Mesenchymal Stem Cell-Derived Exosomes Modulate Chondrocyte Glutamine Metabolism to Alleviate Osteoarthritis Progression.

Osteoarthritis (OA) had a high incidence in people over 65 years old, and there is currently no drug that could completely cure it. This study is aimed at studying the role of exosomes in regulating glutamine metabolism in the treatment of OA. First, we identified the exosomes extracted from the mouse OA model's bone marrow mesenchymal stem cells (MSC). In vitro, compared with the control group, the cell apoptosis in the OA group increased, while the cell proliferation of the OA group was suppressed. After exosomal treatment, cell apoptosis and cell proliferation were reversed. Inflammatory factors (TNFα, IL-6), glutamine metabolic activity-related proteins (c-MYC, GLS1), glutamine, and GSH/GSSG were increased in the OA group. The overexpression of c-MYC reduced the therapeutic effect of exosomes. At the same time, we found that chondrocyte functional factors (collagen II, Aggrecan) were improved under the treatment of exosomes. However, oe-c-MYC reversed the therapeutic effect of exosomes. In vivo, we found that the running capacity of the mice in the OA group was reduced, and the cartilage tissue was severely damaged. In addition, TNFα, IL-6, and chondrocyte apoptosis increased, while the metabolism of collagen II, Aggrecan, and glutamate decreased in the OA group. After exosomal treatment, the mice's exercise capacity, tissue damage, inflammation, and chondrocyte function were improved, and glutamate metabolism was increased. This study showed that exosomes regulated the level of chondrocyte glutamine metabolism by regulating c-MYC, thereby alleviating OA.

TNF-α regulates the early development of avascular necrosis of the femoral head by mediating osteoblast autophagy and apoptosis via the p38 MAPK/NF-κB signaling pathway.

Previous studies have shown that the tumor necrosis factor-α (TNF-α) levels in serum and bone tissues formed in avascular necrosis of femoral head (ANFH) patients were higher than those of normal individuals, indicating TNF-α might play a role in the pathogenesis of ANFH. However, the underlying mechanisms remain unclear. Hematoxylin and eosin staining was performed to show the pathological changes of ANFH bone tissues. TNF-α expression in normal and ANFH tissues was examined by quantitative real-time polymerase chain reaction and western blot analyses. Osteoblast autophagy and apoptosis, as well as signaling pathways activation, were measured by their corresponding marker proteins. Osteoblast proliferation, autophagy, and apoptosis were evaluated using cell counting kit-8, transmission electron microscopy, and flow cytometry. The structures of bone tissues of ANFH were obviously damaged. TNF-α expression was significantly upregulated in ANFH bone tissues compared to normal tissues. Autophagy and apoptosis were remarkably promoted, and p38 mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) signaling pathways were markedly activated in ANFH. Suppression of the p38 MAPK/NF-κB pathway significantly attenuated the TNF-α-induced autophagy, however, enhanced the TNF-α-induced apoptosis in osteoblasts. Increased TNF-α in ANFH regulated osteoblast autophagy and apoptosis by p38 MAPK/NF-κB signaling pathways, blocking the pathway by inhibitors exacerbated TNF-α-induced apoptosis through impairing autophagy flux.

Association of global DNA hypomethylation with post-operative cognitive dysfunction in elderly patients undergoing hip surgery.

BACKGROUND: Post-operative cognitive dysfunction (POCD) is a decline of cognitive status that commonly occurs after surgery in elderly patients. Whether DNA methylation is associated with the development of POCD remains unclear. METHODS: Subjects (N = 124) older than 65 years-of-age undergoing hip replacement surgery were enrolled. A battery of neuropsychiatric tests was used to examine the perioperative cognitive function of the patients. Early POCD was analyzed using the reliable change index (RCI), and subjects were diagnosed with POCD if RCI < -1.96. Peripheral leukocyte DNA was isolated, and DNA methylation was measured via 5-methylcytosine (mC) using Elisa. RESULTS: Twenty-four patients (19.4%) developed early POCD. There was no difference in baseline 5-mC levels by POCD status. The 5-mC levels significantly decreased on day 7 after surgery in patients who developed early POCD (P = .004), but did not change in non-POCD patients. Moreover, post-operative 5-mC levels were significantly lower in POCD patients than those in non-POCD patients (P = .003). Bivariate logistic models adjusted for age, gender, BMI, duration of anesthesia, and education level clearly demonstrated an independent association between post-operative 5-mC level and early POCD. CONCLUSIONS: Post-operative global hypomethylation of leukocyte DNA was associated with the development of early POCD. TRIAL REGISTRATION: ClinicalTrial, NCT02965235. Registered 16 November 2016, https://www.clinicaltrials.gov/ct2/results?term=NCT02965235&rank=1#rowId0.

