Classification and Treatment Strategies of Tibial Tubercle Fractures in Adults.

OBJECTIVES: Tibial tubercle is a crucial player in maintaining the structural integrity and functional stability of the knee joint. Currently, there is no standardized protocol for the classification and treatment of tibial tubercle fractures in adults. This study analyzed the incidence and treatment strategies of tibial tubercle fractures in adults according to the four-column and nine-segment classification system. METHODS: Data of patients with proximal tibial fractures involving tibial tubercle fractures who were treated at our hospital from August 2007 to March 2023 were retrospectively reviewed. The fractures were classified using the AO/OTA classification and four-column and nine-segment classification systems, and the treatment protocol (surgically treated or conservatively treated) was recorded. The number and distribution proportion of patients were counted. A two-sided t-test was conducted to determine the significance of differences between the gender and sides. RESULTS: In total, 169 tibial tubercle fractures were found in 1484 proximal tibial fractures. According to the AO/OTA classification, seven of the 169 patients, (4.1%) were type A, 36 patients (21.3%) were type B, and 126 patients (74.6%) were type C. According to the four-column and nine-segment classification, type 1 cleavage without free fragments was the most common type of fracture (93/169, 55.0%), followed by type 2 dissociative segmental fragments (48/169, 28.4%) and type 3 comminuted fractures (28/169, 16.6%). Overall, 139 of the 169 proximal tibial fractures with tuberosity involvement were treated surgically. Among them, additional fixation of the tubercle fragment was performed in 52 fractures. CONCLUSION: The incidence of tibial tubercle fractures involved in proximal tibial fractures was approximately 11.4% (169/1484) in adults, and approximately one-third of the tubercle bone fragment required additional fixation (30.8%, 52/169). The injury types in the four-column and nine-segment classifications are helpful for accurately judging and making treatment-related decisions for tibial tubercle fractures.

Application of a New M-shaped High Tibial Osteotomy Method: A Technical Note.

High tibial osteotomy (HTO) is used as an alternative to total knee arthroplasty in young patients with knee osteoarthritis. In the conventional HTO, if the distraction distance is large, the osteotomy section will be significantly separated, forming a large bone defect gap, which may lead to delayed healing or even nonunion. We treated a series of 10 patients with medial knee osteoarthritis by a novel M-shaped high tibial osteotomy. This helped to improve greater contact of cortical sections and rapid healing of the osteotomy break. Over a mean follow-up period of 8.5 months (range, 6.0-12.0 months), all patients achieved bone union. None of the patients showed complications such as nonunion or infection. The novel M-shaped HTO procedure can reduce the probability of delayed union/nonunion and avoid the complications associated with bone grafting. Hence, this technique may be an effective alternative for the HTO.

The application of a hollow trephine in femoral retrograde intramedullary nailing technique.

PURPOSE: The purpose of this study was to describe and evaluate the use of a specially designed hollow trephine to create the entry point through the femoral condyle during retrograde interlocking intramedullary nailing for femoral fractures. METHODS: From June 2019 to December 2021, we treated 11 patients (5 men, 6 women; mean age, 64 years; age range 40-77 years) with mid-distal femoral fractures by retrograde intramedullary femoral nailing using a self-designed hollow trephine for femoral condyle reaming and cancellous bone harvesting. The mode of all the nails is static. Patients were followed up at 1, 4, 8, and 12 weeks and for at least 6 months after surgery. The healing process and heterotopic ossification were evaluated by imaging. Partial weight bearing was permitted during the recovery period and complete weight bearing was permitted after clinical healing of the fracture displayed by X-ray. RESULTS: The operation was successful in all patients. Over mean follow-up of 9.3 months (range, 6.0-12.0 months), all patients achieved clinical healing within three months. There were no complications such as knee joint infection, heterotopic ossification, knee joint adhesion and wedge effect. CONCLUSION: The use of the hollow trephine during femoral retrograde intramedullary nailing helps avoid postoperative complications such as heterotopic ossification, knee joint adhesions, and wedge effect. It also facilitates bone graft harvesting.

Baicalein ameliorates oxidative stress and brain injury after intracerebral hemorrhage by activating the Nrf2/ARE pathway via miR-106a-5p/PHLPP2 axis.

