Protective effects of emodin on subchondral bone and articular cartilage in osteoporotic osteoarthritis rats: A preclinical study.

BACKGROUND: Osteoporotic osteoarthritis (OP-OA) is a severe pathological form of OA, urgently requiring precise management strategies and more efficient interventions. Emodin (Emo), an effective ingredient found in the traditional Chinese medicine rhubarb, has been dEmonstrated to promote osteogenesis and inhibit extracellular matrix degradation. In this study, we aimed to investigate the interventional effects of Emo on the subchondral bone and cartilage of the knee joints in OP-OA model rats. METHODS: Thirty-two SD rats were randomly and equally divided into sham, OP-OA, Emo low-dose, and Emo high-dose groups. Micro-CT scanning was conducted to examine the bone microstructure of the rat knee joints. H&E and Safranin O and Fast Green staining (SO&FG) were performed for the pathomorphological evaluation of the rat cartilage tissues. ELISA was used to estimate the rat serum expression levels of inflammatory factors, including interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). Additionally, the CCK-8 assay was utilized for determining the viability of Emo-treated BMSCs. Western blot and real-time PCR analyses were also employed to measure the bone formation indexes and cartilage synthesis and decomposition indexes. Lastly, the osteogenic and chondrogenic differentiation efficiency of the BMSCs was investigated via Alizarin Red and Alcian Blue staining. RESULTS: Emo intervention alleviated the bone microstructural disruption of the subchondral bone and articular cartilage in the OP-OA rats and up-regulated the expression of bone and cartilage anabolic metabolism indicators, decreased the expression of cartilage catabolism indicators, and diminished the expression of inflammatory factors in the rat serum (P<0.05). Furthermore, Emo reversed the decline in the osteogenic and chondrogenic differentiation ability of the BMSCs (P<0.05). CONCLUSION: Emo intervention mitigates bone loss and cartilage damage in OP-OA rats and promotes the osteogenic and chondrogenic differentiation of BMSCs.

Macrophage pyroptosis promotes synovial fibrosis through the HMGB1/TGF- ß1 axis: an in vivo and in vitro study.

Macrophages and fibroblasts are the main effector cells in synovial tissue in the knee joint. Our previous studies showed that there was synovial macrophage pyroptosis in knee osteoarthritis (KOA) and that inhibiting this pyroptosis could alleviate synovial fibrosis. In the present study, we aimed to elucidate the mechanism by which macrophage pyroptosis affects synovial fibrosis. We established an LPS/ATP-induced model in macrophages that mimicked the inflammatory environment of KOA and induced macrophage pyroptosis. The TGF-ß1, SMAD3, and P-SMAD3, and the synovial fibrosis markers (Collagen I, TIMP1, Vimentin, and TGF-ß1) were significantly decreased after fibroblasts were cultured with RAGE inhibitors and SMAD3 inhibitors. Moreover, ELISA and immunofluorescence analysis showed that macrophage pyroptosis induced the release of IL-1ß, IL-18, and HMGB1 and caused the translocation of HMGB1 from the fibroblast nucleus to the cell membrane, where it could bind with RAGE. Subsequently, in the synovial tissue of KOA model rats, we observed that inhibiting HMGB1, RAGE, and SMAD3 could alleviate the expression of synovial fibrosis markers (Collagen I, TIMP1, Vimentin, and TGF-ß1) at both the mRNA and protein levels. Besides, HE and Sirius Red staining were used to observe the transverse diameter of the right knee. In conclusion, macrophage pyroptosis induced IL-1ß, IL-18, and HMGB1, which could be caused HMGB1 to translocate from the fibroblast nucleus and bind with RAGE, activating the TGF-ß1/SMAD3 signaling pathway and affecting synovial fibrosis.

Ultralong waveguide grating antenna enabled by evanescent field modulation.

Waveguide grating antenna (WGA) is a key component for an on-chip optical phased array. In order to form a beam with a small divergence angle, WGAs of several millimeters in length are highly desired. However, in high-index-contrast platforms such as silicon-on-insulator (SOI), such long WGAs typically require weakly modulated gratings with critical feature sizes below 10 nm. In this paper, we experimentally demonstrate a new, to the best of our knowledge, strategy to implement long WGAs. Instead of directly modulating a waveguide, we propose periodically modulating the evanescent field with subwavelength blocks. With this arrangement, weak grating strength can be achieved while maintaining a minimum feature size as large as 100 nm. For proof-of-concept, we experimentally demonstrate a 1-mm-long, single-etched WGA on a conventional 220 nm SOI platform, which achieves a far-field divergence angle of 0.095° and a wavelength scanning sensitivity of 0.168°/nm.