Oxygen embolism after hydrogen peroxide irrigation during hip arthroscopy: a case report.

BACKGROUND: Hydrogen peroxide has been widely used in Orthopaedics including Orthopaedic oncology, trauma and joint surgeries. However, we encountered an oxygen embolism and myoglobinuria after hydrogen peroxide was used to irrigate a septic hip arthroscopically. CASE PRESENTATION: A 61-year-old male patient with right hip septic arthritis underwent an arthroscopic hip washout and debridement. During the operation, the surgeon used 100 ml of 3% hydrogen peroxide to irrigate the joint cavity. Two minutes after irrigation, there was a transient decrease in oxygen saturation, heart rate and blood pressure, with significant subcutaneous emphysema around the wound. Concentrated urine was drained out 8 h after operation which resolved the following day. Post-operatively, the patient was managed in the intensive care unit for a pulmonary embolism and discharged without further complications. CONCLUSION: Medical staff should be aware of the risk of oxygen embolism and be extremely careful when using hydrogen peroxide in patient care. Oxygen embolism following hydrogen peroxide use is rare, however, once encountered, it may bring serious consequences. Therefore, the use of hydrogen peroxide in closed spaces or arthroscopic procedures should be discontinued.

Retraction: Differential expression of exosomal miRNAs in osteoblasts in osteoarthritis [Journal of Central South University. Medical Science, 2018, 43(12):1294-1300. DOI: 10.11817/j.issn.1672-7347.2018.12.003].

The article entitled "Differential expression of exosomal miRNAs in osteoblasts in osteoarthritis" published on Journal of Central South University (Medical Science), in Volume 43, Issue 12, 2018 (DOI: 10.11817/j.issn.1672-7347.2018.12.003) may have an unclear risk of bias due to insufficient understanding for some results. Further experimental studies are needed. We all agree to retract this article, and apologize to the Journal and readers for the possible negative impact.

Mixed cell therapy of bone marrow-derived mesenchymal stem cells and articular cartilage chondrocytes ameliorates osteoarthritis development.

Of the many cell-based treatments that have been tested in an effort to regenerate osteoarthritic articular cartilage, none have ever produced cartilage that compare with native hyaline cartilage. Studies show that different cell types lead to inconsistent results and for cartilage regeneration to be considered successful, there must be an absence of fibrotic tissue. Here we report of a series of experiments in which bone marrow-derived stem cells (BMSCs) and articular cartilage chondrocytes (ACCs) were mixed in a 1:1 ratio and tested for their ability to enhance cartilage regeneration in three different conditions: (1) in an in vitro differentiation model; (2) in an ex vivo cartilage defect model implanted subcutaneously in mice; and (3) as an intra-articular injection in a meniscectomy-induced OA model in rats. The mixed cells were compared with monocultures of BMSCs and ACCs. In all three experimental models there was significantly enhanced cartilage regeneration and decreased fibrosis in the mixed BMSCs+ACCs group compared with the monocultures. Molecular analysis showed a reduction in vascularization and hypertrophy, coupled with higher chondrogenic gene expression resulting from the BMSCs+ACCs treatment. Together, our data suggest that mixed BMSCs+ACCs treatment is highly chondro-protective and is more effective in regenerating damaged cartilage in both the ex vivo cartilage defect and post-trauma OA disease models. The results from this approach could potentially be used for regeneration of cartilage in OA patients.

Protective effects of mitochondria-targeted antioxidants and statins on cholesterol-induced osteoarthritis.

