Impulse-forces during walking are not increased in patients with knee osteoarthritis

Background?Impulsive forces in the knee joint have been suspected to be a co-factor in the development and progression of knee osteoarthritis. We thus evaluated the impulsive sagittal ground reaction forces (iGRF), shock waves and lower extremity joint kinematics at heel strike during walking in knee osteoarthritis (OA) patients and compared them to those in healthy subjects.

Subjects and methods?We studied 9 OA patients and 10 healthy subjects using three-dimensional gait analyses concentrated on the heel strike. Impulse GRF (iGRF) was measured together with peak accelerations (PA) at the tibial tuberosity and sacrum. Sagittal lower extremity joint angles at heel strike were extracted from the gait analyses. As OA is painful and pain might alter movement strategies, the patient group was also evaluated following pain relief by intraarticular lidocaine injections.

Results?The two groups showed similar iGRF, similar tibial and sacral PA, and similar joint angles at heel strike. Following pain relief, the OA patients struck the ground with more extended hip and knee joints and lower tibial PA compared to the painful condition. Although such changes occurred after pain relief, all parameters were within their normal ranges.

Interpretation?OA patients and healthy subjects show similar impulse-forces and joint kinematics at heel strike. Following pain relief in the patient group, changes in tibial PA and in hip and knee joint angles were observed but these were still within the normal range. Our findings make us question the hypothesis that impulse-forces generated at heel strike during walking contribute to progression of OA.     

Comparison of the ACL and ACL graft forces before and after ACL reconstruction: an in-vitro robotic investigation

Background Long-term follow-up studies have indi-cated that there is an increased incidence of arthrosis following anterior cruciate ligament (ACL) reconstruc-tion, suggesting that the reconstruction may not repro-duce intact ACL biomechanics. We studied not only the magnitude but also the orientation of the ACL and ACL graft forces

Methods 10 knee specimens were tested on a robotic testing system with the ACL intact, deficient, and recon-structed (using a bone-patella tendon-bone graft). The magnitude and orientation of the ACL and ACL graft forces were determined under an anterior tibial load of 130 N at full extension, and 15, 30, 60, and 90° of flexion. Orientation was described using elevation angle (the angle formed with the tibial plateau in the sagit-tal plane) and deviation angle (the angle formed with respect to the anteroposterior direction in the transverse plane)

Results ACL reconstruction restored anterior tibial translation to within 2.6 mm of that of the intact knee under the 130-N anterior load. Average internal tibial rotation was reduced after ACL reconstruction at all flexion angles. The force vector of the ACL graft was significantly different from the ACL force vector. The average values of the elevation and deviation angles of the ACL graft forces were higher than that of the intact ACL at all flexion angles

Interpretation Contemporary single bundle ACL reconstruction restores anterior tibial translation under anterior tibial load with different forces (both magni-tude and orientation) in the graft compared to the intact ACL. Such graft function might alter knee kinematics in other degrees of freedom and could overly constrain the tibial rotation. An anatomic ACL reconstruction should reproduce the magnitude and orientation of the intact ACL force vector, so that the 6-degrees-of-freedom knee kinematics and joint reaction forces can be restored.     

Control of frontal plane knee laxity during gait in patients with medial compartment knee osteoarthritis

OBJECTIVE: Patients with medial compartment knee osteoarthritis (OA) adopt an abnormal gait pattern, and often develop frontal plane laxity at the knee. The purpose of this study was to quantify the extent of frontal plane knee joint laxity in patients with medial knee OA and genu varum and to assess the effect of joint laxity on knee joint kinetics, kinematics and muscle activity during gait. DESIGN: Twelve subjects with genu varum and medial compartment knee osteoarthritis (OA group) and 12 age-matched uninjured subjects underwent stress radiography to determine the presence and magnitude of frontal plane laxity. All subjects also went through gait analysis with surface electromyography of the medial and lateral quadriceps, hamstrings, and gastrocnemius to calculate knee joint kinematics and kinetics and co-contraction levels during gait. RESULTS: The OA group showed significantly greater knee instability (P = 0.002), medial joint laxity (P = 0.001), greater medial quadriceps-medial gastrocnemius (VMMG) co-contraction (P = 0.043), and greater knee adduction moments (P = 0.019) than the control group. Medial joint laxity contributed significantly to the variance in both VMMG and the knee adduction moment during early stance. CONCLUSION: The presence of medial laxity in patients with knee OA is likely contributing to the altered gait patterns observed in those with medial knee OA. Greater medial co-contraction and knee adduction moments bodes poorly for the long-term integrity of the articular cartilage, suggesting that medial joint laxity should be a focus of interventions aimed at slowing the progression of disease in individuals with medial compartment knee OA.     

