NOD2 attenuates osteoarthritis via reprogramming the activation of synovial macrophages.

OBJECTIVE: Synovial inflammation, which precedes other pathological changes in osteoarthritis (OA), is primarily initiated by activation and M1 polarization of macrophages. While macrophages play a pivotal role in the inflammatory process of OA, the mechanisms underlying their activation and polarization remain incompletely elucidated. This study aims to investigate the role of NOD2 as a reciprocal modulator of HMGB1/TLR4 signaling in macrophage activation and polarization during OA pathogenesis. DESIGN: We examined NOD2 expression in the synovium and determined the impact of NOD2 on macrophage activation and polarization by knockdown and overexpression models in vitro. Paracrine effect of macrophages on fibroblast-like synoviocytes (FLS) and chondrocytes was evaluated under conditions of NOD2 overexpression. Additionally, the in vivo effect of NOD2 was assessed using collagenase VII induced OA model in mice. RESULTS: Expression of NOD2 was elevated in osteoarthritic synovium. In vitro experiments demonstrated that NOD2 serves as a negative regulator of HMGB1/TLR4 signaling pathway. Furthermore, NOD2 overexpression hampered the inflammatory paracrine effect of macrophages on FLS and chondrocytes. In vivo experiments revealed that NOD2 overexpression mitigated OA in mice. CONCLUSIONS: Supported by convincing evidence on the inhibitory role of NOD2 in modulating the activation and M1 polarization of synovial macrophages, this study provided novel insights into the involvement of innate immunity in OA pathogenesis and highlighted NOD2 as a potential target for the prevention and treatment of OA.

STING/TBK1 Regulates Inflammation in Macrophages and Titanium Particles-Induced Osteolysis.

Inflammatory response in macrophages on account of prostheses-derived wear particles is the leading cause of artificial joint failure. However, the mechanism by which wear particles initiate macrophage inflammation has not been fully elucidated. Previous research studies have identified TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING) as potential factors in inflammation and autoimmune diseases. Here, we found that both TBK1 and STING were increased in synovium from aseptic loosening (AL) patients and were activated in titanium particles (TiPs)-stimulated macrophages. Lentivirus-mediated knockdown of TBK or STING significantly inhibited the inflammatory effects of macrophages, while overexpression of TBK or STING exerted opposite results. In concrete, STING/TBK1 promoted the activation of NF-κB and IRF3 pathways and macrophage M1 polarization. For further validation, a mice cranial osteolysis model was constructed for in vivo assays, and we found that STING-overexpressed lentivirus injection exacerbated osteolysis and inflammation, which was counteracted by TBK1-knockdown injection. In conclusion, STING/TBK1 enhanced TiP-induced macrophage inflammation and osteolysis via orchestrating the activation of NF-κB and IRF3 pathways and M1 polarization, which suggested STING/TBK1 as potential therapeutic targets for preventing AL of prostheses.

Genetically Modified Mesenchymal Stromal Cells in Cartilage Regeneration.

Articular cartilage injury is common in various conditions, including osteoarthritis, rheumatic diseases, and trauma. Current treatments for cartilage injury fail to completely regenerate the damaged cartilage. Mesenchymal stromal cells (MSCs) have emerged as potential candidates for cartilage regeneration. However, MSCs exhibit hypertrophic differentiation, and their chondrogenic ability is reduced in an inflammatory environment. In recent years, genetic modification has been proposed for optimizing MSC-based therapies, some of which are expected to enter clinical trials. This review summarizes recent research findings and developments in genetic engineering strategies to enhance stem cell-based therapy for cartilage regeneration. We also discuss the mechanisms of biofunctions of MSCs in cartilage regeneration and outline the efficacy and safety of the different genetic modification strategies, including viral and nonviral delivery transduction. Finally, we highlight the major challenges and prospects for clinical translation of genetically modified MSCs.

HUCMSC-derived Exosomes Suppress the Titanium Particles-induced Osteolysis in Mice through Inhibiting CCL2 and CCL3.