Imperatorin alleviated NLR family pyrin domain-containing 3 inflammasome cascade-induced synovial fibrosis and synovitis in rats with knee osteoarthritis.

We aimed to clarify the therapeutic effects of imperatorin (IMP) on knee osteoarthritis (KOA). Thirty 3-month-old SD male rats were randomly divided into Normal, monosodium iodoacetate (MIA) and MIA+IMP groups. Their synovial tissues were subjected to histopathological analysis. Primary synovial fibroblasts obtained from additional normal rats were treated by lipopolysaccharide (LPS) and then IMP. The mRNA and protein expressions of factors related to synovitis and synovial fibrosis were detected by qRT-PCR and Western blotting, respectively. The concentrations of inflammatory factors IL-1ß and IL-18 were measured by ELISA. IMP reduced HIF-1α, NLR family pyrin domain-containing 3 inflammasome expression and IL-1ß, IL-18 production in synovial fibroblasts induced by LPS. IMP also downregulated synovial fibrosis markers. In vitro study revealed that MIA-induced synovitis and synovial fibrosis were relieved by IMP. IMP relieves the inflammation associated with synovitis and synovial fibrosis. It reduces the production of pro-inflammatory mediators and cytokines and inhibits TGF-ß1, TIMP-1 and VEGF expressions that promote synovial fibrosis.

Synovial Fibrosis Involvement in Osteoarthritis.

Bone changes have always been the focus of research on osteoarthritis, but the number of studies on synovitis has increased only over the last 10 years. Our current understanding is that the mechanism of osteoarthritis involves all the tissues that make up the joints, including nerve sprouting, pannus formation, and extracellular matrix environmental changes in the synovium. These factors together determine synovial fibrosis and may be closely associated with the clinical symptoms of pain, hyperalgesia, and stiffness in osteoarthritis. In this review, we summarize the consensus of clinical work, the potential pathological mechanisms, the possible therapeutic targets, and the available therapeutic strategies for synovial fibrosis in osteoarthritis to gain insight and provide a foundation for further study.

Agnuside Alleviates Synovitis and Fibrosis in Knee Osteoarthritis through the Inhibition of HIF-1α and NLRP3 Inflammasome.

Increasing evidence has shown that NLRP3 inflammasome activation participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last study also revealed the vital role of NLRP3 inflammasome, highly associated with tissue hypoxia, in the onset and development of knee osteoarthritis (KOA). In this study, we tried to find a possible benign intervention for that pathological process. Agnuside (AGN), a nontoxic, natural small molecule isolated from the extract of Vitex negundo L. (Verbenaceae), has been demonstrated to have antioxidation, anti-inflammatory, analgesia, and many other properties as an iridoid glycoside, although its specific target is still unclear. Therefore, we established MIA-induced KOA model rats and investigated the effects of AGN oral gavage on oxygen-containing state, NLRP3 inflammasome, synovitis, and fibrosis in KOA. Pimonidazole staining and HIF-1α immunohistochemical assay both showed that AGN at the oral dose of 6.25 mg/kg can effectively relieve local hypoxia in synovial tissue. Besides, we observed a decrease of HIF-1α, caspase-1, ASC, and NLRP3 after AGN intervention, both in the mRNA and protein levels. In addition, rats treated with the AGN showed less inflammatory reaction and fibrosis, not only in the expression of NLRP3, inflammasome downstream factors IL-1ß and IL-18, and fibrosis markers TGF-ß, TIMP1, and VEGF but also in the observation of HE staining, anatomical characteristics, Sirius Red staining, and type I collagen immunohistochemistry. Subsequently, we established LPS-induced models of fibroblast-like synoviocytes (FLSs) mimicking the inflammatory environment of KOA and activating NLRP3 inflammasome. FLSs treated with AGN (3 µM) resulted in a downregulation of HIF-1α and the components required for NLRP3 inflammasome activation. Meanwhile, the content of proinflammatory factors IL-1ß and IL-18 in FLS supernatant was also reduced by AGN. In addition, both mRNA and protein levels of the fibrotic markers were significantly decreased after AGN management. To conclude, this study demonstrates that AGN alleviates synovitis and fibrosis in experimental KOA through the inhibition of HIF-1α accumulation and NLRP3 inflammasome activation. Additionally, not only does it reveal some novel targets for anti-inflammatory and antioxidant effects of AGN but also announces its potential value in treating KOA in humans.