The contribution of metabolic factors on the severity of osteoarthritis (OA) is not fully appreciated. This study aimed to define the effects of hypercholesterolemia on the progression of OA. Apolipoprotein E-deficient (ApoE-/-) mice and rats with diet-induced hypercholesterolemia (DIHC) rats were used to explore the effects of hypercholesterolemia on the progression of OA. Both models exhibited OA-like changes, characterized primarily by a loss of proteoglycans, collagen and aggrecan degradation, osteophyte formation, changes to subchondral bone architecture, and cartilage degradation. Surgical destabilization of the knees resulted in a dramatic increase of degradative OA symptoms in animals fed a high-cholesterol diet compared with controls. Clinically relevant doses of free cholesterol resulted in mitochondrial dysfunction, overproduction of reactive oxygen species (ROS), and increased expression of degenerative and hypertrophic markers in chondrocytes and breakdown of the cartilage matrix. We showed that the severity of diet-induced OA changes could be attenuated by treatment with both atorvastatin and a mitochondrial targeting antioxidant. The protective effects of the mitochondrial targeting antioxidant were associated with suppression of oxidative damage to chondrocytes and restoration of extracellular matrix homeostasis of the articular chondrocytes. In summary, our data show that hypercholesterolemia precipitates OA progression by mitochondrial dysfunction in chondrocytes, in part by increasing ROS production and apoptosis. By addressing the mitochondrial dysfunction using antioxidants, we were able attenuate the OA progression in our animal models. This approach may form the basis for novel treatment options for this OA risk group in humans.-Farnaghi, S., Prasadam, I., Cai, G., Friis, T., Du, Z., Crawford, R., Mao, X., Xiao, Y. Protective effects of mitochondria-targeted antioxidants and statins on cholesterol-induced osteoarthritis.

Anti-ganglioside GD2 monoclonal antibody synergizes with cisplatin to induce endoplasmic reticulum-associated apoptosis in osteosarcoma cells.

Cisplatin is an effective chemotherapeutic agent for osteosarcoma (OS) and has been shown to induce endoplasmic reticulum (ER) stress-associated apoptosis in human cancer cells. Ganglioside GD2-specific antibodies can inhibit tumor cell viability without involvement of the immune system. A recent study has shown that antiGD2 monoclonal antibody (mAb) 14G2a effectively inhibits the viability and invasiveness of human OS cells. In this study, we explored the effect of anti-GD2 mAb and cisplatin alone and in combination on ER stress-associated apoptosis in osteosarcoma cells. MG-63 and Saos-2 human OS cells were treated with cisplatin and/or an-GD2 mAb 14G2a for 48 hours. Cisplatin and 14G2a dose-dependently induced apoptosis in MG-63 and Saos-2 cells. They in combination induced 70%-77% of apoptosis in MG-63 cells and 79%-85% of apoptosis in Saos-2 cells, exhibiting a synergistic effect stronger than addition of their individual effects over the control level. Showing no significant effect on the expression of protein kinase RNA-like ER kinase (PERK), cisplatin and 14G2a exhibited a marked synergistic effect on inducing phosphorylation/activation of PERK, phosphorylation/inactivation of eukaryotic translation initiation factor 2α (eIF2α), expression of CHOP, in parallel to inducing the caspase-3 activity and apoptosis in MG-63 and Saos-2 cells. The effects were abolished by lentivirus-mediated knockdown of PERK. Particularly, PERK knockdown abolished 63% and 65% of the combined apoptotic effect of cisplatin and 14G2a on MG-63 and Saos-2 cells, respectively. In conclusion, this study provides the first evidence supporting that cisplatin and 14G2a synergize to induce ER stress-associated apoptosis in human OS cells through activating the PERK ER stress pathway by synergistically inducing phosphorylation/activation of PERK. Our findings add new insights into the pharmacologic effects of anti-GD2 mAb in anticancer treatment and suggest that cisplatin plus anti-GD2 mAb could be a new effective therapeutic strategy for OS.

[Differential expression of exosomal miRNAs in osteoblasts in osteoarthritis].

