Nuclear factor erythroid 2–related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is key in maintaining redox homeostasis and the pathogenesis of osteoarthritis (OA) involves oxidative distress. We thus investigated whether Nrf2/ARE signaling may control expression of key chondrogenic differentiation and hyaline cartilage maintenance factor SOX9. In human C-28/I2 chondrocytes SOX9 expression was measured by RT–qPCR after shRNA-mediated knockdown of Nrf2 or its antagonist the Kelch-like erythroid cell-derived protein with cap “n” collar homology-associated protein 1 (Keap1). Putative ARE-binding sites in the proximal SOX9 promoter region were inactivated, cloned into pGL3, and co-transfected with phRL–TK for dual-luciferase assays to verify whether Nrf2 transcriptionally regulates SOX9. SOX9 promoter activity without and with Nrf2-inducer methysticin were analyzed. Sox9 expression in articular chondrocytes was correlated to cartilage thickness and degeneration in wild-type (WT) and Nrf2-knockout mice. Data were analyzed by one-way ANOVA, a Student's t-test, or Wilcoxon rank-sum test, according to the normal distribution. Statistical significance was set to p < 0.05. While Keap1-specific RNAi increased SOX9 expression, Nrf2-specific RNAi significantly decreased it. Putative ARE sites (ARE. 1. , ARE. 2. ) were identified in the SOX9 promoter region. ARE. 2. mutagenesis significantly reduced SOX9 promoter activity, while truncation of ARE. 1. did not. A functional ARE. 2. site was thus essential for methysticin-mediated induction of SOX9 promoter activity. Knee cartilage of young Nrf2-knockout mice further revealed significantly fewer Sox9-positive chondrocytes as compared to old Nrf2-knockout animals, which further showed thinner cartilage and more severe cartilage erosion. Our data suggest that SOX9 expression in articular cartilage is directly Nrf2-dependent and that pharmacological Nrf2 activation may hold potential to diminish age-dependent
Although remnant-preserved ACL reconstruction (ACLR) restores knee joint stability and dampens the problem of acute ACL rupture-induced knee pain, an increasing number of patients still develop post-traumatic osteoarthritis (PTOA) after 10 to 15 years of ACLR. We previously found that remnant-preserved ACLR with concomitant medial and lateral meniscus repair may not prevent cartilage degeneration and weaken muscle strength, while the clinical features of PTOA are not clear. We hypothesized that remnant-preserved ACLR with concomitant medial and lateral meniscus tears is related to early cartilage damage, worse function recovery, patient-reported outcomes (PROs) and delayed duration to return to sports. The aim is to evaluate the remnant-preserved ACLR with complicated meniscal injuries in predicting which patients are at higher risk of
Summary. In a rabbit model of early osteoarthritis, structural changes in femoral condyle cartilage were severer in the lateral compartment and preceded alterations in the underlying bone. In the medial compartment, altered bone properties occurred together with structural changes in cartilage. Introduction. Early
Abstract. INTRODUCTION. The mechanisms underlying abnormal joint mechanics are poorly understood despite it being a major risk factor for developing osteoarthritis. Glutamate signalling has been implicated in
Knee osteoarthritis is a common, debilitating condition. Intra articular corticosteroid injections are a commonly used non-operative treatment strategy. Intra articular hip injection with Ketorolac (an NSAID) has proven to be as efficacious as corticosteroids. No prior study compares the efficacy of Ketorolac relative to corticosteroids for relief of discomfort in knee osteoarthritis. The study design was a single centre double blinded RCT. Severity of
Medial meniscus tear has been proposed as a potential etiology of spontaneous osteonecrosis of the knee (SONK). Disruption of collagen fibers within the meniscus causes meniscal extrusion, which results in alteration in load distribution in the knee. A recent study has demonstrated high incidence of medial meniscus extrusion in the knee with SONK. Our purpose was to determine whether the extent of medial meniscus extrusion correlates with the severity of SONK in the medial femoral condyle. Anteroposterior and lateral knee radiographs were taken with the patients standing. Limb alignment was expressed as the femorotibial angle (FTA) obtained from the anteroposterior radiograph. The stage of progression of SONK was determined according to the radiological classification system described by Koshino. After measurement of anteroposterior, mediolateral, and superoinferior dimensions of the hypointense T1 signal intensity lesion of MRI, its ellipsoid volume was calculated with the three dimensions. Meniscal pathology (degeneration, tear, and extrusion) were also evaluated by MRI. Of the 18 knees with SONK, we found 5 knees at the radiological stage 2 lesions, 9 knees at the stage 3, and 4 knees at the stage 4. Whereas the ellipsoid volume of SONK lesion significantly increased with the stage progression, the volume was significantly greater at stage 4 than stage 2 or 3. All the 18 knees with SONK in the present study showed substantial extrusion (> 3mm) and degeneration of the medial meniscus. While medial meniscal extrusion increased with the stage progression, medial meniscus was significantly extruded at stage 3 or 4 compared with