OBJECTIVE: Wear particles induce inflammation and the further osteolysis around the prosthesis, has been proven to be the main cause of aseptic hip joint loosening. In this research, we aimed to clarify whether human umbilical cord mesenchymal stem cells (HUCMSCs) could inhibit the titanium particles-induced osteolysis and shed light upon its mechanism. METHODS: The expression of chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5) were examinjed in clinical specimens of aseptic hip prosthesis loosening patients. Local injection of lentivirus that knocked down CCL2 or CCL3 in a cranial osteolysis mice model were used to exam the effect of CCL2 and CCL3 on titanium particles-induced osteolysis in vivo. Transwell assay was used to examine the effect of CCL2 and CCL3 on titanium particles-induced activation of macrophage in vitro. Furthermore, the therapeutic effect of HUCMSCs, and exosomes from HUCMSCs were also examed in vivo and vitro. Immunohistochemical and real-time PCR were used to examine the expression of relative pathways. Analysis of variance (ANOVA) and Student-Newman-Keuls post hoc t test were used to analyze the results and determine the statistical significance of the differences. RESULTS: Results showed that titanium particles caused the osteolysis at the mice cranial in vivo and a large number of macrophages that migrated, while local injection of HUCMSCs and exosomes did inhibit the cranial osteolysis and migration. An exosome inhibitor GW4869 significantly increased the osteolysis area in the mice cranium osteolysis model, and increased the number of migrated macrophages. Immunohistochemical results suggested that the expression of CCL2, CCL3 and CD68 in the cranial in Titanium particles mice increased significantly, but was significantly reduced by HUCMSCs or exosomes. HUCMSC and exosomes down-regulate the expression of CCL3 in vitro and in vivo. CONCLUSION: HUCMSCs and HUCMSC-derived exosomes could suppress the titanium particles-induced osteolysis in mice through inhibiting chemokine (C-C motif) ligand 2, chemokine (C-C motif) ligand 3.

Osteoporosis Diagnostic Model Using a Multichannel Convolutional Neural Network Based on Quantitative Ultrasound Radiofrequency Signal.

Quantitative ultrasound (QUS) is a promising screening method for osteoporosis. In this study, a new method to improve the diagnostic accuracy of QUS was established in which a multichannel convolutional neural network (MCNN) processes the raw radiofrequency (RF) signal of QUS. The improvement in the diagnostic accuracy of osteoporosis using this new method was evaluated by comparison with the conventional speed of sound (SOS) method. Dual-energy X-ray absorptiometry was used as the diagnostic standard. After being trained, validated and tested in a data set consisting of 274 participants, the MCNN model could significantly raise the accuracy of osteoporosis diagnosis compared with the SOS method. The adjusted MCNN model performed even better when adjusted by age, height and weight data. The sensitivity, specificity and accuracy of the adjusted MCNN method for osteoporosis diagnosis were 80.86%, 84.23% and 83.05%, respectively; the corresponding values for SOS were 50.60%, 73.68% and 66.67%. The area under the receiver operating characteristic curve of the adjusted MCNN method was also higher than that of SOS (0.846 vs. 0.679). In conclusion, our study indicates that the MCNN method may be more accurate than the conventional SOS method. The MCNN tool and ultrasound RF signal analysis are promising future developmental directions for QUS in screening for osteoporosis.

MiR-92a/KLF4/p110δ regulates titanium particles-induced macrophages inflammation and osteolysis.

As total joint replacement is widely applied for severe arthropathy, peri-prosthetic aseptic loosening as one of the main causes of implant failure has drawn wide attention. Wear particles such as titanium particles (TiPs) derived from prosthesis can initiate macrophages inflammation and sequentially activate osteoclasts, which results in bone resorption and osteolysis for long-term. Therefore, inhibiting wear particles induced macrophages inflammation is considered as a promising therapy for AL. In this research, we found that the inhibition of p110δ, a member of class IA PI3Ks family, could significantly dampen the TiPs-induced secretion of TNFα and IL-6. By the transfection of siRNA targeting p110δ, we confirmed that p110δ was responsible for TNFα and IL-6 trafficking out of Golgi complex without affecting their expression in TiPs-treated macrophages. As the upstream transcription-repressor of p110δ, Krüppel-like factor 4 (KLF4), targeted by miR-92a, could also attenuate TiPs-induced inflammation by mediating NF-κB pathway and M1/M2 polarization. To further ascertain the roles of KLF4/p110δ, TiPs-induced mice cranial osteolysis model was established and vivo experiments validated that KLF4-knockdown could exacerbate TiPs-induced osteolysis, which was strikingly ameliorated by knockdown of p110δ. In summary, our study suggests the key role of miR-92a/KLF4/p110δ signal in TiPs-induced macrophages inflammation and osteolysis.