OBJECTIVE: To analyze the differentially expressed exosomal miRNAs in subchondral osteoblasts in patients with osteoarthritis (OA) and to investigate the key miRNAs potentially involved in the occurrence and progression of OA.
 Methods: Subchondral bones were harvested from 6 patients with OA. All subjects were divided into two groups which was based on the severity of joint wear: An OA group, severely worn side of subchondral bone, and a control group, less worn side of subchondral bone. The exosomes were extracted from osteoblast cells and their characteristics were identified. Then exosomal miRNAs were extracted and sequencing analysis was conducted to compare the expression in the two groups. The most differentially expressed ones (log2Ratio≥2) were subject to miRNA target prediction and quantitative reverse transcription PCR (RT-qPCR) to further quantify the difference.
 Results: Osteoblast extractions were confirmed to be exosomes, which were small double-membranous vesicles with 30-200 nm in diameter and 50-150 nm in peak value of particle size under the scanning microscope. High-throughput sequencing revealed 124 miRNAs whose expression significantly increased in the OA group. The most differentially expressed one with maximum fold change was hsa-miR-4717-5p and its target gene was RGS2. RT-qPCR demonstrated hsa-miR-4717-5p expression in the OA group was relatively higher than that in the control group (2.243 vs 0.480, P<0.01).
 Conclusion: There is distinct difference in expression profiles of exosomal miRNAs in subchondral osteoblasts between patients with OA and normal subjects. Up-regulated expression of miRANs might participate in OA occurrance and progression.

[Effect of alendronate amount on the static mechanical properties of bone cement].

OBJECTIVE: To determine the effect of alendronate amount on the static mechanical properties of bone cement before elution and 4 weeks after elution, and determine suitable amount of alendronate in cement from the perspective of biomechanics. METHODS: Samples of compression strength and bending strength (modulus) were prepared with bone cement adding 0, 10, 50, 100, 500 and 1000 mg alendronate in 50 g Cemex®XL bone cement powders respectively (named as G0-G5 groups). The compression strength, bending strength, and bending modulus of bone cement were examinated by INSTRON 8032 tester before the elution and 4 weeks after the elution. Some broken samples of 4-point bending test were examinated by scanning electronic microscopy (SEM), and some other samples of bending strength (modulus) tests by micro-CT. RESULTS: No significant difference was found in the compression strength before the elution,4 weeks after elution in the 6 groups, and before and after the elution in the respective groups (P>0.05). Compared with G0 group, G1-G4 groups had no obvious difference in the bending strength before the elution and 4 weeks after the elution (P>0.05), while G5 group had difference (P<0.05). There was no significant difference in the bending strength before and after the elution in the respective groups (P>0.05). Taken G0 group as the control group, G1-G4 groups had no visible effects on the bending modulus 4 weeks after the elution (P>0.05), while G5 group decreased it significantly (P<0.05). Bending modulus before the elution in the 6 groups didn't show obvious difference (P>0.05), while bending modulus before and after the elution in the respective groups displayed a marked difference (P<0.05). CONCLUSION: Less than 500 mg alendronate added in Cemex?XL 50 g bone cement powder does not decrease the compressive strength, flexural strength and flexural modulus before the elution and 4 weeks after the elution.

[Effect of alendronate-loaded bone cement on osteoblast].

OBJECTIVE: To determine the effect of bone cement, with different amounts of alendronate on osteoblast, and determine the cytotoxicity of alendronate-integrated bone cement from the viewpoint of cell biology. METHODS: According to different additions (0, 10, 50, 100, 500, 1 000 mg) of alendronate in 50 g Cemex®XL bone cement powder, the experiments were divided into 6 groups, namely G0-G5 groups. In all groups, the adhesive capacity of osteoblast-like cells MG-63 was evaluated by electron microscope, the optical density (OD) value of cells by MTT colorimetry method, the alkaline phosphatase activity (AKP) by AKP assay kit, the apoptosis rates by Annexin-V-FITC apoptosis detection kit, and the bone mineralization potentiality by phase contrast microscope. RESULTS: The adhesive capacity of MG-63 was good in all groups. Compared with the G0 group, the cell apoptosis was inhibited in G1-G4 groups while in G5 group the cell apoptosis was promoted and cell proliferation was inhibited (P<0.05). In all groups, no significant difference was found in alkaline phosphatase activity and bone mineralization potentiality (P>0.05). CONCLUSION: Less than 500 mg alendronate added in Cemex®XL 50 g bone cement powder has no cytotoxicity on osteoblasts.

Endowing Pt(IV) with Perfluorocarbon Chains and Human Serum Albumin Encapsulation for Highly Effective Antitumor Chemoimmunotherapy.