Intracerebral hemorrhage (ICH) is a devastating stroke subtype. Baicalein (BAI) has been reported to be effective in ischemic stroke. The aim of the present study was to investigate the mechanism of BAI on brain injury after ICH. Firstly, ICH mouse models were established by injecting collagenase into the right of basal ganglia, followed by detection of neurobehavioral scores, brain edema, oxidative stress (OS) level, neuronal apoptosis and pathological changes. Average neurologic scores, brain water content, and blood-brain barrier permeability and MDA level in ICH mice were reduced after BAI treatment, while serum SOD and GSH-Px levels were increased and neuronal apoptosis and pathological injury of the brain tissues were mitigated. miR-106a-5p downregulation averted the effect of BAI on ICH mice. miR-106a-5p targeted PHLPP2 and PHLPP2 overexpression reversed the effect of BAI on ICH mice. BAI activated the Nrf2/ARE pathway by inhibiting PHLPP2 expression. In conclusion, BAI inhibited OS and protected against brain injury after ICH by activating the Nrf2/ARE pathway through the miR-106a-5p/PHLPP2 axis.

Proximal avulsion of five ligaments and revised diagonal principle in tibial plateau fractures.

PURPOSE: The aim of the study was to analyze the incidence of proximal avulsion of the five main ligaments and to revise the diagonal tension/compression concept in tibial plateau fractures. METHODS: Computed tomographic images of 1263 cases of tibial plateau fractures were retrospectively analyzed by the OTA/AO classification and four-column nine-segment classification. The correlation between proximal avulsion of five ligaments and the injury mechanism was analyzed. RESULTS: In total, 1263 tibial plateau fractures in 1253 patients were included. A total of 92 cases (7.3%) associated with proximal avulsions were identified among the 1263 tibial plateau fracture cases obtained from our institution's database. The 92 avulsions occurred in 82 patients, among whom 10 patients had two different avulsions in a single knee. The incidence of proximal avulsion fracture of the medial and lateral collateral ligament was 3.6% (45/1263) and 2.1% (26/1263), respectively. The incidence of avulsion of the anterior cruciate ligament and avulsion of the posterior cruciate ligament was much lower at 0.2% (2/1263) and 0.1% (1/1263), respectively. Proximal avulsion of the patellar ligament occurred in 18 cases (incidence rate = 1.4%). Several combinations of injuries, composed of distal tibial plateau fractures and proximal avulsion of ligaments, were identified. CONCLUSIONS: Among the patients with tibial plateau fracture, the incidence of proximal avulsion of the five ligaments was 7.3% (92/1263). The four-column and nine-segment classification is an exhaustive method for recording injuries in these ligaments. The revised diagonal injury concept is useful for understanding the injury mechanism and choosing the appropriate surgical strategy.

Classification and morphology of hyperextension tibial plateau fracture.

PURPOSE: This study was aimed at analyzing the incidence and characteristics of hyperextension tibial plateau fractures (HTPFs) by using a computed tomography (CT)-based "four-column and nine-segment" classification. METHODS: In the coronal plane, HTPFs are divided into four types: pure hyperextension, hyperextension-varus, hyperextension-valgus, and hyperextension-bicondylar. Fractures in the sagittal plane were divided into three types: type 1, pure depression; type 2, cleavage extending to the posterior cortex with no displacement; and type 3, cleavage extending to the posterior cortex with a significant displacement. A retrospective analysis of CT images of the tibial plateau fractures from December 2007 to December 2021 was conducted. Fracture mapping was analyzed and drawn using the new classification system. RESULTS: A total of 136 (10.9%, 136/1253) fractures fulfilled the radiographic criteria for HTPF pattern in 136 knees (53.5 ± 13.3 years). There were 11 knees with pure hyperextension fracture (8.1%), 23 with hyperextension-varus fracture (16.9%), 46 with hyperextension-valgus fracture (33.8%), and 56 with hyperextension-bicondylar fracture (41.2%) in the coronal plane. Furthermore, there were 64 (47.1%), 47 (34.6%), and 25 (18.4%) cases of type 1, type 2, and type 3 fractures, respectively, in the sagittal plane. In the three-dimensional heat map, the fracture lines were mainly located at the anterior rim of the tibial plateau, while the posterior articular surface was rarely involved. CONCLUSIONS: The main manifestations of HTPF are anterior compression and posterior avulsion injury. The CT-based four-column and nine-segment classification system could be used to categorize the injury characteristics of HTPF in the coronal and sagittal planes.

Is annular repair technique useful for reducing reherniation and reoperation after limited discectomy?