LncRNA Neat1 promotes the macrophage inflammatory response and acts as a therapeutic target in titanium particle-induced osteolysis.

Aseptic loosening (AL), secondary to particle-caused periprosthetic osteolysis, is one of the main reasons of artificial joint failure. Suppressing the macrophage inflammatory response caused by wear particles extends the life of prosthesis, and the long noncoding RNAs (lncRNAs) may play a predominant part in it. Here, titanium particles' (TiPs') stimulation increases both the cytoplasmic and nuclear levels of lncRNA Neat1 in bone marrow derived macrophages (BMDMs), which further induces the inflammatory response. Mechanically, Neat1 facilitates Bruton's tyrosine kinase (BTK) transcription by reducing the transcriptional factor KLF4, which further activates the NF-κB pathway, NLRP3 inflammation, and M1 polarization in BMDMs. Cytoplasmic Neat1 also works as an miRNA sponge in miR-188-5p-regulated BTK expression in the post-transcriptional stage. In vivo, Neat1 downregulation can reduce the TiP-induced pro-inflammatory factors and reverse the osteolysis induced by BTK overexpression. In addition, the PLGA-based microparticles loaded with si-Neat1 are developed for the treatment of the mouse calvarial osteolysis model via local injection, presenting satisfactory anti-osteolysis efficacy. These findings indicate that Neat1 is a key regulator of AL. STATEMENT OF SIGNIFICANCE: Due to released particles, aseptic loosening (AL) is the most common reason for prosthesis failure and surgical revision and represents a substantial economic burden worldwide. Herein, we reported that lncRNA Neat1 is a key regulator in regulating wear particles-induced osteolysis by activating NF-κB pathway, NLRP3 inflammation and M1 polarization via BTK, and the underlying mechanisms of Neat1-BTK interaction were further portrayed. For potential clinical application, the microparticles are developed for effective si-Neat1 delivery, leading to a dramatically enhanced effect for the treatment of osteolysis, which might be a novel strategy to extend the life of the implant.

Increased expression of osteopontin in subchondral bone promotes bone turnover and remodeling, and accelerates the progression of OA in a mouse model.

Osteopontin (OPN) has been proved to be closely related to the pathogenesis of osteoarthritis (OA), but the role of OPN in the pathogenesis of OA has not been fully clarified. Current studies on OPN in OA mostly focus on articular cartilage, synovial membrane and articular fluid, while ignoring its role in OA subchondral bone turnover and remodeling. In this study, we used a destabilization OA mouse model to investigate the role of OPN in OA subchondral bone changes. Our results indicate that increased expression of OPN accelerates the turnover and remodeling of OA subchondral bone, promotes the formation of h-type vessels in subchondral bone, and mediates articular cartilage degeneration induced by subchondral bone metabolism. In addition, our results confirmed that inhibition of PI3K/AKT signaling pathway inhibits OPN-mediated OA subchondral bone remodeling and cartilage degeneration. This study revealed the role and mechanism of OPN in OA subchondral bone, which is of great significance for exploring specific biological indicators for early diagnosis of OA and monitoring disease progression, as well as for developing drugs to regulate the metabolism and turnover of subchondral bone and alleviate the subchondral bone sclerosis of OA.

Osteoporosis Diagnosis Based on Ultrasound Radio Frequency Signal via Multi-channel Convolutional Neural Network.

Osteoporosis is a metabolic osteopathy syndrome, and the incidence of osteoporosis increases significantly with age. Currently, bone quantitative ultrasound (QUS) has been considered as a potential method for screening and diagnosing osteoporosis. However, its diagnostic accuracy is quite low. By contrast, deep learning based methods have shown the great power for extracting the most discriminative features from complex data. To improve the osteoporosis diagnostic accuracy and take advantages of QUS, we devise a deep learning method based on ultrasound radio frequency (RF) signal. Specifically, we construct a multi-channel convolutional neural network (MCNN) combined with a sliding window scheme, which can enhance the number of data as well. By using speed of sound (SOS), the quantitative experimental results of our preliminary study indicate that our proposed osteoporosis diagnosis method outperforms the conventional ultrasound methods, which may assist the clinician for osteoporosis screening.