Effects of lateral-wedged insoles on kinetics at the knee

Lateral-wedged insoles have been shown to help clinically alleviate pain associated with medial compartment osteoarthritis. This study analyzed the effects of lateral-wedged insoles on the gait and medial knee compartment load of 17 healthy subjects. Three-dimensional gait analysis was performed for each subject with and without wearing a 5 degrees lateral-wedged insole. Subjects walked at a constant velocity for both conditions. A motion analysis system and force plate were used to calculate temporal and spatial parameters, joint angles, moments, and powers. An analytical model was developed to estimate medial compartment loads at the knee for each subject during both conditions. Results were compared with a Student's paired t test. There were no significant differences in temporal and spatial parameters, joint angles at the hip, knee, and ankle, or kinetics at the hip and ankle. However, the external varus moment and estimated medial compartment load at the knee were reduced significantly with the addition of the lateral-wedged insole. These results suggest that the pain relief and improvement in function reported by patients with osteoarthritis while using lateral-wedged insoles may be achieved by a reduction in external varus moment and medial compartment load.     

Localization of the full‐thickness cartilage lesions in medial and lateral unicompartmental knee osteoarthritis

This study's aim was to determine the patterns of osteoarthritis (OA) in both unicompartmental medial and lateral OA of the knee. Forty patients with medial and 20 with lateral unicompartmental knee osteoarthritis were studied to determine the location of full‐thickness cartilage lesions. Intraoperatively, the distance between margins of the lesion and reference lines were measured. The femoral measurements were transposed onto lateral radiographs to determine the relationship between the lesion site and knee flexion angles. Both tibial and femoral lesions were significantly (p < 0.01) more posterior in lateral OA than medial OA. In medial OA, the lesion center was, on average, at 11° (SD 3°) of flexion, whereas in lateral OA, it was at 40° (SD 3°). The smallest medial femoral lesions were near full extension and, as they enlarged, they extended posteriorly. The smallest lateral femoral lesions extended from 20° to 60° flexion. As these lesions enlarged, they extended both anteriorly and posteriorly. There was a well‐defined relationship between the site of the lesions and their size, suggesting that they develop and progress in a predictable manner. The relationship was different for medial and lateral OA, suggesting that different mechanical factors are important in initiating the different types of OA. The lesions in medial OA occur in extension, perhaps initiated by events occurring at heel strike. The lesions in lateral OA begin at flexion angles above those occurring during the single leg stance phase of the gait cycle, so activities other than gait are likely to induce lateral OA. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1339–1346, 2009     

Auditory biofeedback in spastic diplegia

Using a simple auditory feedback device that produces a continuous buzzing signal on heel contact, we studied the effects of augmented auditory biofeedback on the gait of four spastic diplegic children. The purpose of the biofeedback was to attempt to increase dorsiflexion at heel strike without causing other compensatory changes at the knee and hip, which might lead to crouch gait. We measured velocity, stride length, and thigh, knee, and ankle angles at the heel strike, midswing, and toe-off phases of gait. Four subjects, aged 5-8 years, were given a standard gait training program, supplemented with biofeedback two times per week in a clinical setting and 1 h daily in a home program over an 8-week period. Three computer video gait analyses of the sagittal plane were conducted without biofeedback in the pre- and posttraining conditions and twice with biofeedback over the course of treatment. We performed linear regression analysis of joint angles at heel strike, midswing, and toe-off as a function of days into the study for each patient. Angle-angle diagrams for a test subject before, during, and after treatment indicate changes toward a normal gait pattern with biofeedback. The linear regression analysis showed a statistically significant (p less than 0.01) shift toward dorsiflexion at heel strike with repeated exposure to biofeedback. A compensatory crouch gait was not induced. The linear regression analyses for hip and knee angles were not statistically significant (p greater than 0.25), indicating a disassociation of movement among hip, knee, and ankle.     