Relationship between the pyroptosis of fibroblast­like synoviocytes and HMGB1 secretion in knee osteoarthritis.

High mobility group box 1 (HMGB1) is an important downstream product of pyroptosis in macrophages, and it serves a vital role in numerous inflammatory diseases. Previous studies have reported that HMGB1 is released by fibroblast­like synoviocytes (FLSs) that are activated by inflammatory cytokines in knee osteoarthritis (KOA); however, the mechanism via which FLS promotes HMGB1 secretion in KOA remains unknown. According to our previous study, pyroptosis occurs in FLSs of patients with KOA and is mediated by Nod­like receptor protein (NLRP)1 or NLRP3 inflammasomes. However, the specific relationship between HMGB1 secretion and FLS pyroptosis requires further investigation. In the present study, the association between HMGB1 secretion and FLS pyroptosis was investigated in vitro and in vivo. In this study, western blotting, ELISA and reverse transcription­quantitative PCR were used to measure expression levels of proteins and mRNA. Caspase­1 activity assay and Hoechst 33342/PI double staining were used to observe the pyroptosis of FLSs. Hematoxylin and eosin staining was used to observe the destruction of cartilage in KOA. Increased expression levels of pyroptosis­related proteins and HMGB1 in the synovium of rat anterior cruciate ligament transection­induced KOA models were identified, and these changes were significantly mitigated via the intra­articular injection of a caspase­1 inhibitor. In vitro, FLSs were treated with lipopolysaccharide (LPS) + ATP to induce pyroptosis, and HMGB1 secretion was subsequently measured. LPS + ATP significantly increased the expression levels of pyroptosis­related proteins and HMGB1 in FLSs, and these effects were significantly mitigated by small interfering RNAs targeting NLRP1, NLRP3, apoptosis­associated speck­like protein with a caspase­recruitment domain or caspase­1. Therefore, the present results indicated that NLRP1/NLRP3 inflammasome­mediated and caspase­1­dependent FLS pyroptosis increased HMGB1 secretion in KOA. These findings may provide a therapeutic strategy to decrease synovial inflammatory responses during KOA progression.

Network Pharmacology Approach to Uncover the Mechanism Governing the Effect of Simiao Powder on Knee Osteoarthritis.

OBJECTIVE: To explore the molecular mechanism of Simiao powder in the treatment of knee osteoarthritis. METHODS: Based on oral bioavailability and drug-likeness, the main active components of Simiao powder were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). GeneCard, OMIM, DisGeNET, DrugBank, PharmGkb, and the Therapeutic Target Database were used to establish target databases for knee osteoarthritis. Cytoscape software was used to construct a visual interactive network diagram of "active ingredient - action target - disease." The STRING database was used to construct a protein interaction network and analyze related protein interaction relationships. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) biological process enrichment analysis were performed on the core targets. Additionally, Discovery Studio software was used for molecular docking verification of active pharmaceutical ingredients and disease targets. RESULTS: Thirty-seven active components of Simiao powder were screened, including 106 common targets. The results of network analysis showed that the targets were mainly involved in regulating biological processes such as cell metabolism and apoptosis. Simiao powder components were predicted to exert their therapeutic effect on the AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, and HIF-1 signaling pathway. The molecular docking results showed that the active components of Simiao powder had a good match with the targets of IL1B, MMP9, CXCL8, MAPK8, JUN, IL6, MAPK1, EGF, VEGFA, AKT1, and PTGS2. CONCLUSION: Simiao powder has multisystem, multicomponent, and multitarget characteristics in treating knee osteoarthritis. Its possible mechanism of action includes inhibiting the inflammatory response, regulating immune function, and resisting oxidative stress to control the occurrence and development of the disease. Quercetin, wogonin, kaempferol, beta-sitosterol, and other active ingredients may be the material basis for the treatment of knee osteoarthritis.