The annular defect because of the primary lumbar disc herniation (LDH) or surgical procedure is considered a primary reason for recurrent herniation and eventually reoperation. Efforts to close the defect with annular repair devices have been attempted several times, but the results were controversial. The present aims to detect whether the annular repair techniques were useful for reducing the re-herniation and re- operation rate. The Pubmed, Cochrane library, and Embase databases were searched to retrieve relevant studies published before January 1, 2021. Continuous variables were compared by calculating the standard difference of the means (SDM), whereas categorical dichotomous variables were assessed using relative risks (RRs). A random-effects model was used if the heterogeneity statistic was significant; otherwise, a fixed-effects model was used. A total of 10 researches were suitable for the meta-analysis, including four different repair techniques and 1907 participates. Compared with the control group, there was no statistical difference with the ODI, VAS-leg, and VAS-back scales for patients treated with the annular repair. However, using an annular repair device was associated with a significant reduction in the re- herniation (p=0.004) and re-operation (0.004) rates. There was no difference between the groups with perioperative complications. However, much more device-related long-term complications happened in the annual repair group (p=0.031) though it still decreased the overall re-operation rate significantly (p=0.006).Our results demonstrated that using an annular repair device was safe and beneficial for reducing re-herniation and re-operation rates.

Classification and Treatment Strategies of Concomitant Fibular Column Injuries in Tibial Plateau Fractures.

BACKGROUND: About 1/3 of tibial plateau fractures are associated with proximal fibula fractures, but most proximal fibula fractures are often ignored. The aim of this study was to precisely explain the classification and treatment strategies of six injury types of the fibular column associated with tibial plateau fractures. METHODS: Patients with ipsilateral proximal fibula and tibial plateau fractures treated in our hospital were retrospectively reviewed from Aug 2007 to Mar 2020. Two experienced surgeons and two radiologists divided fibular column injury into 6 injury types according to the AO classification and four-column nine-segment classification. The treatment scheme (surgically treated or conservatively treated) was also recorded. RESULTS: In total, 355 proximal fibula fractures were included. Type 2 fibular head fracture was the most common type of injury in 122, and the segregate of superior tibiofibular syndesmosis was the rarest type in 3. In avulsion injury proximal of fibular pattern, the proportion of patients who need surgical intervention is the highest. CONCLUSIONS: Six injury types in the four-column nine-segment classification covered all types of bony and soft tissue injuries of the fibular column and concisely explained the injury mechanism. The classification is helpful for the precise judgement and decision-making of the concomitant fibular column injuries in tibial plateau fractures.

Association between interleukin-21 gene rs6822844 polymorphism and rheumatoid arthritis susceptibility.

Controversial results concerning the association between a polymorphism rs6822844 in the interleukin (IL) 21 (IL-21) gene and rheumatoid arthritis (RA) have existed. A meta-analysis to confirm above relationships is necessary to be performed immediately. We conducted a search in the PubMed database, covering all papers published up to 20 October 2018. Overall, six case-control studies with 3244 cases and 3431 healthy controls were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Publication bias was assessed with both Egger's and Begg's tests. After calculation, we found that IL-21 rs6822844 polymorphism could decrease RA risk in overall genetic models (allelic contrast: OR = 0.77, 95% CI = 0.62-0.97, P=0.024; TG versus GG: OR = 0.68, 95% CI = 0.50-0.92, P=0.013, and dominant genetic model: OR = 0.72, 95% CI = 0.55-0.94, P=0.016). Similarly, stratified analysis by race, source of control, significantly decreased association was found in Asians, Caucasians and hospital-based (HB) control source. Finally, in the subgroup analysis of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status, poorly decreased relationship was detected between IL-21 rs6822844 polymorphism and RF negative and ACPA positive RA risk, respectively. No obvious evidence of publication bias was detected in overall analysis. In summary, our study indicated that IL-21 rs6822844 polymorphism was significantly associated with decreased RA susceptibility.

A single-nucleotide polymorphism (rs1805087) in the methionine synthase (METH) gene increases the risk of prostate cancer.