Tumor metastases and reoccurrence are considered the leading causes of cancer-associated deaths. As an emerging therapeutic method, increasing research efforts have been devoted to immunogenic cell death (ICD)-inducing compounds to solve the challenge. The clinically approved chemotherapeutic Pt complexes are not or are only poorly able to trigger ICD. Herein, the axial functionalization of the Pt(II) complex cisplatin with perfluorocarbon chains into ICD-inducing Pt(IV) prodrugs is reported. Strikingly, while the Pt(II) complex as well as the perfluorocarbon ligands did not induce ICD, the Pt(IV) prodrug demonstrated unexpectantly the induction of ICD through accumulation in the endoplasmic reticulum and generation of reactive oxygen species in this organelle. To enhance the pharmacological properties, the compound was encapsulated with human serum albumin into nanoparticles. While selectively accumulating in the tumorous tissue, the nanoparticles demonstrated a strong tumor growth inhibitory effect against osteosarcoma inside a mouse model. In vivo tumor vaccine analysis also demonstrated the ability of Pt(IV) to be an ideal ICD inducer. Overall, this study reports on axially perfluorocarbon chain-modified Pt(IV) complexes for ICD induction and chemoimmunotherapy in osteosarcoma.

Inhibition effect of curcumin on TNF-α and MMP-13 expression induced by advanced glycation end products in chondrocytes.

AIMS: Accumulation of advanced glycation end products (AGEs) plays a pivotal role in the mechanism by which aging contributes to osteoarthritis (OA). In the present study, we examined the effect of curcumin, a pharmacologically safe phytochemical agent, on AGE-induced tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-13 (MMP-13) in rabbit chondrocytes. METHODS: Chondrocytes were derived from rabbit articular cartilage by enzymatic digestion. TNF-α and MMP-13 mRNA was monitored by RT-PCR. TNF-α protein was determined using cytokine-specific ELISA. The reactive oxygen species was determined by the fluorescent probe 29,79-dichlorofluorescein diacetate. The phosphorylation and nuclear translocation of the nuclear factor-ĸB (NF-ĸB) system were studied by Western blot and immunofluorescence respectively. RESULTS: Curcumin significantly decreased AGE-stimulated TNF-α and MMP-13 mRNA and suppressed the NF-ĸB activation via inhibition of ĸBα (I-ĸBα) phosphorylation, I-ĸBα degradation and p65 nuclear translocation. CONCLUSIONS: These novel pharmacological actions of curcumin on AGE-stimulated chondrocytes provide new suggestions that curcumin has nutritional potential as a naturally occurring anti-inflammatory agent for treating OA.

[Measurement of proximal femoral morphology and analysis of 500 cases in Hunan Province].

OBJECTIVE: To evaluate the effect of age and gender on the femoral morphology to guide prosthesis selection in operation and design. METHODS: A total of 500 females and males were collected from the departments of orthopedics and medical radiology, Second Xiangya Hospital, Central South University. Informed consent was obtained from all subjects. All patients underwent anteroposterior position scan of the left or right hip joint using Philips Digital Diagnost DR system. The shooting range included the hip joint and at least 2/3 of the proximal femur. The images were measured with Onis 2.3 software. We measured 13 parameters from the patients, including the external parameters of the femur, radius-length parameters of femoral medullary cavity, and morphological parameters of the femoral medullary cavity. RESULTS: Compared with Westeners, the offset was smaller, while the neck shaft angle was significantly larger in Chinese population (P<0.05). Most parameters of the proximal femoral medullary cavity diameter were significantly smaller in Chinese population than those in Westerners (P<0.05). The canal flare index in Chinese population was significantly larger than that in the Westerners (P<0.01). According to the Noble classification, in Chinese population, the proportion of champagne flute type was significantly larger, while the proportion of standard type was significantly smaller than that in Westerners. There was significant difference in the proximal femur between Chinese population and Westerners. The largest difference of the proximal morphology was presented between males and females in the 31-50 years old people (P<0.05), while the smallest was in the over 70 years old population (P>0.05). The main differences between 31 and 70 years old were the diameter of femoral head, the offset of isthmus, the medullary cavity diameter and extracortical width at isthmus level and the medullary cavity diameter at the level of the lesser trochanter (P<0.05). The modullary transverse diameter at 20 mm below the lesser trochanter and isthmus and extracortical width of isthmus in the male and female group was positively correlated with age (P<0.01), while the parameters of the proximal femoral canal morphology in the female group were negatively correlated with age. The female canal parameters had a stronger correlation. CONCLUSION: Chinese proximal femoral parameters are significantly different from Westerners. When people, especially females, get older, the medullary cavity diameter of the isthmus and proximal femur becomes wider and the morphology of the femur becomes straight. The difference in the femoral morphology between the male and female decline with the age. There is almost no difference for the over 70 years old. For the 31-70 years old, The male femoral cavity diameter is larger and the position of isthmus is lower than in the females.