Casticin suppresses monoiodoacetic acid-induced knee osteoarthritis through inhibiting HIF-1α/NLRP3 inflammasome signaling.

Knee osteoarthritis (KOA) is a disabling chronic inflammatory disease that is closely associated with synovium tissue hypoxia and synovial fibrosis. Casticin, a compound purified from the Chinese herb Viticis Fructus, has been proved effective in preventing inflammation and fibrosis in previous studies. However, the effect of casticin on synovial fibrosis in KOA is not clear. In present study, we aimed to investigate how did casticin affect synovial fibrosis on monoiodoacetic acid (MIA)-induced KOA in rats. The MIA-induced knee osteoarthritis model and lipopolysaccharide (LPS) stimulated primary synovial fibroblasts inflammation model were established. Pathological and morphological changes in synovial tissue were observed by H&E and sirius red staining. The hypoxia of synovium was detected by pimonidazole staining and immunohistochemistry of hypoxia-inducible factors 1α (HIF-1α). The levels of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome components, fibrogenic markers (TGF-ß, COL1A1 and TIMP1) and inflammatory cytokines were examined by western blotting, qRT-PCR or ELISA in both KOA rat models and primary synovial fibroblasts. Our data suggested that casticin improved hypoxia and inflammation in synovium tissue, as well the synovial fibrosis in rats. Besides, casticin inhibited the activation of NLRP3 inflammasome in MIA-induced KOA rats and synovial fibroblasts. In conclusion, our findings demonstrated that casticin alleviated MIA-induced KOA by inhibiting of HIF-1α/NLRP3 inflammasome activation. Therefore, casticin could be a potential treatment strategy for KOA.

Network Pharmacology Approach to Uncover the Mechanism Governing the Effect of Radix Achyranthis Bidentatae on Osteoarthritis.

BACKGROUND: This study used a network pharmacology approach to elucidate the molecular mechanism governing the effect of Radix Achyranthis Bidentatae (RAB) on osteoarthritis (OA). METHODS: Based on oral bioavailability and drug-likeness, the main active components of RAB were screened via the Traditional Chinese Medicine Systems Pharmacology platform. The GeneCard, OMIM, PharmGkb, Therapeutic Targets database, and DrugBank database were used to establish a database of osteoarthritis targets. The interactive active network map of "ingredient-target" was constructed with Cytoscape software (Version 3.7.1). The protein-protein interaction network was constructed with the STRING database, and the related protein interaction relationship was analysed. GO biological function analysis and KEGG enrichment analysis for core targets were performed. Finally, docking of the active components with the core target was carried out. RESULTS: Sixteen active components of RAB were obtained, and 63 potential targets for OA were identified. Network analysis results indicate that these targets are primarily involved in regulating biological processes, such as cell metabolism, apoptosis, and cell proliferation. Pathways involved in the treatment of osteoarthritis include virus-related signalling pathways, apoptosis signalling pathways, IL-17 signalling pathways, and PI3K/AKT signalling pathways. CONCLUSION: RAB has the characteristics of being multi-system, multi-component and multi-target. Possible mechanisms of action for RAB include regulating the immune and inflammatory responses, reducing chondrocyte apoptosis, and protecting the joint synovial membrane and cartilage to control disease development. The active ingredients in RAB, such as sterols and flavonoids, exhibit strong potential as candidate drugs for the treatment of osteoarthritis.

Interventional effects of the direct application of "Sanse powder" on knee osteoarthritis in rats as determined from lipidomics via UPLC-Q-Exactive Orbitrap MS.