Methionine synthase (METH, i.e., MTR) is a key enzyme in the folate pathway, which plays a critical role in the synthesis, repair, and methylation of DNA. The association between METH gene polymorphisms and prostate cancer susceptibility remains ambiguous. Thus, we performed an updated meta-analysis of METH single-nucleotide polymorphism rs1805087 involving 12 independent case-control studies comprising 9986 prostate cancer patients and 40134 controls. The odds ratio and 95% confidence intervals were applied to evaluate the relation of this single-nucleotide polymorphism with prostate cancer. Statistical analysis was performed in STATA 11.0. A significant association was found between rs1805087 and increased prostate cancer risk, overall and with Hardy-Weinberg equilibrium. In subgroup analyses (based on ethnicity, source of control, genotyping methods, or publication status), similar associations were observed (e.g., genotype GA vs. AA: odds ratio 1.19, 95% confidence interval 1.01-1.40 among whites; G allele vs. A allele: odds ratio 1.14, 95% confidence interval 1.02-1.28 among hospital-based controls). Thus, the common polymorphism (rs1805087) of METH may be associated with increased prostate cancer risk. Further studies with a larger sample size and detailed gene-environment interactions should be conducted to identify the role of METH polymorphisms in prostate cancer susceptibility.

Periodic Mechanical Stress Stimulates GIT1-Dependent Mitogenic Signals in Rat Chondrocytes Through ERK1/2 Activity.

BACKGROUND/AIMS: The mitogenic effects of periodic mechanical stress on chondrocytes have been studied extensively, but the mechanisms whereby chondrocytes sense and respond to mechanical stimuli remain to be determined. We explored the question and verified the key role of G protein coupled receptor kinase interacting protein 1 (GIT1) signaling in periodic mechanical stress-induced chondrocyte proliferation. METHODS: Two steps were undertaken in the experiment. In the first step, the cells were maintained under non-pressure conditions or periodic mechanical stress for 1 h prior to Western blot analysis. In the second step, the cells were pretreated with short hairpin RNA (shRNA) targeted to GIT1 or Src or control scrambled shRNA, or transfected with GIT1 wild-type or GIT1 mutant Y321F, or focal adhesion kinase (FAK) wild-type or FAK mutants Y397F or Y576F/Y577, respectively. Moreover, the cells were pretreated with blocking antibody against integrin ß1 or PP2. Then the cells were maintained under non-pressure conditions or periodic mechanical stress for 1 h prior to Western blot analysis, and for 3 days, 8 h per day, prior to direct cell counting and CCK-8 assay, respectively. RESULTS: Periodic mechanical stress significantly induced sustained phosphorylation of GIT1 at Tyr321. Reduction of GIT1 with shRNA targeted to GIT1 and GIT1 mutant Y321F inhibited periodic mechanical stress-promoted chondrocyte proliferation, accompanied by attenuated extracellular signal-regulated kinase (ERK)1/2 and FAK phosphorylation at Tyr576/577. However, activation of Src and FAK-Tyr397 was not prevented upon GIT1 suppression. Furthermore, pretreatment with blocking antibody against integrin ß1, Src-selective inhibitor, PP2, and shRNA targeted to Src blocked GIT1 activation under periodic mechanical stress. In addition, GIT1 phosphorylation at Tyr321 was not reduced upon pretreatment with FAK mutants Y397F or Y576F/Y577 under conditions of periodic mechanical stress. CONCLUSION: These findings collectively suggested that periodic mechanical stress promoted chondrocyte proliferation through at least two separate pathways, integrin ß1-Src-GIT1-FAK(Tyr576/577)-ERK1/2, and the other parallel GIT1-independent integrin ß1-FAK(Tyr397)-ERK1/2.

Therapeutic effect of MIPPSO in the thoracolumbar vertebra fracture.

The purpose of this study was to compare the efficacy of minimally invasive percutaneous pedicle screw osteosynthesis (MIPPSO) and traditional open pedicle screw osteosynthesis (TOPSO) in the treatment of thoracolumbar vertebra fracture. A retrospective case-control study was conducted in 120 patients with thoracolumbar vertebral fractures treated in the Affiliated Jiangyin Hospital of Southeast University Medical School (Jiangyin, China) from January 2013 to September 2014. They were randomly divided into two groups: MIPPSO and TOPSO groups with 60 cases in each group. The operation time, blood loss, incision length, post-operative bed rest time, hospital stay, visual analogue scale (VAS) pain scores and Oswestry disability index (ODI) scores before and after operation were recorded and analyzed. Inflammatory indexes including serum C-reactive protein (CRP) and creatine kinase (CK), the anterior vertebral height ratio and kyphosis Cobb's angle changes were also observed. The basic data of the two groups were similar, and there was no significant difference in the operation time between the two groups. The perioperative blood loss, length of incision, bed rest time and total hospital stay in the minimally invasive group were less than those in the open group. Levels of post-operative inflammation indicators such as CRP and CK were significantly higher than those of pre-operative (P<0.05), which was more obvious in the TOPSO group (P<0.05). VAS, ODI scores, anterior vertebral height and Cobb's angle were significantly improved at three days, one and 12 months after surgery compared with those before operation. MIPPSO for the treatment of thoracolumbar fractures can achieve similar clinical effects with traditional incision surgery. In addition, it has the advantages of less trauma, less bleeding and shorter post-operative bed rest time and hospital stay.