Effects of knee pain relief in osteoarthritis on gait and stair-stepping

Osteoarthritic knee pain affects patient mobility. Relief of knee pain in osteoarthritis has been reported to increase loading of the knee during gait, but it is unknown whether such pain relief enhances knee loading during more demanding activities such as stair-stepping. The gait of 19 patients and stair-stepping of 14 patients with painful medial compartment osteoarthritis of the knee was assessed before and after pain-relieving intraarticular injection of the knee and compared with those of 21 healthy control subjects. There were significant increases in gait velocity, cadence, maximum external knee adduction moment (indicating increased loading in the medial compartment of the knee), and maximum external hip adduction and ankle abduction moments immediately after the injection. With the exception of velocity and ankle abduction moment, these variables were returned to levels that were not statistically different from those of the control subjects. However, no significant differences were found during stair-stepping in the external adduction-abduction moments about the knee, hip, or ankle after injection. Furthermore, the postinjection magnitudes of these variables during stair-stepping were significantly less than those of the controls. Therefore, although the relief of knee pain is sufficient to enhance gait function in osteoarthritis of the knee, it is insufficient to enhance stair-stepping function.     

Walking pattern in 9 women with hip dysplasia 18 months after periacetabular osteotomy

Background Periacetabular osteotomy improves radiographic predictors of osteoarthrosis and diminishes pain and functional impairment. No changes in function quantified by gait analysis have yet been documented. We evaluated the functional outcome of periacetabular osteotomy in relation to gait.

Methods The gait pattern of 9 women (median age 39 years) with hip dysplasia who were treated with unilateral periacetabular osteotomy was analyzed before periacetabular osteotomy and an average of 1.5 years afterwards. Data were collected using 5 video cameras and 2 force plates. An inverse dynamics approach was used to calculate sagittal joint angles and moments in the stance phase.

Results Postoperatively, all subjects walked with an increased extension of the knee joint during the entire stance phase compared to the preoperative movement pattern.

Interpretation The subjects achieved a more upright walking pattern but continued to relieve the hip joint by maintaining a reduced flexor moment.     

Change in intersegmental foot and ankle motion after a high tibial osteotomy in genu varum patients

High tibial osteotomy (HTO) is a well‐established treatment for medial compartment knee osteoarthritis (OA), which shifts the weight‐bearing axis from the medial to the lateral side of the knee. As the adjacent ankle joint may be directly affected by the change in biomechanics, this study aimed to evaluate the change in the intersegmental foot and ankle motion after HTO in patients with genu varum. The study included 24 patients who underwent HTO, and 48 older healthy participants as a control group. Segmental foot kinematics were evaluated using a 3D multisegment foot model, and gait data of temporal and spatial parameters were obtained. After HTO, normalized stride length significantly increased with a tendency for increases in gait speed. In hallux kinematics relative to the forefoot, the sagittal motions of both the patients and the control group were similar throughout the majority of the gait cycle. In forefoot kinematics relative to the hindfoot, the pre‐HTO state revealed significant pronation throughout the gait cycle, while the post‐HTO state showed a similar position and motion to the control group. In hindfoot kinematics relative to the tibia, coronal motions of the pre‐HTO state showed supination throughout the gait cycle, while supination during the stance phase decreased after HTO. Genu varum patients with medial compartment knee OA showed different gait parameters and intersegmental motion during gait when compared with age‐ and gender‐matched controls. The effect of HTO was demonstrated by the normalization of midfoot compensation in patients with genu varum.     

Tibial intramedullary nails -- should they be removed? A retrospective study of 71 patients

Background Anterior knee pain and young age of the patient have been considered justification for removal of a tibial intramedullary nail. There have been few reports on the outcome after nail removal, however.

Patients and methods We studied 71 patients in whom 72 tibial nails had been removed. We used self-assess-ment questionnaires to evaluate the location, intensity, and frequency of pain before and after removal. The degree of satisfaction was scored on a visual analog scale.

Results 39 of 71 patients had less pain after removal of the nail, but were not asymptomatic. 14 patients had unaltered pain, and 18 patients had increased pain. 4 of 6 patients who had been treated with fasciotomy were not satisfied with the outcome of nail removal.

