was achieved using a CNN-long short-term memory (LSTM) model integrating elastography with B-mode and Doppler images.

[YU Tian-yuan's experience in the clinical application of Danzhong (CV 17) for mental illness].

To summarize YU Tian-yuan's experience of applying Danzhong (CV 17) for mental illness in acupuncture and tuina. YU Tian-yuan uses Danzhong (CV 17) alone or in combination with other acupoints to treat mental illnesses such as insomnia, palpitation and chest distress. Professor YU emphasizes 4 tips when treating diseases, nourishing the heart to tranquilize by light stimulation; regulating spirit by combined stimulation; leaving the acupoints and holding on the meridian for a wide range of stimulation; using rubbing and pushing manipulation in several directions for regulating qi to soothe the chest. And in clinical practice, formed a unique therapy to treat mental illness.

Locking compression plate + T-type steel plate for postoperative weight bearing and functional recovery in complex tibial plateau fractures.

BACKGROUND: Complex tibial plateau fractures can seriously affect quality of life and physical and mental health of patients. The anatomical relationship between the proximal tibial bone and soft tissue is complex, resulting in different types of tibial plateau fractures. Violent trauma can lead to displaced fracture, serious soft tissue injury, and potentially, dislocation of the knee joint. Therefore, tibial plateau fractures are extremely unstable. AIM: To assess the use of locking compression plate (LCP) + T-type steel plate for postoperative weight bearing and functional recovery of complex tibial plateau fractures. METHODS: Ninety-seven patients with complex tibial plateau fractures who underwent surgery at our hospital were selected for retrospective study. Forty-nine patients had been treated with LCP + T-type steel plate limited internal fixation (study group), and 48 patients with bilateral ordinary steel plate support (control group). The operation process index, postoperative rehabilitation related index, Rasmussen score of the knee joint, tibial plateau varus angle (TPA), tibial plateau retroversion angle (PA), and surgical complications of the two groups were compared. RESULTS: The operation time and intraoperative bone graft volume in the study group were lower than those in the control group (P < 0.05). There were no significant differences in surgical bleeding, anterior external incision length, postoperative drainage, hospital stay duration, and fracture healing time between the groups (P > 0.05). There was no significant difference in the TPA and PA angle between the groups immediately and 18 mo after surgery (P > 0.05). At 12 mo after surgery, the Rasmussen scale score was higher in the study group than in the control group (P < 0.05). There was no significant difference in the Rasmussen scale score at 18 mo after surgery, and the radiology score at 12 and 18 mo after surgery, between the two groups (P > 0.05). The postoperative complication rate in the study group (3.77%) was lower than that in the control group (15.09%; P < 0.05). CONCLUSION: LCP + T-type steel plate internal fixation has advantages in terms of minimizing trauma and enabling early postoperative functional exercise, promoting functional recovery and lower limb weight-bearing, and reducing postoperative complications.

Copper-Catalyzed Si-H Bond Insertion Reaction of N-Propargyl Ynamides with Hydrosilanes.

Transition-metal-catalyzed Si-H bond insertion reactions are generally limited to stabilized diazo compounds. An efficient copper-catalyzed Si-H bond insertion reaction of N-propargyl ynamides with hydrosilanes is described, allowing practical and atom-economic construction of valuable organosilanes in generally moderate to excellent yields under mild reaction conditions. Notably, this reaction constitutes a new method of Si-H bond insertion reaction involving vinyl cations as key intermediates.

Tuina for peripherally-induced neuropathic pain: A review of analgesic mechanism.

Peripherally-induced neuropathic pain (pNP) is a kind of NP that is common, frequent, and difficult to treat. Tuina, also known as massage and manual therapy, has been used to treat pain in China for thousands of years. It has been clinically proven to be effective in the treatment of pNP caused by cervical spondylosis, lumbar disc herniation, etc. However, its analgesic mechanism is still not clear and has been the focus of research. In this review, we summarize the existing research progress, so as to provide guidance for clinical and basic studies. The analgesic mechanism of tuina is mainly manifested in suppressing peripheral inflammation by regulating the TLR4 pathway and miRNA, modulating ion channels (such as P2X3 and piezo), inhibiting the activation of glial cells, and adjusting the brain functional alterations. Overall, tuina has an analgesic effect by acting on different levels of targets, and it is an effective therapy for the treatment of pNP. It is necessary to continue to study the mechanism of tuina analgesia.