Spermidine activates RIP1 deubiquitination to inhibit TNF-α-induced NF-κB/p65 signaling pathway in osteoarthritis.

Spermidine has been known to inhibit the production of pro-inflammatory cytokines. However, there are no reports about anti-inflammatory effects of spermidine on osteoarthritis (OA). Herein, we examined whether OA progression could be delayed by intraperitoneal injection (i.p.) of spermidine in the anterior cruciate ligament transection (ACLT) and TNF-α induced arthritis (TIA) mouse models. During the process, human FLS cells (H-FLS) were used to investigate the potential ubiquitination mechanism of spermidine-mediated RIP1 in TNF-α-induced NF-κB/p65 signaling. We found that spermidine attenuated synovitis, cartilage degeneration and osteophyte formation, resulting in substantially lower OARSI scores and TNF-α scores in spermidine-treated ACLT and TIA mice. In terms of the mechanism, 9 µM spermidine did not affect the viability, proliferation, cell cycle and apoptosis of H-FLS, and exerted inhibitory effects by activating CYLD-mediated RIP1 deubiquitination on TNF-α-induced NF-κB/p65 signaling in H-FLS. From these data, we can conclude that spermidine attenuates OA progression by the inhibition of TNF-α-induced NF-κB pathway via the deubiquitination of RIP1 in FLS. Therefore, intake of spermidine could be a potential therapy for preventing OA.

ZBTB20-mediated titanium particle-induced peri-implant osteolysis by promoting macrophage inflammatory responses.

Aseptic loosening (AL) caused by wear particles released from implant surfaces is one of the main causes for the failure of artificial joints, which is initiated by macrophage inflammatory responses. Emerging evidence suggests that the member of a broad-complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) family as well as zinc finger and BTB domain-containing protein 20 (ZBTB20) can inhibit IκBα gene transcription, promote NF-κB activation, and initiate innate immune responses. The molecular mechanism(s) by which ZBTB20 contributes to titanium particle (TiP)-induced macrophage inflammatory responses and osteolysis has not been fully elucidated. Here, we showed that ZBTB20 increased either in the AL group's synovial membranes or in TiP-stimulated bone-marrow-derived macrophages (BMDMs) as compared to that in the control groups. Moreover, the knockdown of ZBTB20 led to the inhibition of proinflammatory factors induced by TiPs in BMDMs, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-ß (IFN-ß). Here, we also reported that the knockdown of ZBTB20 suppressed TiP-induced NF-κB activation and M1 polarization as well as stabilized the trans Golgi network (TGN) in BMDMs. The dual-luciferase reporter assay identified the binding between the IκBα promoter and ZBTB20, and IκBα knockdown could rescue the antiinflammatory effects induced by the ZBTB20 knockdown in BMDMs. Finally, we found that sh-ZBTB20 lentivirus injection could reduce TiP-induced osteolysis in mouse calvaria, inhibiting TiP-induced proinflammatory factors and loss of bone volume/total volume (BV/TV) as well as bone mineral density (BMD). These results suggest that ZBTB20 positively regulated NF-κB activation and M1 polarization as well as the production of TGN-derived tubular carriers in BMDMs, playing a positive role in macrophage activation and mouse cranial osteolysis induced by TiPs. It may be a potential therapeutic target for the prevention of aseptic loosening of prostheses.

Association between the ABO blood group and primary knee osteoarthritis: A case-control study.