Interpretation The results of nail removal to alleviate pain are poor. Removal of a nail should not be undertaken unless there is a convincing indication.     

Effect of bone marrow grafting on the titanium porous-coated implant in bilateral total knee arthroplasty

Background and purpose Poor bone ingrowth into the porous coating of tibial components has been reported. We hypothesized that iliac marrow grafting might be useful to enhance bone ingrowth into a porous-coated implant. The first part of this study was to examine the presence of fibroblast colony-forming units (CFUF) containing osteogenic precursor cells in tibial bone marrow and iliac bone marrow. The second aim was to compare the clinical and radiographic results after bilateral total knee arthroplasty (TKA) with and without autologous bone marrow transplantation to the bone-implant interface.

Methods Simultaneous bilateral TKA was performed in 21 patients with osteoarthritis. Aspirated iliac bone marrow was transplanted to the interface of one randomly selected porous-coated tibial component in each patient, and contralateral knees served as controls. All of the 21 patients were followed for 5 years.

Results The average number of CFU-F was significantly lower in tibial marrow than in iliac marrow (p = 0.008). The final fluoroscopically-guided radiographs revealed a decrease in the number of knees with radiolucent lines after marrow grafting compared to those without grafting (p = 0.004).

Interpretation Iliac bone marrow is useful as a bone grafting material to enhance the biological fixation in porous-coated implants.     

All-polyethylene vs. metal-backed tibial component in total knee arthroplasty-a randomized RSA study comparing early fixation of horizontally and completely cemented tibial components: part 2. Completely cemented components: MB not superior to AP components

Background Uncertainty exists as to whether metal backing (MB) of the tibial component is better than an all-polyethylene component (AP). This is valid for both horizontally and completely cemented components. We evaluated completely cemented MB vs. AP (Part 2).

Patients and methods In a randomized study, 39 patients (40 knees) with knee arthrosis were operated with cemented low-conforming total knee arthroplasty (AGC, Biomet) with a tibial component of uniform thickness (8 mm), cemented both beneath the tibial tray and around the stem. 20 patients had an all-polyethylene (AP) tibial component and 20 patients had an identical but metal-backed (MB) tibial component. We used clinical examination and radiostereometric analysis (RSA) to evaluate the hypothesis that MB improves component fixation. Fixation was evaluated using RSA up to 2 years after surgery. Clinical assessment was performed preoperatively and after 2 years using the Hospital for Special Surgeons (HSS) score.

Results We found no differences in micromotion, and no differences in clinical scores could be detected between the groups at any time point.

Interpretation Our findings indicate that there was equal initial fixation of the AP and MB stemmed monobloc components when they were cemented beneath the tibial plateau and around the stem.

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Bi‐Cruciate Retaining Total Knee Arthroplasty Does Not Restore Native Tibiofemoral Articular Contact Kinematics During Gait

Bi‐cruciate retaining (BCR) total knee arthroplasty (TKA) design preserves both anterior and posterior cruciate ligaments with the potential to restore normal posterior femoral rollback and joint kinematics. Abnormal knee kinematics and “paradoxical” anterior femoral translation in conventional TKA designs have been suggested as potential causes of patient dissatisfaction. However, there is a paucity of data on the in vivo kinematics and articular contact behavior of BCR‐TKA. This study aimed to investigate in vivo kinematics, articular contact position, and pivot point location of the BCR‐TKA during gait. In vivo kinematics of 30 patients with unilateral BCR‐TKA during treadmill walking was determined using validated dual fluoroscopic imaging tracking technique. The BCR‐TKA exhibited less extension than the normal healthy knee between heel strike and 48% of gait cycle. Although the average external rotation trend observed for BCR TKA was similar to the normal healthy knee, the range of motion was not fully comparable. The lowest point of the medial condyle showed longer anteroposterior translation excursion than the lateral condyle, leading to a lateral‐pivoting pattern in 60% of BCR TKA patients during stance phase. BCR‐TKA demonstrated no statistical significant differences in anterior–posterior translation as well as varus rotation, when compared to normal healthy knees during the stance phase. However, sagittal plane motion and tibiofemoral articular contact characteristics including pivoting patterns were not fully restored in BCR TKA patients during gait, suggesting that BCR TKA does not restore native tibiofemoral articular contact kinematics. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1929–1937, 2019     