Mesenchymal stem cells in osteoarthritis: The need for translation into clinical therapy.

Widely used for cell-based therapy in various medical fields, mesenchymal stem cells (MSCs) show capacity for anti-inflammatory effects, anti-apoptotic activity, immunomodulation, and tissue repair and regeneration. As such, they can potentially be used to treat osteoarthritis (OA). However, MSCs from different sources have distinct advantages and disadvantages, and various animal models and clinical trials using different sources of MSCs are being conducted in OA regenerative medicine. It is now widely believed that the primary tissue regeneration impact of MSCs is via paracrine effects, rather than direct differentiation and replacement. Cytokines and molecules produced by MSCs, including extracellular vesicles with mRNAs, microRNAs, and bioactive substances, play a significant role in OA repair. This chapter outlines the properties of MSCs and recent animal models and clinical trials involving MSCs-based OA therapy, as well as how the paracrine effect of MSCs acts in OA cartilage repair. Additionally, it discusses challenges and controversies in MSCs-based OA therapy. Despite its limits and unanticipated hazards, MSCs have the potential to be translated into therapeutic therapy for future OA treatment.

Is it reasonable to shorten the length of cemented stems? A finite element analysis and biomechanical experiment.

Background: Uncemented short stems have been shown to optimize load distribution on the proximal femur, reducing stress shielding and preserving bone mass. However, they may adversely affect the initial stability of the stems. To date, most research conducted on short stems has predominantly centered on uncemented stems, leaving a notable dearth of investigations encompassing cemented stems. Therefore, this study aimed to investigate the length of cemented stems on the transmission of femoral load patterns and assess the initial stability of cemented short stems. Method: A series of finite element models were created by gradient truncation on identical cemented stem. The impact of varying lengths of the cemented stem on both the peak stress of the femur and the stress distribution in the proximal femur (specifically Gruen zones 1 and 7) were assessed. In addition, an experimental biomechanical model for cemented short stem was established, and the initial stability was measured by evaluating the axial irreversible displacement of the stem relative to the cement. Result: The maximum von-Mises stress of the femur was 58.170 MPa. Spearman correlation analysis on the shortened length and von-Mises stress of all nodes in each region showed that the p-values for all regions were less than 0.0001, and the correlation coefficients (r) for each region were 0.092 (Gruen Zone 1) and 0.366 (Gruen Zone 7). The result of the biomechanical experiment showed that the irreversible axial displacement of the stem relative to cement was -870 µm (SD 430 µm). Conclusion: Reducing the length of a cemented stem can effectively enhance the proximal load of the femur without posing additional fracture risk. Moreover, the biomechanical experiment demonstrated favorable initial stabilities of cemented short stems.

Inhibition of Leukotriene A4 Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis.

OBJECTIVE: Chronic inflammation plays an important role in the osteoarthritis (OA) pathology but how this influence OA disease progression is unclear. Leukotriene B4 (LTB4) is a potent proinflammatory lipid mediator generated from arachidonic acid through the sequential activities of 5-lipoxygenase, 5-lipoxygenase-activating protein, Leukotriene A4 hydrolase (LTA4H) and its downstream product LTB4. The aim of this study is to investigate the involvement and the potential therapeutic target of the LTB4 pathway in OA disease progression. DESIGN: Both clinical human cartilage samples (n = 7) and mice experimental OA models (n = 6) were used. The levels of LTA4H and leukotriene B4 receptor 1 were first examined using immunostaining in human OA/non-OA cartilage and mice experimental OA models. We also determined whether the LTA4H pathway was associated with cartilage degeneration and synovitis inflammation in OA mice models and human articular chondrocytes. RESULTS: We found that both LTA4H and LTB4 receptor (BLT1) were highly expressed in human and mice OA cartilage. Inhibition of LTA4H suppressed cartilage degeneration and synovitis in OA mice model. Furthermore, inhibition of LTA4H promoted cartilage regeneration by upregulating chondrogenic genes expression such as aggrecan (ACAN), collagen 2A1 (COL2A1), and SRY-Box transcription factor 9 (SOX9). CONCLUSIONS: Our results indicate that the LTA4H pathway is a crucial regulator of OA pathogenesis and suggest that LTA4H could be a therapeutic target in combat OA.