BACKGROUND: Our previous clinical evidence suggested that the direct application of "Sanse powder" the main ingredient of "Yiceng" might represent an alternative treatment for knee osteoarthritis. However, the mechanism underlying its effect is poorly understood. In this study, we investigated the mechanism of the effect of direct "Sanse powder" application for the treatment of knee osteoarthritis (KOA) in rats by using lipidomics. METHODS: KOA rats were established by cutting the anterior cruciate ligament, and the cold pain threshold and mechanical withdrawal threshold (MWT) of seven rats from each group were measured before modelling (0 days) and at 7, 14, 21 and 28 days after modelling. Histopathological evaluation of the synovial tissue was performed by haematoxylin and eosin (H&E) staining after modelling for 28 days. Interleukin-1ß (IL-1ß), pro-interleukin-1ß (pro-IL-1ß) and tumor necrosis factor-α (TNF-α) proteins in synovial tissue were measured by western blot, and the mRNA expression levels of IL-1ß and TNF-α in synovial tissue were measured using Real-time reverse transcription polymerase chain reaction (qRT-PCR), the levels of IL-1ß and TNF-α in rat serum were measured by enzyme-linked immunosorbent assay (ELISA), Serum lipid profiles were obtained by using ultra-performance liquid chromatography combined with quadrupole-Exactive Orbitrap mass spectrometry (UPLC-Q-Exactive Orbitrap MS). RESULTS: The results confirmed that the direct application of "Sanse powder" had a significant protective effect against KOA in rats. Treatment with "Sanse powder" not only attenuated synovial tissue inflammation but also increased the levels of the cold pain threshold and MWT. In addition, the lipidomics results showed that the levels of diacylglycerol (DAG), triacylglycerols (TAGs), lysophosphatidylcholine (LPC), phosphatidylcholine (PC), fatty acid esters of hydroxy fatty acids (FAHFAs), and phosphatidylethanolamine (PE) were restored almost to control levels following treatment. CONCLUSIONS: Lipidomics provides a better understanding of the actions of direct application "Sanse powder" therapy for KOA.

Vanillic Acid Reduces Pain-Related Behavior in Knee Osteoarthritis Rats Through the Inhibition of NLRP3 Inflammasome-Related Synovitis.

Objectives: Synovitis plays an important role in knee osteoarthritis (KOA) pain. The activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in fibroblast-like synoviocytes (FLSs) promotes KOA development. In this study, we aimed to investigate whether vanillic acid (VA), a monomer derived from Chinese herbal medicines, could target NLRP3 inflammasome-related synovitis to reduce pain. Methods: Rats in the KOA and KOA + VA groups were injected with monosodium iodoacetate (MIA) in the knee to induce KOA. From day 14, the KOA + VA group was given VA at 30 mg/kg every day via gastric intubation. FLSs were collected from the synovial tissues. We examined both the protein and gene expression of caspase-1, apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), NLRP3, components of the NLRP3 inflammasome, and interleukin-1ß (IL-1ß) and IL-18 in vivo and in vitro. Results: The upregulation of caspase-1, ASC, and NLRP3 in the KOA model were reduced by VA. VA also lowered the level of IL-1ß and IL-18 in the KOA model. In addition, VA relieved pain-related behavior of KOA model rats and downregulated the pain mediators CGRP, NGF, and TrkA in FLSs. Interestingly, we also observed reduced synovial fibrosis in the animal experiments. Conclusion: Our research showed that VA reduces synovitis and pain-related behaviors in a rat model of KOA, which provides the basis for further investigations into the potential therapeutic impact of VA in KOA.

Mechanism of Action of Periplogenin on Nasopharyngeal Carcinoma Based on Network Pharmacology and Experimental Study of Vitamin E Coupled with Periplogenin Self-Assembled Nano-Prodrug for Nasopharyngeal Carcinoma.

Periplogenin is a compound extracted from cortex periplocae. In the monomers' screening for inhibiting nasopharyngeal carcinoma, we found that periplogenin can inhibit nasopharyngeal carcinoma; however, its mechanism is still unclear. In this study, the chemical structure of periplogenin was uploaded to the PubChem database in order to obtain the target of periplogenin. The NPC's differential genes were obtained by analyzing the nasopharyngeal carcinoma data in the GEO database by R software. The common target of periplogenin and nasopharyngeal carcinoma was obtained through Cytoscape. Through R software analysis, ALB, epidermal growth factor receptor (EGFR), MAPK1, ESR1, MAPK8, SRC, CASP3, HSP90AA1, AR, MAPK14 may be the main targets of periplogenin in NPC. Through go enrichment analysis, it was found that periplogenin acted mainly on nasopharyngeal carcinoma through response to steroid metabolic process, cellular response to steroid hormone stimulus, hormone-mediated, and steroid hormone signaling pathway. After enrichment analysis on the Kyoto Encyclopedia of Genes and Genomes pathway, it was found that periplocan may inhibit NPC through the MAPK signaling pathway (the main signaling pathway), and the signaling pathway of proteoglycans in cancer, and the PI3K/AKT signaling pathway as well. In this study, we also carried out the experimental study of vitamin E together with periplogenin self-assembled nano-prodrugs in the treatment of NPC, and the results showed that tumor weight of PBS group was 0.531±0.039 g, while that of PPG group and MPSSV-NPs group was 0.258±0.059 g and 0.169±0.033 g, respectively, which was lower than PBS group. And the tumor inhibition rate of MPSSV-NPs was 69.41%, which was significantly higher than that of the PPG group (51.38%). This study demonstrated the mechanism of inhibition of nasopharyngeal carcinoma (NPC) by the monomer of periplogenin based on network pharmacology. We preliminarily confirmed that vitamin E coupled with a periplogenin self-assembled nano-prodrug has obvious effect in treating nasopharyngeal carcinoma.