Lateral thrust of anterior cruciate ligament-insufficient knees and posterior cruciate ligament-insufficient knees

Leaving anterior cruciate ligament (ACL) insufficiency and posterior cruciate ligament (PCL) insufficiency untreated frequently leads to osteoarthritis (OA). The purpose of this study was to evaluate dynamically the lateral thrust of ACL-insufficient knees and PCL-insufficient knees, and from the findings investigate the relationship between cruciate ligament insufficiency and OA occurrence. An acceleration sensor was attached to the affected and control anterior tibial tubercles, acting in medial-lateral and perpendicular directions. The lateral thrust immediately after heel strike was measured continuously by a telemeter under stabilised walking conditions. When compared to the contralateral healthy knee, the peak value of lateral acceleration immediately after heel strike was significantly larger in the ACL-insufficient knee; and lateral thrust was increased, but not significantly, in the PCL-insufficient knee. Given that lateral thrust of the knee during walking increases due to ACL or PCL injury, it may be a principal contributor to OA progression.     

The effects of ACL deficiency on mediolateral translation and varus-valgus rotation

Background The anterior cruciate ligament (ACL) constrains the anterior translation and axial rotation of the tibia. However, the effect of ACL injury on the mediolateral translation and varus-valgus rotation of the tibia is unknown. Because of the oblique orientation of the ACL, we hypothesized that ACL deficiency alters mediolateral translation and varus-valgus rotation.

Methods The kinematics of 9 cadavers from full extension to 90° of flexion under various loading conditions were measured before and after ACL resection using a robotic testing system.

Results ACL deficiency increased the medial translation of the tibia and valgus rotation, especially at 15° and 30° of flexion. For example, at 15°, ACL deficiency increased the medial translation from 1.2 (SD 0.9) mm to 1.8 (SD 1.1) mm in response to a quadriceps load. The valgus rotation also increased from 0.8° (SD 0.6) to 1.7° (SD 0.8).

Interpretation ACL deficiency altered both the mediolateral tibial translation and valgus-varus rotation under various loading conditions. The increased medial tibial translation could shift the contact in the medial compartment towards the medial tibial spine, a region where degeneration is observed in ACL-deficient patients. In addition to restoring anterior laxity, ACL reconstruction might need to restore the mediolateral translation of the tibia and varus-valgus rotation of the knee.     

Detection of gene expression in synovium of patients with osteoarthritis using a random sequencing method

Background The etiology of osteoarthritis (OA) is multifactorial and current research attributes it to a complex network of biochemical factors. We attempted to identify important molecules in OA joint destruction.

Patients and methods Synovium was collected from 2 women with hip OA. Total RNA was extracted from the combined synovium. Messenger RNAs (mRNAs) were randomly sequenced for identification with the oligo-capping method. mRNA expression of 9 genes that were found to be frequently expressed was compared in synovium from 7 OA patients and 2 control patients with no signs of arthritis.

Results We sequenced 7,339 mRNAs in total and identified 4,247 different kinds, which were ranked in order of frequency. Fibronectin was the protein most frequently expressed (230/7,339), followed by matrix metalloproteinases (MMPs) 1 and 3. The 9 genes selected were those encoding fibronectin 1, MMP1, MMP3, tissue inhibitor of metalloproteinase 3, apolipoprotein L-I (APOL1), syndecan binding protein, insulin-like growth factor binding protein 5, heat shock protein 90, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5). We investigated expression of these 9 genes in synovium from the 7 individual patients with OA. All 9 genes were expressed in OA and control synovium. Expression of MMP1 mRNA was weak in OA samples, however, while expression of ADAMTS5 and APOL1 mRNAs was weak in the controls and some of the OA samples.

Interpretation ADAMTS5 and APOL1 may have important roles in the mechanism of OA.     