BACKGROUND: Recent studies have suggested association between the ABO blood group and inflammation, which was a crucial pathological process of primary knee osteoarthritis. The aim of this study was to investigate the association between the ABO blood group and primary knee osteoarthritis â€‹and the severity of primary knee osteoarthritis evaluated by the Kellgren/Lawrence score, as well as the histopathologic association in a subgroup of patients. METHODS: We performed a retrospective review of patients with primary knee osteoarthritis that served as the case group â€‹and a random sampling of healthy blood donors that served as the control group. The severity of knee osteoarthritis at the first outpatient visit was evaluated by the Kellgren/Lawrence scoring system. Further study was performed to investigate the expression of blood group antigens in synovial tissue of the knee in both cases and controls. RESULTS: A total of 1126 cases and 30299 controls were involved. The proportion of AB blood group was higher in the case group than in the control group (9.7% vs. 7.8%), and logistic regression revealed that the AB blood group was a risk factor of primary knee osteoarthritis (P â€‹= â€‹0.025 and 0.048 for univariate and multivariate analysis, respectively), independent of age (P â€‹= â€‹0.973) and sex (P â€‹= â€‹0.520). Patients of the blood group AB had a higher Kellgren/Lawrence score (P â€‹= â€‹0.017). The immunohistochemical study indicated association between LeY antigen and primary knee osteoarthritis (P â€‹= â€‹0.029). CONCLUSIONS: This study suggested that the blood group AB was associated with primary knee osteoarthritis, as well as its radiological severity. Further study indicated that LeY antigen, which was related to the blood group, was associated with primary knee osteoarthritis. TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study revealed that blood group AB and LeY antigen was associated with primary knee osteoarthritis, which shed new light on the nature of osteoarthritis, and the development of novel therapy for osteoarthritis.

The USP14-NLRC5 pathway inhibits titanium particle-induced osteolysis in mice by suppressing NF-κB and PI3K/AKT activities.

Total hip arthroplasty (THA) is a widely-used surgical intervention for treating patients with end-stage degenerative and inflammatory osteoarthropathy. However, wear particles from the artificial titanium joint can induce osteolysis, limiting the long-term survivorship of THA. Monocyte/macrophage lineage cells are the key players in the response to wear particles, and the proinflammatory NF-κB and phosphoinositide 3-kinase (PI3K)-AKT Ser/Thr kinase (AKT)-signaling pathways have been shown to be the most important contributors to wear particle-induced osteolysis. In contrast, ubiquitin-specific protease 14 (USP14) specifically removes the polyubiquitin chains from the nucleotide-binding and oligomerization domain (NOD)-like receptor family Caspase recruitment domain (CARD)-containing 5 (NLRC5) and thereby enhances the NLRC5-mediated inhibition of NF-κB signaling. In this study, we aimed to clarify the role of the USP14-NLRC5 pathway in wear particle-induced osteolysis in vitro and in vivo We found that NLRC5 or USP14 overexpression inhibits titanium particle-induced proinflammatory tumor necrosis factor α (TNFα) production and NF-κB pathway activation, and it also decreases M1 macrophage polarization and PI3K/AKT pathway activation. Of note, NLRC5 and USP14 overexpression attenuated titanium particle-induced cranial osteolysis in mice. In conclusion, the findings of our study indicate that the USP14-NLRC5 pathway inhibits titanium particle-induced osteolysis by suppressing the NF-κB and PI3K/AKT pathways both in vitro and in vivo.

Efficiency of Zoledronic Acid in Inhibiting Accelerated Periprosthetic Bone Loss After Cementless Total Hip Arthroplasty in Osteoporotic Patients: A Prospective, Cohort Study.

OBJECTIVE: To investigate the influence of preoperative osteopenia/osteoporosis on periprosthetic bone loss after total hip arthroplasty (THA) and the efficiency of zoledronate (ZOL) treatment in periprosthetic bone preservation. METHODS: This multicenter, prospective cohort study was conducted in four centers between April 2015 and October 2017. Patients were assigned to Normal BMD, Osteopenia, and Osteoporosis+ZOL groups. Patients with osteopenia received daily oral calcium (600 mg/d) and vitamin D (0.5 µg/d), while patients in the Osteoporosis+ZOL group received additional ZOL annually (5 mg/year). Periprosthetic bone mineral density (BMD) in seven Gruen zones, radiographic parameters, Harris hip score, EuroQol 5-Dimensions (EQ-5D) score, and BMD in hip and spine were measured within 7 days, 3 months, 12 months postoperation and annually thereafter. RESULTS: A total of 266 patients were enrolled, while 81 patients that completed the first year follow-up were involved in the statistical analysis. The mean follow-up time was 1.3 years. There were significant decreases of mean BMD in total Gruen zones (-4.55%, P < 0.05) and Gruen zone 1 (-10.22%, P < 0.01) in patients with osteopenia during the first postoperative year. Patients in the Osteoporosis+ZOL group experienced a marked increase in BMD in Gruen zone 1 (+16%) at the first postoperative year, which had a significant difference when compared with the Normal BMD group (P < 0.05) and the Osteopenia Group (P < 0.001). Low preoperative BMD in hip and spine was predictive of bone loss in Gruen zone 1 at 12 months after THA in patients with normal BMD (R2 = 0.40, P < 0.05). CONCLUSIONS: Patients with osteopenia are prone to higher bone loss in the proximal femur after cementless total hip arthroplasty (THA). ZOL, not solely calcium and vitamin D, could prevent the accelerated periprosthetic bone loss after THA in patients with osteopenia and osteoporosis.