stage 2. A significant increase in FTA was found with the stage progression. FTA was significantly greater at stage 4 than stage 2 or 3. Multiple linear regression analysis revealed that medial meniscus extrusion and FTA were useful predictors of the volume of SONK lesion. This study has clearly shown a significant correlation between the extent of medial meniscus extrusion and the stage and volume of SONK lesion. Degeneration and tears of the medial meniscus in combination with extrusion may result in loss of hoop stress distribution in the medial compartment, which could increase the load in the medial femoral condyle. In addition to meniscal pathology, knee alignment can influence load distribution in the medial compartment biomechanically. Multiple linear regression analysis indicates that an increase in FTA concomitant with a greater extrusion of medial meniscus could result in greater lesion and advanced radiological stage of SONK. Taken together, alteration in compressive force transmission through the medial compartment by meniscus extrusion and varus alignment could develop subchondral insufficiency fractures in the medial femoral condyle, which is considered to be one of the main contributing factors to SONK development. There was high association of medial meniscus extrusion and FTA with the radiological stage and volume of SONK lesion. Increased loading in the medial femoral condyle with greater extrusion of medial meniscus and varus alignment may contribute to expansion and secondary
Magnetic resonance imaging (MRI) is a useful diagnostic tool in evaluating meniscus pathology in the knee. Data from available literature suggests sensitivity and specificity rates around 90% when compared to the gold standard findings at knee arthroscopy. We sought to evaluate the sensitivity, specificity and precision rate (positive predictive value) of MRI at diagnosing meniscus tears within our unit. A retrospective audit of a total of 79 MRI reports and arthroscopic findings spanning a one year period was carried out. There were 66 positive MRI reports and 13 negative reports. There were 6 false positives 4 false negatives when compared to arthroscopic findings. The sensitivity of MRI for detecting meniscus tears was 93.7% with 60 out of 64 tears detected. All 4 false negatives also had at least grade III
The patellofemoral joint is an important source of symptoms in osteoarthritis of the knee. We have used a newly designed surgical model of patellar strengthening to induce osteoarthritis in BALB/c mice and to establish markers by investigating the relationship between osteoarthritis and synovial levels of matrix metalloproteinases (MMPs). Osteoarthritis was induced by using this microsurgical technique under direct vision without involving the cavity of the knee. Degeneration of cartilage was assessed by the Mankin score and synovial tissue was used to determine the mRNA expression levels of MMPs. Irrigation fluid from the knee was used to measure the concentrations of MMP-3 and MMP-9. Analysis of cartilage degeneration was correlated with the levels of expression of MMP. After operation the patellofemoral joint showed evidence of mild osteoarthritis at eight weeks and further degenerative changes by 12 weeks. The level of synovial MMP-9 mRNA correlated with the Mankin score at eight weeks, but not at 12 weeks. The levels of MMP-2, MMP-3 and MMP-14 mRNA correlated with the Mankin score at 12 weeks. An increase in MMP-3 was observed from four weeks up to 16 weeks. MMP-9 was notably increased at eight weeks, but the concentration at 16 weeks had decreased to the level observed at four weeks. Our observations suggest that MMP-2, MMP-3 and MMP-14 could be used as markers of the progression of
Summary. Macroscopic grading, histologic grading, morphometry, mineral analysis, and mechanical testing were performed to better understand the changes that occur in the cartilage, calcified cartilage, and subchondral bone in early osteoarthritis. Introduction. The earliest changes in osteoarthritis (OA) remain poorly understood due to the difficulty in detecting OA before patients feel pain. We have published details of the mature bovine patella model showing the pre-OA state where no gross macroscopic changes are visible yet microstructural changes indicate very early degeneration. In this new study, we proceed to investigate this model further by more comprehensively quantifying the changes in articular cartilage (AC), zone of calcified cartilage (ZCC), and subchondral bone (SB) in pre and early OA. Methods. Patellae from mature cow were studied. Gross examination with India ink was used to classify macroscopic cartilage degeneration. Two groups were selected in this study: one with no visible surface degeneration (pre-OA) and the other with mild to moderate macroscopically visible surface degeneration (early OA). Histologic staining with Safranin O and Fast Green was analysed with two osteoarthritic scoring systems: Mankin and OOCHAS. Differential Interference Contrast (DIC) microscopy was used to quantify morphometric changes. Degree of mineralisation was analysed with energy dispersive X-ray spectroscopy (EDS) to quantify the calcium and phosphorus content of the mineralised tissues. Material properties of calcified cartilage and subchondral bone were tested macroscopically using 3 point bending. Results. In the early OA group, cartilage was fissured and showed matrix