The association between joint stress from physical activity and self-reported osteoarthritis: an analysis of the Cooper Clinic data

OBJECTIVE: The purpose was to evaluate the association between estimated joint stress from physical activity (PA) and hip/knee osteoarthritis (OA). DESIGN: A nested case-control study was performed using data from the Aerobics Center Longitudinal Study. Participants without self-reported OA at baseline who attended the clinic between 1974 and 1993 and returned a follow-up questionnaire in 1990 or 1995 were eligible. Cases were those who reported a physician diagnosis of OA of the knee and/or hip at follow-up (N = 415). A random sample of persons in the remaining cohort were classified as controls (N = 1995). PA was measured at baseline by self-report and subjects were classified as 'moderate/high' or 'low' joint stress by PA type. Those reporting no PA were classified as sedentary with 'no' joint stress (the reference group). Men and women were analyzed separately. Stratified analysis and multiple logistic regression were used to assess the relationship between hip/knee OA and joint stress as predicted by PA. RESULTS: After adjustment for age, body mass index, years of follow-up, and history of hip/knee joint injury, among men, there was no association between hip/knee OA and low joint stress while moderate/high joint stress was associated with reduced risk of hip/knee OA (adjusted odds ratio (OR) = 0.62, 95% confidence interval (CI) = 0.43-0.89). Among women, both levels of joint stress were associated with reduced risk of hip/knee OA (OR = 0.58, 95% CI = 0.34-0.99 for low and OR=0.24, 95% CI = 0.11-0.52 for moderate/high). CONCLUSIONS: PA may reduce the risk of hip/knee OA, especially among women. Further research should assess the combined effects of frequency, intensity, duration and joint stress level of PA on incidence of hip/knee OA.     

Increased knee joint loads during walking are present in subjects with knee osteoarthritis

OBJECTIVE: This study tests the hypothesis that the peak external knee adduction moment during gait is increased in a group of ambulatory subjects with knee osteoarthritis (OA) of varying radiographic severity who are being managed with medical therapy. Tibiofemoral knee OA more commonly affects the medial compartment. The external knee adduction moment can be used to assess the load distribution between the medial and lateral compartments of the knee joint. Additionally, this study tests if changes in the knee angles, such as a reduced midstance knee flexion angle, or reduced sagittal plane moments previously identified by others as load reducing mechanisms are present in this OA group. DESIGN: Thirty-one subjects with radiographic evidence of knee OA and medial compartment cartilage damage were gait tested after a 2-week drug washout period. Thirty-one normal subjects (asymptomatic control subjects) with a comparable age, weight and height distribution were also tested. Significant differences in the sagittal plane knee motion and peak external moments between the normal and knee OA groups were identified using t tests. RESULTS: Subjects with knee OA walked with a greater than normal peak external knee adduction moment (P=0.003). The midstance knee flexion angle was not significantly different between the two groups (P=0.625) nor were the peak flexion and extension moments (P> 0.037). CONCLUSIONS: Load reducing mechanisms, such as a decreased midstance knee flexion angle, identified by others in subjects with endstage knee OA or reduced external flexion or extension moments were not present in this group of subjects with knee OA who were being managed by conservative treatment. The finding of a significantly greater than normal external knee adduction moment in the knee OA group lends support to the hypothesis that an increased knee adduction moment during gait is associated with knee OA.     

Opioid requirement after arthroscopy is associated with decreasing glucose levels and increasing PGE2 levels in the synovial membrane

Background Increased prostaglandin E2 (PGE2) release has been suggested to contribute to the enhanced nociceptor sensitivity that underlies chronic osteoarthritis pain. We have previously shown increased levels of lactate and glycerol in synovium postoperatively. Thus, we wanted to investigate whether the local trauma response is related to subjective pain.

Methods We monitored metabolic and inflammatory changes with microdialysis in the knee joint synovial membrane of 14 patients after arthroscopy, in relation to pain requiring systemic opioids. The adipose tissue of the contralateral thigh served as reference. The concentrations of glucose, lactate, pyruvate, glycerol and PGE2, and also local blood flow were analyzed over 3 hours postoperatively.

Results In the 6 patients requiring systemic opioid analgesia, the initial concentrations of glucose and PGE2 in the synovial tissue were increased compared to those not requiring opioids, and decreased following opioid administration. In the reference tissue there was no difference between groups regarding glucose, and the PGE2 concentration was below the detection limit. No significant differences in the levels of other compounds, in relation to the need for opioids, were found, either in synovial tissue or in reference tissue. Overall, the synovial tissue blood flow was stable.

Interpretation Pain after arthroscopy is reflected by increased glucose utilization and PGE2 production by the synovial membrane.