NOD2 negatively regulated titanium particle-induced osteolysis in mice.

For patients undergoing total joint replacement (TJR), one of the complications, aseptic loosening, could cause serious consequences, such as revision surgery. In early research, pattern recognition receptors (PRRs) were reported to play vital roles in recognizing wear particles from the prosthesis and initiating an inflammation response. In this research, we aimed to clarify the role of nucleotide-binding and oligomerization domain containing protein 2 (NOD2), one of the PRRs, in macrophage-induced aseptic loosening in vivo and in vitro. High expressions of NOD2 and TNFα were observed from twenty patients who underwent primary or revision total hip replacements (THR). The effect of NOD2 on the activation of inflammation pathways was observed in RAW264.7 cells and CRISPR-Cas9 NOD2-knockout mice. The expressions of NOD2, the NF-κB pathway, the MAPK pathway and proinflammatory cytokine TNF-α in macrophages stimulated by wear particles were up-regulated. Otherwise, inhibition of NOD2 further up-regulated the expressions of NOD2, the NF-κB pathway, the MAPK pathway and TNF-α. Knockdown of the NOD2 gene enhanced the cranial osteolysis induced by titanium particles in a mouse model. In conclusion, our study demonstrated that NOD2 plays a negative role in osteolysis induced by titanium particles in vitro and in vivo.

Antiresorptive Agents are More Effective in Preventing Titanium Particle-Induced Calvarial Osteolysis in Ovariectomized Mice Than Anabolic Agents in Short-Term Administration.

Aseptic loosening due to wear particle-induced osteolysis is the main cause of arthroplasty failure and the influence of postmenopausal osteoporosis and anti-osteoporosis treatment on Titanium (Ti) particle-induced osteolysis remains unclear. 66 C57BL/6J female mice were used in this study. Ovariectomy (OVX) was performed to induce osteopenia mice and confirmed by micro-CT. The Ti particle-induced mouse calvaria osteolysis model was established subsequently and both OVX and Sham-OVX mice were divided into four groups, respectively: Ti (-) group, Ti group, Ti + zoledronic acid (ZOL) group (50ug/kg, local administration, single dose) and Ti + teriparatide (TPTD) group (40ug/kg/d, subcutaneous injection*14d). Mice calvarias were collected for micro-CT and histomorphometric analysis 2 weeks after particle induction. 8 weeks after bilateral OVX, significantly reduced BMD and microstructure parameters in both proximal tibia and calvaria were observed in OVX mice when comparing with Sham-OVX mice. OVX mice in Ti group had not only markly decreased BMD and BV/TV, but also significantly increased total porosity, eroded surface area and osteoclast numbers when comparing with Sham-OVX mice. Shown by Two-way ANOVA analysis, the interaction terms between OVX and Ti implantation on micro-CT and histomorphometry parameters didn't reach significant difference. As illustrated by micro-CT and histological analysis, ZOL treatment markedly inhibited Ti particle-induced osteolysis in OVX mice and Sham-OVX mice, and there were significant differences when comparing to both Ti and Ti+TPTD group. The combination of osteoporosis and Ti particle implantation result in aggravated bone resorption, accompanied with increased osteoclasts and excessive inflammation response. ZOL was more effective in preventing Ti particle-induced osteolysis in both OVX mice and Sham-OVX mice than TPTD in short-term administration. ZOL exert the protective effects on Ti particle-induced bone loss via the suppression of osteoclasts.