Asymmetric dearomatization catalysed by chiral Brønsted acids via activation of ynamides.

Chiral Brønsted acid-catalysed asymmetric synthesis has received tremendous interest over the past decades, and numerous efficient synthetic methods have been developed based on this approach. However, the use of chiral Brønsted acids in these reactions is mostly limited to the activation of imine and carbonyl moieties, and the direct activation of carbon-carbon triple bonds has so far not been invoked. Here we show that chiral Brønsted acids enable the catalytic asymmetric dearomatization reactions of naphthol-, phenol- and pyrrole-ynamides by the direct activation of alkynes. This method leads to the practical and atom-economic construction of various valuable spirocyclic enones and 2H-pyrroles that bear a chiral quaternary carbon stereocentre in generally good-to-excellent yields with excellent chemo-, regio- and enantioselectivities. The activation mode of chiral Brønsted acid catalysis revealed in this study is expected to be of broad utility in catalytic asymmetric reactions that involve ynamides and the related heteroatom-substituted alkynes.

3D object reassembly using region-pair-relation and balanced cluster tree.

BACKGROUND AND OBJECTIVE: Object reassembly is a key technology in scenarios such as surgical planning and broken object restoration. Based on previous research, this work intends to explore the general tasks of 3D object reassembly, including conventional object reconstruction and bone fracture reduction. METHODS: We introduce an efficient and robust region-pair-relation descriptor, which incorporates strong geometric constraints and remains invariant to rotation and translation. We segment the fractured objects using balanced cluster tree, and develop a coarse-to-fine method for object reassembly. The matching quality of potential region contact pairs at different depths is estimated recursively from the root of the tree. Once the best contact pairs are determined, the least squares method is implemented to obtain the matching results. In addition, we also provide a semi-interactive manipulation to deal with the complex objects. RESULTS: For most types of broken objects, our approach can generate high accuracy matching results within 10 s, with the cluster tree depth equals to 11. It allows the automatic reassembly of different-sized fragments. For bone fracture blocks with cancellous structures, a semi-interactive operation is integrated so that the precise matching can also be achieved in 30 s. CONCLUSION: The proposed framework can be expanded to various object reassembly tasks in either automated or semi-automated manner, including the fracture reduction problem which used to be an intensive manual process. Therefore, our work shows significant advantages in medical applications.

[Effects of community succession on plant reproductive allocation and ecological stoichiometry for two dominant species in the Hulunbuir Grassland, China]. / ç¾¤è½æ¼”æ›¿å¯¹å‘¼ä¼¦è´å°”è‰åœ°ä¸¤ç§ä¼˜åŠ¿æ¤ç‰©ç¹æ®–åˆ†é åŠç”Ÿæ€åŒ–å­¦è®¡é‡çš„å½±å“.

To explore the physiological and ecological adaptability of different dominant species during grassland community succession, we measured soil nutrients, plant biomass and C, N and P contents of two dominant species using the method of spatial sequences instead of chronosequences in the successive series of Agropyron michnoi community - A. michnoi + A. cristatam community - A. cristatam community in Hulunbuir Grassland. During the succession progress, the contents of soil total C, total C, available N and available P increased significantly. The N and P contents and N/P of leaves, stems and roots of A. michnoi and A. cristatam increased significantly, while the C/N showed opposite response. The leaf C content of A. michnoi and the C contents of leaves, stems and roots of A. cristatam significantly increased. The leaf C/P of A. michnoi and the C/P of leaves and roots of A. cristatem increased significantly, while the C/P of stems and roots of A. michnoi and the stem C/P of A. cristatem decreased significantly. In the community co-dominated by A. michnoi and A. cristatam, A. michnoi improved its interspecific competitiveness by reducing C content in stems and roots and increasing the C content in leaves, while A. cristatem adapted to environmental changes by reducing root to shoot ratio and reproductive ratio. A. michnoi was limited by N availability (N/P<14) in different communities, while A. cristatem was limited by P availability in single dominant community(N/P>16)and by both N and P in co-dominant community (14

Melone's concept revisited in comminuted distal radius fractures: the three-dimensional CT mapping.