Inhibition of Synovial Macrophage Pyroptosis Alleviates Synovitis and Fibrosis in Knee Osteoarthritis.

Increasing evidence has shown that macrophage pyroptosis in different tissues participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last studies also revealed the vital role of synovial fibroblast pyroptosis in the onset and development of knee osteoarthritis (KOA). In this study, we aimed to investigate whether synovial macrophage pyroptosis did occur and whether this form of cell death should be related to synovitis and fibrosis of KOA. In the synovial tissue of KOA model rats, we observed a decrease of caspase1, NLRP3, ASC, and GSDMD caused by macrophage depletion in both the mRNA and protein expressions. Besides, rats treated with the specific caspase1 inhibitor Ac-YVAD-CMK showed less inflammatory reaction and fibrosis, not only in the expression of proinflammatory factors IL-1ß, IL-18, and HMGB1 and fibrosis markers TGF-ß, PLOD2, COL1A1, and TIMP1 but also in the observation of HE staining, Sirius Red staining, and the transverse diameters of the right knees. Subsequently, we established an LPS+ATP-induced model in macrophages mimicking the inflammatory environment of KOA and inducing macrophage pyroptosis. Macrophages transfected with caspase1 siRNA showed reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins were also downregulated. In addition, the level of fibrotic markers in synovial fibroblasts were significantly decreased after coculture with siRNA GSDMD-transfected macrophages. To conclude, synovial macrophage pyroptosis may occur in the pathological processes of KOA and inhibition of synovial macrophage pyroptosis alleviates synovitis and fibrosis in KOA model rats.

Effect of intramedullary nail and locking plate in the treatment of proximal humerus fracture: an update systematic review and meta-analysis.

BACKGROUND: To evaluate the effect of intramedullary nail and locking plate in the treatment of proximal humerus fracture (PHF). METHODS: China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), Wan-fang database, Chinese Biomedicine Database (CBM), PubMed, EMBASE, Web of Science, and Cochrane Library were searched until July 2018. The eligible references all show that the control group uses locking plates to treat PHF, while the experimental group uses intramedullary nails to do that. Two reviewers independently retrieved and extracted the data. Reviewer Manager 5.3 was used for statistical analysis. RESULTS: Thirty-eight retrospective studies were referred in this study which involves 2699 patients. Meta-analysis results show that the intramedullary nails in the treatment of proximal humeral fractures are superior to locking plates in terms of intraoperative blood loss, operative time, fracture healing time, postoperative complications, and postoperative infection. But there is no significance in constant, neck angle, VAS, external rotation, antexion, intorsion pronation, abduction, NEER, osteonecrosis, additional surgery, impingement syndrome, delayed union, screw penetration, and screw back-out. CONCLUSIONS: The intramedullary nail is superior to locking plate in reducing the total complication, intraoperative blood loss, operative time, postoperative fracture healing time and postoperative humeral head necrosis rate of PHF. Due to the limitations in this meta-analysis, more large-scale, multicenter, and rigorous designed RCTs should be conducted to confirm our findings. TRIAL REGISTRATION: PROSPERO CRD42019120508.

Excessive mechanical stress induces chondrocyte apoptosis through TRPV4 in an anterior cruciate ligament-transected rat osteoarthritis model.