Small Heterodimer Partner Negatively Regulates TLR4 Signaling Pathway of Titanium Particles-Induced Osteolysis in Mice.

Arthroplasty has been widely performed worldwide. However, peri-prosthetic osteolysis and aseptic loosening induced by macrophages activated by wear particles still remain a predominant cause of long term prosthetic failure. Our study aimed to identify the role of small heterodimer partner (SHP) in secretion of proinflammatory cytokines by macrophages through Toll-like Recepters (TLR)s signaling pathway activated by wear particles both in vivo and in vitro. The effect of SHP on activation of TLR4 pathway and secretion of cytokines was observed in RAW264.7 cells and SHP gene over-expressed mice. Expression of TLR4, TRAF6, NEMO complex and proinflammatory cytokine TNF-α in macrophages stimulated by wear particles was up-regulated, while SHP was down-regulated. On the other hand, inhibition of SHP up-regulated the expression of NEMO complex and proinflammatory cytokine TNF-α in RAW264.7 stimulated by wear particles, while over-expression of SHP gene showed an opposite result. Over-expression of SHP gene could inhibit cranial osteolysis induced by wear particles in mice model. In conclusion, SHP down-regulates TLR4 signaling pathway to reduce osteolysis induced by titanium particles via in vitro and in vivo experimental models.

All-arthroscopic anatomical reconstruction of anterior talofibular ligament using semitendinosus autografts.

PURPOSE: We introduced a new technique of all-arthroscopic anatomical anterior talofibular ligament (ATFL) reconstruction using semitendinosus autografts. METHODS: From June 2012 to June 2013, 28 patients with chronic ATFL rupture underwent arthroscopic anatomic reconstruction of the ATFL. They were divided into the Broström group (n = 16) and reconstruction group (n = 12). The American Orthopaedic Foot and Ankle Society (AOFAS) score and visual analogue score (VAS) was recorded before the operation, 12 months after the operation and 30 months after the operation. Physical examination and radiographs were performed in follow-ups. RESULTS: The patients had higher AOFAS score after the operation in both the Broström group and the reconstruction group. 12 months after operation, the patients in the reconstruction group showed significantly higher AOFAS score and lower VAS score than those in the Broström group (P = 0.003 and 0.001, respectively), while the difference between the two groups was not statistically significant 30 months later (P = 0.425 and 0.323, respectively). Contemporary numbness of the lateral dorsal part of the foot appeared in one (8.3%) patient in the reconstruction group and two (12.5%) patients in the Broström group, and the symptoms diminished after neurotrophic treatment. No other complications, including recurrent instability, were encountered. No donor-side morbidity such as infection or delayed wound healing was observed. CONCLUSIONS: The novel surgical technique enhanced post-operative rehabilitation by providing better ankle joint function than modified Broström procedure at 12 months after operation, while the advantage was not statistically significant 30 months later. The long-term outcome requires further investigation. The technique of all-arthroscopic anatomical ATFL reconstruction using semitendinosus autografts proved to be a viable option for ATFL injuries.

Biomechanical comparison of pure magnesium interference screw and polylactic acid polymer interference screw in anterior cruciate ligament reconstruction-A cadaveric experimental study.

BACKGROUND: Polylactic acid polymer interference screws are commonly used in anterior cruciate ligament (ACL) reconstructions, especially in proximal tibia fixation. However, several concerns have been raised, including the acid products during its degradation in vivo. In recent years, biodegradable magnesium (Mg)-based implants have become attractive because of their favourable mechanical properties, which are more similar to those of natural bone when compared with other degradable materials, such as polymers, apart from their alkaline nature during degradation. METHODS: We developed a pure Mg interference screw for ACL reconstruction. In the present study, 24 fresh cadaver knees were used to compare the mechanical properties of pure Mg interference screws and polylactic acid polymer interference screws for ACL reconstruction via their application on the proximal tibia tested using specific robotics. RESULTS: Results showed that the pure Mg interference screw group showed similar mechanical stability to the polylactic acid polymer interference screw group, implying comparable postoperative fixation effects. CONCLUSION: As there are no commercially available Mg-based interference screws for ACL reconstruction clinically and the in vivo degradation of pure Mg promotes bone formation, our cadaveric study supports its clinical tests for ACL reconstruction.