Periodic Mechanical Stress Stimulates Cav-1-Dependent IGF-1R Mitogenic Signals in Rat Chondrocytes Through ERK1/2.

BACKGROUND/AIMS: The biological effects of periodic mechanical stress on the mitogenesis of chondrocytes have been studied extensively over the past few years. However, the mechanisms underlying the ability of chondrocytes to sense and respond to mechanical stimuli remain to be determined. In the current study, we analyzed the mechanisms by which periodic mechanical stress is translated into biochemical signals and verified the key role of non-integrin mechanosensors including Caveolin-1 (Cav-1), and insulin-like growth factor-1 receptor (IGF-1R) in chondrocyte proliferation. METHODS: Two steps were undertaken in the experiment. In the first step, the cells were maintained under static conditions or periodic mechanical stress for 0 h and 1 h prior to Western blot analysis. In the second step, the cells were pretreated with short hairpin RNA (shRNA) targeted to Cav-1 or IGF-1R or control scrambled shRNA. Moreover, they were pretreated with their selective inhibitors methyl ß-cyclodextrin (MCD) or Linsitinib (OSI-906). They were maintained under static conditions or periodic mechanical stress for 1 h prior to Western blot analysis, and for 3 days, 8 h per day, prior to direct cell counting and CCK-8 assay, respectively. RESULTS: Periodic mechanical stress significantly induced sustained phosphorylation of Cav-1 at Tyr14 and IGF-1R at Tyr1135/1136. Proliferation was inhibited by pretreatment with Cav-1 inhibitor MCD and by shRNA targeted to Cav-1 in chondrocytes in response to periodic mechanical stress. Meantime, MCD and shRNA targeted to Cav-1 also attenuated IGF-1R, and extracellular signal-regulated kinase (ERK)1/2 activation. In addition, inhibiting IGF-1R activity by Linsitinib and shRNA targeted to IGF-1R abrogated chondrocyte proliferation and phosphorylation level of ERK1/2 subjected to periodic mechanical stress, while the phosphorylation site of Cav-1 was not affected. CONCLUSION: These findings collectively suggested that periodic mechanical stress promoted chondrocyte proliferation through Cav-1-IGF-1R-ERK1/2.

Integrative computational approach to evaluate risk genes for postmenopausal osteoporosis.

In recent years, numerous studies reported over a hundred of genes playing roles in the etiology of postmenopausal osteoporosis (PO). However, many of these candidate genes were lack of replication and results were not always consistent. Here, the authors proposed a computational workflow to curate and evaluate PO related genes. They integrate large-scale literature knowledge data and gene expression data (PO case/control: 10/10) for the marker evaluation. Pathway enrichment, sub-network enrichment, and gene-gene interaction analysis were conducted to study the pathogenic profile of the candidate genes, with four metrics proposed and validated for each gene. By using the authors' approach, a scalable PO genetic database was developed; including PO related genes, diseases, pathways, and the supporting references. The PO case/control classification supported the effectiveness of the four proposed metrics, which successfully identified eight well-studied top PO genes (e.g. TGFB1, IL6, IL1B, TNF, ESR2, IGF1, HIF1A, and COL1A1) and highlighted one recently reported PO genes (e.g. IFNG). The computational biology approach and the PO database developed in this study provide a valuable resource which may facilitate understanding the genetic profile of PO.

Association of ADAM12 gene polymorphisms with knee osteoarthritis susceptibility.