AIMS: Chondrocyte apoptosis is the most common pathological feature of cartilage in osteoarthritis (OA). Excessive mechanical stress can induce chondrocyte apoptosis and destroy cartilage tissue. Transient receptor potential channel vanilloid 4 (TRPV4) is a mechanosensitive ion channel that mediates chondrocyte response to mechanical stress. Here, we investigated the potential role of TRPV4 in chondrocyte apoptosis induced by excessive mechanical stress. MAIN METHODS: Using a rat OA anterior cruciate-ligament transection (ALCT) model, we detected immunolocalization of calmodulin protein and mRNA and protein levels of TRPV4, calmodulin, and cleaved caspase-8 in articular cartilage. Primary chondrocytes were isolated and cultured in vitro, and Fluo-4AM staining was used to assess intracellular Ca2+ levels in order to evaluate TRPV4-mediated Ca2+ influx. Flow cytometry and western blot were performed to detect apoptosis and apoptosis-related protein levels in chondrocytes, respectively. KEY FINDINGS: TRPV4 was upregulated in ALCT-induced OA articular cartilage, and we found that administration of a TRPV4 inhibitor attenuated cartilage degeneration. Additionally, TRPV4 specifically mediated extracellular Ca2+ influx, leading to chondrocyte apoptosis in vitro, which was inhibited by transfection of TRPV4 small-interfering RNA or administration of a TRPV4 inhibitor. Moreover, increased Ca2+ influx triggered apoptosis by upregulating FAS-associated protein with death domain and cleaved caspase-3, -6, -7, and -8 levels, with these effects abolished by TRPV4 knockdown or TRPV4 inhibition. SIGNIFICANCE: These results indicated that TRPV4 was upregulated in OA articular cartilage, and that excessive mechanical stress might induce chondrocyte apoptosis via TRPV4-mediated Ca2+ influx, suggesting TRPV4 as a potential drug target in OA.

[Distal Chevron osteotomy of the first metatarsal and soft-tissue release for hallux valgus].

OBJECTIVE: To explore distal Chevron osteotomy of the first metatarsal and soft-tissue release for the treatment of mild and moderate hallux valgus. METHODS: From June 2015 to June 2017, 32 patients(40 feet) with mild and moderate hallux valgus were treated with distal Chevron osteotomy with soft tissue release. including 3 males(3 feet) and 29 females (37 feet), aged from 22 to 80 years old with an average of 57.57 years old. The courses of disease ranged from 2 to 32 years with an average of 14 years. Among them, 9 feet were mild, 31 feet were moderate. Patients were combined with bunion, pain around the first metatarsal joint, and pain increased during weight-bearing walking before opertaion. AP and lateral X-rays on weight-bearing were performed, hallux valgus angle(HVA) and intermetatarsal angle(IMA) between the first and the second metatarsal were examined before and after operation. AOFAS score was applied to evaluate clinical effects. RESULTS: All patients were followed up from 12 to 24 months with an average of 15.2 months.Fracture wounds were healed well without infection and metatarsal head necrosis occurred. Preoperative HVA (32.08±5.59)° and IMA (11.63±2.24)° decreased to (10.31±4.36)° and (5.02°±2.34)°after operation at 12 months, and had statistical difference before and after operation (P<0.05). AOFAS score increased from 56.75±6.42 before operation to 88.80±3.99 after operation at 12 months(P<0.05). CONCLUSIONS: Distal Chevron osteotomy of the first metatarsal and soft-tissue release for the treatment of mild and moderate hallux valgus could obtain good effects and provide more options for hallux valgus treatment.

Increased HIF-1α in Knee Osteoarthritis Aggravate Synovial Fibrosis via Fibroblast-Like Synoviocyte Pyroptosis.

Fibroblast-like synoviocytes (FLSs) are the main effector cells of knee osteoarthritis (KOA) synovial fibrosis. Our last report showed that NLRP1 and NLRP3 inflammasomes may mediate LPS/ATP-induced FLSs pyroptosis in KOA. In the present study, we found an elevated hypoxia-inducible factor-1α (HIF-1α) level in the synovial tissue of KOA model rats, and inhibiting the increase of HIF-1α could improve synovial fibrosis in rats. Subsequently, we established LPS/ATP-induced model in FLSs mimicking the inflammatory environment of KOA. FLSs transfected with siRNA HIF-1α showed a reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins was also downregulated. Additionally, FLSs transfected with or without siRNA GSDMD were exposed to hypoxia. GSDMD silencing can significantly reduce both gene and protein levels of fibrogenic markers transforming growth factor-ß (TGF-ß), procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2), collagen type I α1 chain (COL1A1), and tissue inhibitor of metalloproteinases 1 (TIMP1). Taken together, our findings indicate that increased HIF-1α is highly involved in the KOA synovial fibrosis. Moreover, elevated HIF-1α may aggravate synovial fibrosis via FLS pyroptosis.