BACKGROUND: There is no consensus in the literature about the ideal classification of the distal radius fracture for the clinical practice. The traditional Melone classification system divides the distal radius into four basic components, the shaft, radial styloid, dorsal medial fragment, and volar medial fragment. The aim of this study was to identify fracture lines in comminuted distal radius fractures using three-dimensional mapping of computed tomography (CT) images to test the hypothesis that fracture fragments can be divided according to the Melone classification. METHODS: Fifty-nine consecutive OTA/AO 23C3 fractures presented at the hospital between January 2018 and October 2019 were retrospectively reviewed. The fracture lines were characterized in the axial, sagittal, and coronal CT planes. After reducing the fractures in a three-dimensional (3D) model, the fracture lines were plotted from the CT images and were then superimposed on one another and oriented to fit a standard template. The area of articular surfaces was measured and compared to quantify the differences between the radial bone fragments. RESULTS: Thirty-five cases (59.3%) in this study fit the Melone classification and 24 cases (40.7%) did not. On the radiocarpal surface, there was a greater concentration of fracture lines in the dorsal area of the radius than in the volar area. On the distal radioulnar joint (DRUJ), the fracture lines were focused around two specific concentrated regions. For the articular surface area, the mean area of the radial styloid, volar medial fragment, and dorsal medial fragment was 141.13 ± 90.16 mm2, 147.79 ± 75.94 mm2, and 79.05 ± 70.73 mm2, respectively. There was a significant difference in articular surface area for the Melone fragments (P = 0.002). CONCLUSIONS: The Melone classification system is not suitable for characterizing all C3 fractures. The findings of this study confirm that the dorsal medial fragments are relatively comminuted and small. Extra care should be given to these small fragments when reducing the fracture.

Blockade of Discoidin Domain Receptor 2 as a Strategy for Reducing Inflammation and Joint Destruction in Rheumatoid Arthritis Via Altered Interleukin-15 and Dkk-1 Signaling in Fibroblast-Like Synoviocytes.

OBJECTIVE: This study was undertaken to uncover the pathophysiologic role of discoidin domain receptor 2 (DDR-2), a putative fibrillar collagen receptor, in inflammation promotion and joint destruction in rheumatoid arthritis (RA). METHODS: In synovial tissue from patients with RA and from mice with collagen antibody-induced arthritis (CAIA) (using Ddr2-/- and DBA/1 mice), gene and protein expression levels of DDR-2, interleukin-15 (IL-15), and Dkk-1 were measured by quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. Gene knockdown of DDR2 in human RA fibroblast-like synoviocytes (FLS) was conducted via small interfering RNA. Interaction between the long noncoding RNA H19 and microRNA 103a (miR-103a) was assessed in RA FLS using RNA pulldown assays. Cellular localization of H19 was examined using fluorescence in situ hybridization assays. Chromatin immunoprecipitation and dual luciferase reporter assays were applied to verify H19 transcriptional and posttranscriptional regulation by miR-103a. RESULTS: DDR2 messenger RNA (mRNA) expression was significantly associated with the levels of IL-15 and Dkk-1 mRNA in the synovial tissue of RA patients (r2 = 0.2022-0.3293, all P < 0.05; n = 33) and with the serum levels of IL-15 and Dkk-1 in mice with CAIA (P < 0.05). In human RA FLS, activated DDR-2 induced the expression of H19 through c-Myc. Moreover, H19 directly interacted with and promoted the degradation of miR-103a. CONCLUSION: These results indicate a novel role for activated DDR-2 in RA FLS, showing that DDR-2 is responsible for regulating the expression of IL-15 and Dkk-1 in RA FLS and is involved in the promotion of inflammation and joint destruction during pathophysiologic development of RA. Moreover, DDR-2 inhibition, acting through the H19-miR-103a axis, leads to reductions in the inflammatory reaction and severity of joint destruction in mice with CAIA, suggesting that inhibition of DDR-2 may be a potential therapeutic strategy for RA.