Previous studies that evaluated the association between a disintegrin and metalloprotease 12 (ADAM12) gene polymorphisms and knee osteoarthritis (KOA) have given controversial and indefinite results. Therefore, we performed a meta-analysis to confirm this correlation. We searched the PubMed, Embase, and SinoMed databases for all papers published up to April 11, 2017. Overall, five different studies, totaling 2,353 cases and 3,668 controls, were retrieved on the basis of the search criteria for KOA susceptibility related to four polymorphisms (rs3740199, rs1278279, rs1871054, and rs1044122) in the ADAM12 gene. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Publication bias was assessed using Egger's and Begg's tests. The rs3740199 G/C polymorphism was found to be associated with increased KOA risk in men (e.g., CG versus GG: OR = 1.44, 95% CI = 1.02-2.04, P = 0.040), but not in the overall analysis and in analyses of other subgroups. Significantly increased associations were also found for the rs1871054 polymorphism (e.g., C versus T allele: OR = 1.85, 95% CI = 1.49-2.30, P < 0.001). However, there were no associations for the rs1278279 and rs1044122 polymorphisms. Furthermore, no obvious evidence of publication bias was detected. Our study indicated that the rs1871054 polymorphism of ADAM12 was significantly associated with increased KOA risk.

Interleukin 10 gene rs1800896 polymorphism is associated with the risk of prostate cancer.

Numerous studies have uncovered the association of Interleukin-10 (IL-10) gene rs1800896 polymorphism with the risk of prostate cancer (PCa); however, their conclusions were inconsistent. Therefore, we conducted this meta-analysis to evaluate the role of IL-10 rs1800896 polymorphism in the risk of PCa. 16 eligible studies in 15 articles involving 6,301 cases and 6,510 controls were identified by researching PubMed, Google, CNKI, and EMBASE up to April 1, 2017. Our results revealed that IL-10 rs1800896 polymorphism was associated with the decreased risk of PCa under the homozygous model. Subgroup analysis by ethnicity revealed that rs1800896 polymorphism decreased the risk of PCa among Caucasians. In conclusion, IL-10 gene rs1800896 polymorphism is associated with the decreased risk of PCa. Larger studies with more diverse ethnic populations are needed to confirm these results.

Correlation between protein kinase catalytic subunit alpha-1 gene rs13361707 polymorphism and gastric cancer susceptibility in asian populations.

A single nucleotide polymorphism (SNP) of the protein kinase catalytic subunit alpha-1 gene (PRKAA1) that confers susceptibility to gastric cancer (GC) was identified by genome-wide association in several case-control studies. However, the results remained controversial and ambiguous. Therefore, we performed a larger meta-analysis to confirm this association. We searched the PubMed, Embase, WanFang, and CNKI databases, without any restriction on language, covering all papers published until Feb 22, 2017. Overall, 14 case-control studies with 14,485 cases and 14,792 controls were retrieved based on the search criteria. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to quantify the strength of the association. Publication bias was assessed by Egger's and Begg's tests. We found that the PRKAA1 rs13361707 C/T polymorphism had no association with GC risk in any of the pooled genetic models (for example, the T-allele vs. C-allele allelic contrast model yielded the following estimates: OR = 0.87, 95% CI = 0.73-1.05, Pheterogeneity = 0.000). Furthermore, in analyses stratified by either source of control or geographical origin of subjects, a statistically significant inverse relationship was detected between PRKAA1 rs13361707 C/T polymorphism and GC risk. No obvious evidence of publication bias was detected in the pooled meta-analysis. Furthermore, we observed that individuals carrying T-allele (TT or TC) genotypes had a lower expression of PRKAA1. Our present study indicated that PRKAA1 rs13361707 C/T was not significantly associated with GC risk, despite few positive results in the subgroups.

Effects of mesenchymal stem cells on interleukin-1ß-treated chondrocytes and cartilage in a rat osteoarthritic model.