Effects of MMP-1 1G/2G polymorphism on osteoarthritis: A meta-analysis study.

OBJECTIVE: The aim of this meta-analysis was to clarify the role of Matrix metalloproteinase 1 (MMP-1) -1607 1G/2G (rs1799750) polymorphism on the osteoarthritis (OA) risk. METHODS: Articles were selected by retrieving the Web of Science, Embase and Pubmed. The strength of the association between -1607 1G/2G polymorphism and OA risk was assessed by odds ratios (ORs) with the corresponding 95% confidence interval (CI) for each study. RESULTS: No significant association between -1607 1G/2G polymorphism and OA risk was found in all the models overall (2G2G vs 1G1G, OR (95%CI) = 0.69 (0.36-1.32), P = 0.54; 2G2G + 2G1G vs 1G1G, OR (95%CI) = 0.88 (0.47-1.63), P = 0.69; 2G2G vs 2G1G + 1G1G, OR (95%CI) = 1.30 (0.68-2.47), P = 0.41; 2 G vs 1G, OR (95%CI) = 0.90 (0.86-1.54), P = 0.66). By subgroup analysis, significant association was found in the "< 60 years" group (2G2G vs 1G1G, OR (95%CI) = 3.46 (2.13-5.62), P = 0.00; 2G2G + 2G1G vs 1G1G, OR (95%CI) = 0.49 (0.31-0.79), P = 0.00; 2G2G vs 2G1G + 1G1G, OR (95%CI) = 2.74 (1.80-4.16, P = 0.00; 2 G vs 1G, OR (95%CI) = 0.56 (0.35-0.89), P = 0.01). CONCLUSIONS: This meta-analysis showed that -1607 1G/2G polymorphism may increase the susceptibility to OA among the younger populations (<60 years). More studies with detailed information are needed to validate our conclusion. LEVEL OF EVIDENCE: Level I Diagnostic Study.

Transient receptor potential ankyrin 1 (trpa1) mediates il-1ß-induced apoptosis in rat chondrocytes via calcium overload and mitochondrial dysfunction.

BACKGROUND: Chondrocyte apoptosis is a central feature in the progression of osteoarthritis (OA), and would be triggered by sustained elevation of intracellular calcium ion (Ca2+), also known as a cellular second messenger. Transient receptor potential ankyrin 1 (TRPA1) is a membrane-associated cation channel, and the activation of which causes an influx of cation ions, in particularly Ca2+, into the activated cells. Therefore, we investigate the potential role of TRPA1 in mediating Ca2+ influx to promote chondrocyte apoptosis in OA. METHODS: The expression of TRPA1 in interleukin (IL)-1ß-treated rat chondrocytes was assessed by Polymerase chain reaction (PCR) and Western blot (WB), and the functionality of TRPA1 channel by Ca2+ influx measurements. Meanwhile, the chondrocyte apoptosis in IL-1ß-treated cells was measured by TUNEL assay and flow cytometry. The measurement of mitochondrial membrane potential and apoptosis-associated proteins after inhibition of TRPA1 were also performed in IL-1ß-treated rat chondrocytes. RESULTS: After being induced by IL-1ß, the gene and protein expression of TRPA1 was increased in the dose-dependent manner. Meanwhile, Ca2+ influx mediated by TRPA1 in rat chondrocytes was also enhanced. Pharmacological inhibition of TRPA1 downregulated the apoptotic rate in IL-1ß-treated rat chondrocytes. In addition, the membrane potential depolarization was improved and significantly increased expression of apoptosis-associated proteins also reduced by the TRPA1 antagonist. CONCLUSIONS: We found the IL-1ß caused the increased functional expression of TRPA1, the activation of which involved IL-1ß-induced apoptosis in rat chondrocytes. The potential mechanism may be linked to the intracellular calcium overload mediated by TRPA1 and attendant mitochondrial dysfunction.