loss. In its hydrated state, average cartilage thickness was significantly greater (p<0.05) in the early OA group by 24% compared to pre-OA group. The early OA group showed an 88% increase in ZCC thickness. Early OA tissue was graded significantly higher in OOCHAS grading and structure scores, cellularity, and staining scores of Mankin grading but not in the tidemark integrity score. Pre-OA and early OA tissues showed no significant differences in ZCC or SB mineralisation although all samples showed an increase in the degree of mineralisation going from the upper to the deeper ZCC and SB. Macroscopic mechanical testing showed no significant differences in mechanical properties between pre-OA and early OA groups. However within groups, the ZCC was an order of magnitude less stiff than the SB. Micromechanical testing showed that deeper ZCC and SB were stiffer than their regions closer to the joint surface. Conclusions. Early
Introduction. Advanced stage and a large area of necrotic bone are known risk factors for failure after transtrochanteric rotational osteotomy of the hip in patients with osteonecrosis. The purpose of this study was to determine whether there were other risk factors for failure of this osteotomy. Methods. One hundred and five patients (113 hips) underwent transtrochanteric anterior rotational osteotomy for femoral head osteonecrosis and were followed for a mean period of 51 months post-operatively. Radiographic failure was defined as secondary collapse or
To investigate the effect of instability on the remodelling of a minor articular surface offset, we created a 0.5 mm coronal step-off of the medial femoral condyle in 12 New Zealand white rabbits and transected the anterior cruciate ligament (ACL). A control group of 12 rabbits had only ACL resection and the opposite knee was used as the non-operated control. The
Introduction. The purpose of this study was to evaluate the outcome of vascularized iliac bone grafting for idiopathic osteonecrosis of the femoral head. Methods. We reviewed the clinical and radiological results of 35 operations performed on 29 patients who had osteonecrosis of the femoral head (ONFH) in which a pedicle iliac bone grafting was performed for minimum follow-up of 10 years. The average age was 35 years (range, 17 to 62 years). According to the Japanese Orthopaedic Association classification for ONFH, there were 28 stage 2, 7 stage 3-A, 17 type C-1 hips, and 18 type C-2 hips. After a bone tunnel of 1.5 × 5 cm was made in the anterior aspect of the femoral head and curettage of necrotic lesion was performed, the pedicle bone with the deep circumflex iliac artery (DCIA) was inserted into the anterolateral portion of the femoral head. The average follow-up period was 13 years and 6 months. Weight bearing was not allowed for 2 months after the operation. Survival rate of the femoral head was calculated by Kaplan-Meier methods, and collapse of the femoral head and configuration of the femoral head was investigated at final follow-up. Results. Collapse of the femoral head occurred in 19 hip joints of 35 studied. Although only 16 of 28 stage 2 hips showed collapse, all 7 stage 3 hips collapsed. Four of 17 hips (24%) showed collapse in patients with type C-1 necrosis, whereas, 15 of 18 hips (83%) developed collapse in patients with type C-2 necrosis. When the bone graft was inserted in the anterolateral portion of the femoral head, the incidence of collapse was reduced. In patients without collapse for more than 12 years,
Introduction. The treatment of osteonecrosis of the femoral head (ONFH) in young and active patients remains a challenge. The purpose of this study was to determine and compare the clinical and radiographic results of the two different hip resurfacing systems; hemi-resurfacing and metal-on-metal total hip resurfacing in patients with ONFH. Methods. This study was a retrospective review of 20 patients with 30 hips who had ONFH and underwent hemi-resurfacing or total hip resurfacing between November 2002 and February 2006. We mainly performed hemi-resurfacing for early stage ONFH, and total hip resurfacing for advanced stages. Fifteen hips in 11 patients had a hemi-resurfacing component (Conserve, Wright Medical Co) with a mean age at operation of 50 years and an average follow-up of 5.5 years. Fifteen hips in 10 patients had a metal-on-metal total hip resurfacing component (Birmingham hip resurfacing, Smith & Nephew Co.) with a mean age at operation of 40 years and an average follow-up years. Results. The average postoperative Japanese Orthopaedic Association (JOA) hip scores were 86 points in hemi-resurfacing and 96 points in total hip resurfacing. The difference of pain score was a main factor to explain the difference of total JOA hip score in the two groups. Both implants were radiographically stable, but radiolucent lines around the metaphyseal stem were more frequent in total hip resurfacing. In hemi-resurfacing patients, ten of 15 hips had groin pain or groin discomfort and three hips were revised to total hip arthroplasties (THA) because of femoral neck fracture, acetabular protrusio, and