In the present study, the effects and mechanisms of mesenchymal stem cells (MSCs) on interleukin (IL)-1ß-stimulated rat chondrocytes, as well as cartilage from a rat model of osteoarthritis (OA) induced by anterior cruciate ligament transection and medial meniscectomy were investigated. Confluent rat chondrocytes were treated with IL-1ß (10 ng/ml), then cultured indirectly with or without MSCs at a ratio of 2:1. Total RNA and protein were collected at various time-points, and western blot and reverse transcription-quantitative polymerase chain reaction analyses were used to investigate the expression of type II collagen (Col2), aggrecan, matrix metalloproteinase-13 (MMP-13) and cyclooxygenase-2 (COX-2). The activation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB) p65 and inhibitory-κ-B-α (IκBα) were also assessed by western blotting. In addition, the in vivo effects of MSCs in a rat OA model were assessed by histology and western blot analysis. The results indicated that in vitro, IL-1ß markedly upregulated the expression of MMP-13, COX-2, phosphorylated ERK1/2, JNK, p38 MAPK and NF-κB p65, and inhibited the expression of Col2, aggrecan and IκBα. Conversely, MSCs enhanced the expression of Col2, aggrecan and IκBα, and inhibited the expression of MMP-13 and NF-κB p65 in IL-1ß-stimulated rat chondrocytes. In vivo histological and western blot analyses revealed analogous results to the in vitro findings. The results of the present study demonstrated that MSCs suppressed the inflammatory response and extracellular matrix degradation in IL-1ß­induced rat chondrocytes, as well as cartilage in a osteoarthritic rat model, in part via the NF-κB signaling pathway.

Comparison of the efficacy of bone marrow mononuclear cells and bone mesenchymal stem cells in the treatment of osteoarthritis in a sheep model.

OBJECTIVE: To evaluate the therapeutic efficacy of uncultured bone marrow mononuclear cells (BMMCs) and bone mesenchymal stem cells in an osteoarthritis (OA) model of sheep. METHODS: Induction of sheep OA was performed surgically through anterior cruciate ligament transection and medial meniscectomy. After 12 weeks, concentrated BMMCs obtained from autologous bone marrow harvested from anterior iliac crest or a single dose of 10 million autologous bone mesenchymal stem cells (BMSCs) suspended in phosphate-buffered saline (PBS) was delivered to the injured knee via direct intra-articular injection. Animals of the PBS group received vehicle alone. The contra-lateral joints were selected randomly as the control group. Knees of the four groups were compared macroscopically and histologically, and glycosaminoglycan (GAG) contents normalized to cartilage wet weight were measured at lesions of cartilage from medial condyle of the femur head. Gene expression levels of type II collagen (Col2A1), Aggrecan and matrix metalloproteinase-13 (MMP-13) in cartilage were measured based on RT-PCR and prostaglandin E2 (PGE2), Tumor Necrosis Factor-α (TNF-α) and Transforming Growth Factor beta (TGF-ß) concentrations in synovial fluid were determined with ELISA assays at 8 weeks after injection. RESULTS: At 8 weeks post cell transplantation, partial cartilage repair was observed in the cell therapy, but not the PBS group (P<0.05). The BMSCs group showed higher regeneration of cartilage and lower proteoglycan loss than the BMMCs group (P<0.05). Concentrated BMMCs injection led to a weaker treatment effect, but also inhibited PGE2, TNF-α and TGF-ß levels in synovial fluid and promoted higher levels of Aggrecan and Col2A1 and downregulation of MMP-13 in sheep chondrocytes in a similar manner to BMSCs, compared with the PBS group. CONCLUSIONS: Bone marrow cells showed therapeutic efficacy in a sheep model of OA. Despite similar therapeutic potential, the easier and faster process of collection and isolation of BMMCs supports their utility as an effective alternative for OA treatment in the clinic.

Periodic mechanical stress enhances rat chondrocyte area expansion and migration through Src-PLCgamma1-ERK1/2 signaling.

The signal transduction pathways of chondrocyte area expansion and migration under periodic mechanical stress remain a matter of debate. We explore this question by performing cell culture experiments in our self-developed periodic stress field and perfusion culture system. Under periodic mechanical stress, we find that both rat chondrocyte area and migration are significantly amplified. These changes are associated with increases in the phosphorylation of Src, PLCgamma1 and ERK1/2. Area expansion, migration and phosphorylation of PLCgamma1-Tyr(783) and ERK1/2-Thr(202)/Tyr(204) are inhibited (p<0.05) after pretreatment with Src inhibitor (PP2). We further demonstrate that area expansion, migration and phosphorylation of ERK1/2-Thr(202)/Tyr(204) are significantly inhibited (p<0.05) after pretreatment with PLCgamma1 inhibitor (U73122); the phosphorylation site of Src-Tyr(418) is not affected. After pretreatment with an ERK1/2 inhibitor (PD98059), area expansion and migration are inhibited (p<0.05), while the phosphorylation sites of Src-Tyr(418) and PLCgamma1-Tyr(783) are not affected. These findings suggest that periodic mechanical stress promotes chondrocyte area expansion and migration in part through the Src-PLCgamma1-ERK1/2 signaling pathway.