Both Acetabular and Femoral Reconstructions With Impaction Bone Grafting in Revision Total Hip Arthroplasty: Case Series and Literature Review.

Background: Extensive bone loss on femur and acetabulum posed a big challenge to orthopedists in total hip revision surgeries. Impaction bone grafting (IBG) as a valuable bone preservation technique could effectively address this problem. Either IBG revision on the femoral or acetabular side was well studied, while its use on both sides in one operation was not. The aim of this study is to present the outcomes of IBG on both femoral and acetabular sides at first-time hip revision. Methods: We retrospectively reviewed 8 patients (mean follow-up of 5.8 years) undergoing first-time revision with IBG on both acetabular and femoral sides at our institution. The Paprosky classification system was used to classify bone defects. Freeze-dried allografts and cemented prostheses were used in all patients. Postoperative complications and rerevision rates were reported. Results: Five patients presented a Paprosky type IIC acetabular defect, 3 with a type IIIB, IIIA, and IIC defect, respectively. Three patients presented with a type IV femoral defect, 3 with a type IIIB defect, and 2 with a type II defect. Two patients developed complications, while one had an intraoperative femoral fracture and one had delayed wound healing. At the latest follow-up, no patient had rerevisions or operations related to the prosthesis. Conclusions: IBG in combination with cemented prosthesis is a profitable biological reconstruction revision technique that could provide satisfying midterm outcomes. We first propose the use of blood clots mixed with bone grafts for potential bone incorporation enhancement, while its specific effects need to be verified in further studies.

Inhibition of p38 pathway leads to OA-like changes in a rat animal model.

OBJECTIVES: The p38 mitogen-activated protein kinase (MAPK) signal transduction pathway is involved in a variety of inflammatory responses, including cytokine generation, cell differentiation proliferation and apoptosis. Here, we examined the effects of systemic p38 MAPK inhibition on cartilage cells and OA disease progression by both in vitro and in vivo approaches. METHODS: p38 kinase activity was evaluated in normal and OA cartilage cells by measuring the amount of phosphorylated protein. To examine the function of p38 signalling pathway in vitro, normal chondrocytes were isolated and differentiated in the presence or absence of p38 inhibitor SB203580 and analysed for chondrogenic phenotype. Effect of systemic p38 MAPK inhibition in normal and OA (induced by menisectomy) rats were analysed by treating animals with vehicle alone [dimethylsulphoxide (DMSO)] or p38 inhibitor (SB203580). Damage to the femur and tibial plateau was evaluated by modified Mankin score, histology and immunohistochemistry. RESULTS: Our in vitro studies have revealed that a down-regulation of chondrogenic and an increase of hypertrophic gene expression occurs in the normal chondrocytes when p38 is neutralized by a pharmacological inhibitor. We further observed that the basal levels of p38 phosphorylation were decreased in OA chondrocytes compared with normal chondrocytes. These findings together indicate the importance of this pathway in the regulation of cartilage physiology and its relevance to OA pathogenesis. At the in vivo level, systematic administration of a specific p38 MAPK inhibitor, SB203580, continuously for more than a month led to a significant loss of proteoglycan, aggrecan and cartilage thickness. On the other hand, SB203580-treated normal rats showed a significant increase in Terminal dUTP nick end-labelling (TUNEL)-positive cells, cartilage hypertrophy markers such as Type 10 collagen, Runt-related transcription factor and MMP-13 and substantially induced OA-like phenotypic changes in the normal rats. In addition, menisectomy-induced OA rat models that were treated with p38 inhibitor showed aggravation of cartilage damage. CONCLUSIONS: In summary, this study has provided evidence that the component of the p38 MAPK pathway is important to maintain cartilage health, and its inhibition can lead to severe cartilage degenerative changes. The observations in this study highlight the possibility of using activators of the p38 pathway as an alternative approach in the treatment of OA.

Pseudotumor in a well-fixed metal-on-polyethylene uncemented hip arthroplasty.

The incidence of pseudotumor formation has been reported to be 1% in patients with metal-on-metal resurfacing arthroplasties. This complication is not exclusive to these patients. We report a case of pseudotumor formation secondary to femoral head-neck corrosion after a metal-on-polyethylene uncemented total hip arthroplasty.