Introduction. The purpose of this study was to examine if Sugioka's transtrochanteric rotational osteotomy (TRO) of the femoral head could be a valid option in treating idiopathic osteonecrosis of the femoral head. Methods. Thirty-two TROs performed in 29 patients between 1985 and 2006 were studied. Patient age at operation ranged from 16 to 56 years (average, 36 years). Thirteen hips were in women and 19 hips in men. Height was 165 cm and weight 63 kg (Body Mass Index 23) on average. Risk factors were corticosteroid use in 18 hips and excessive alcohol consumption in 15 hips (2 of them had both backgrounds), while neither of them was found with 1 hip. Bilateral hips were affected in 19 patients and 3 of them underwent bilateral TROs sequentially. The femoral head was rotated anteriorly in 26 hips and posteriorly in 6 hips. For fixation of the osteotomy site, large femoral screws had been used till 1995 (Group 1, 9 hips), and since 1996 an AO angle plate or a compression hip screw has been used (Group 2, 13 hips). Since 2003, pre-operative planning was performed more meticulously and the distal part of the joint capsule was cut after osteotomy as described by Atsumi (Group 3, 10 hips). The average follow-up period was 6.5 years (range, 2 to 21 years). Results. The average Japanese Orthopaedic Association hip score was 55 points pre-operatively, 63 points at 1 year, and 61 points at the latest follow-up. With pain increase, re-collapse of the rotated femoral head, fracture of the proximal fragment, nonunion, trochanteric detachment, joint space narrowing,
Osteophytes are products of active endochondral and intramembranous ossification, and therefore could theoretically provide significant efficacy as bone grafts. In this study, we compared the bone mineralisation effectiveness of osteophytes and cancellous bone, including their effects on secretion of growth factors and anabolic effects on osteoblasts. Osteophytes and cancellous bone obtained from human patients were transplanted onto the calvaria of severe combined immunodeficient mice, with Calcein administered intra-peritoneally for fluorescent labelling of bone mineralisation. Conditioned media were prepared using osteophytes and cancellous bone, and growth factor concentration and effects of each graft on proliferation, differentiation and migration of osteoblastic cells were assessed using enzyme-linked immunosorbent assays, MTS ((3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)) assays, quantitative real-time polymerase chain reaction, and migration assays.Objectives
Methods
An experimental piglet model induces avascular necrosis (AVN)
and deformation of the femoral head but its secondary effects on
the developing acetabulum have not been studied. The aim of this
study was to assess the development of secondary acetabular deformation
following femoral head ischemia. Intracapsular circumferential ligation at the base of the femoral
neck and sectioning of the ligamentum teres were performed in three
week old piglets. MRI was then used for qualitative and quantitative
studies of the acetabula in operated and non-operated hips in eight
piglets from 48 hours to eight weeks post-surgery. Specimen photographs and
histological sections of the acetabula were done at the end of the
study. Objectives
Methods
Achieving deep flexion after total knee replacement remains a challenge. In this study we compared the soft-tissue tension and tibiofemoral force in a mobile-bearing posterior cruciate ligament-sacrificing total knee replacement, using equal flexion and extension gaps, and with the gaps increased by 2 mm each. The tests were conducted during passive movement in five cadaver knees, and measurements of strain were made simultaneously in the collateral ligaments. The tibiofemoral force was measured using a customised mini-force plate in the tibial tray. Measurements of collateral ligament strain were not very sensitive to changes in the gap ratio, but tibiofemoral force measurements were. Tibiofemoral force was decreased by a mean of 40% (
We stably transfected early passage chondrocytes with an anti-apoptotic Bcl-2 gene We conclude that NO-induced chondrocyte death involves a mechanism which appears to be subject to regulation by an anti-apoptotic Bcl-2 gene. Therefore, Bcl-2 gene therapy may prove to be of therapeutic value in protecting human articular chondrocytes.
We report the effects of local administration of osteogenic protein-1 on the biomechanical properties of the overstretched anterior cruciate ligament in an animal model. An injury in the anterior cruciate ligament was created in 45 rabbits. They were divided into three equal groups. In group 1, no treatment was applied, in group II, phosphate-buffered saline was applied around the injured ligament, and in group III, 12.5 μg of osteogenic protein-1 mixed with phosphate-buffered saline was applied around the injured ligament. A control group of 15 rabbits was assembled from randomly-selected injured knees from among the first three groups. Each rabbit was killed at 12 weeks. The maximum load and stiffness of the anterior cruciate ligament was found to be significantly greater in group III than either group 1 (p = 0.002, p = 0.014) or group II (p = 0.032, p = 0.025). The tensile strength and the tangent modulus of fascicles from the ligament were also significantly greater in group III than either group I (p = 0.002, p = 0.0174) or II (p = 0.005, p = 0.022). The application of osteogenic protein-1 enhanced the healing in the injured anterior cruciate ligament, but compared with the control group the treated ligament remained lengthened. The administration of osteogenic protein-1 may have a therapeutic role in treating the overstretched anterior cruciate ligament.