Recombinant platelet-derived growth factor-BB alleviates osteoarthritis in a rat model by decreasing chondrocyte apoptosis in vitro and in vivo

Osteoarthritis (OA) is a common joint disease that mainly affects the diarthrodial joints. Treatments for OA include non-pharmacological interventions, topical and oral therapies, intra-articular therapies and joint surgery. However, all the treatments mentioned above mainly aim to control the symptoms instead of improving or reversing the joint condition. In this research, we observed the effect of recombinant platelet-derived growth factor (PDGF)-BB on OA in a monosodium iodoacetate (MIA)–induced rat model and revealed the possible mechanisms. In vitro, the level of inflammation in the chondrocytes was gradually alleviated, and the apoptosis rate was gradually decreased by PDGF-BB at increasing concentrations. The levels of p-p38, Bax and caspase-3 decreased, and the level of p-Erk increased with increasing PDGF-BB concentration. In vivo, PDGF-BB could significantly reverse chondrocyte and matrix loss. Furthermore, high concentrations of PDGF-BB could alleviate cartilage hyperplasia to remodel the tissue. The level of collagen II was up-regulated, and the levels of collagen X and apoptosis were down-regulated by increasing concentrations of PDGF-BB. In conclusion, recombinant PDGF-BB alleviated OA by down-regulating caspase-3-dependent apoptosis. The effects of PDGF-BB on OA mainly include inhibiting chondrocyte loss, reducing cartilage hyperplasia and osteophyte formation, and regulating collagen anabolism.     

Proteomics of human primary osteoarthritic chondrocytes exposed to extremely low-frequency electromagnetic fields (ELF EMFs) and to therapeutic application of musically modulated electromagnetic fields (TAMMEF)

Osteoarthritis (OA) is the most frequent joint disease, characterized by degradation of extracellular matrix and alterations in chondrocyte metabolism. Some authors reported that electromagnetic fields (EMFs) can positively interfere with patients affected by OA, even though the nature of the interaction is still debated. Human primary osteoarthritic chondrocytes isolated from the femoral heads of OA-patients undergoing to total hip replacement, were cultured in vitro and exposed 30?min/day for two weeks to extremely-low-frequency electromagnetic field (ELF) with fixed frequency (100?Hz) and to therapeutic application of musically modulated electromagnetic fields (TAMMEF) with variable frequencies, intensities and waveforms. Sham-exposed (S.E.) cells served as control group. Cell viability was measured at days 2, 7 and 14. After two weeks, cell lysates were processed using a proteomic approach. Chondrocyte exposed to ELF and TAMMEF system demonstrated different viability compared to untreated chondrocytes (S.E.). Proteome analysis of 2D-Electrophoresis and protein identification by mass spectrometry showed different expression of proteins derived from nucleus, cytoplasm and organelles. Function analysis of the identified proteins showed changes in related-proteins metabolism (glyceraldeyde-3-phosphate-dehydrogenase), stress response (Mn-superoxide-dismutase, heat-shock proteins), cytoskeletal regulation (actin), proteinase inhibition (cystatin-B) and inflammation regulatory functions (S100-A10, S100-A11) among the experimental groups (ELF, TAMMEF and S.E.). In conclusion, EMFs do not cause damage to chondrocytes, besides stimulate safely OA-chondrocytes and are responsible of different protein expression among the three groups. Furthermore, protein analysis of OA-chondrocytes treated with ELF and the new TAMMEF systems could be useful to clarify the pathogenetic mechanisms of OA by identifying biomarkers of the disease.     

Modulation of murine osteoarthritis

Up to nine out of 10 male STR/ORT mice develop osteoarthritis (OA) of the medial tibial cartilage at an early age. This has now been shown to be related to changes in the activity and distribution of monoamine oxidase which is related to the metabolism of catecholamines. Treatment with diclofenac sodium tended to normalize this activity but there was no significant histological improvement. It was therefore postulated that two influences were involved in the development of OA: a cellular and an extracellular factor. The first was improved by diclofenac sodium; the second, namely oedema of the matrix, was improved by tribenoside. In very preliminary studies, feeding the two drugs simultaneously resulted in 7/9 mice having no sign of OA.     

Partitioning of knee joint internal forces in gait is dictated by the knee adduction angle and not by the knee adduction moment

Medial knee osteoarthritis is a debilitating disease. Surgical and conservative interventions are performed to manage its progression via reduction of load on the medial compartment or equivalently its surrogate measure, the external adduction moment. However, some studies have questioned a correlation between the medial load and adduction moment. Using a musculoskeletal model of the lower extremity driven by kinematics–kinetics of asymptomatic subjects at gait midstance, we aim here to quantify the relative effects of changes in the knee adduction angle versus changes in the adduction moment on the joint response and medial/lateral load partitioning. The reference adduction rotation of 1.6° is altered by ±1.5° to 3.1° and 0.1° or the knee reference adduction moment of 17 N m is varied by ±50% to 25.5 N m and 8.5 N m. Quadriceps, hamstrings and tibiofemoral contact forces substantially increased as adduction angle dropped and diminished as it increased. The medial/lateral ratio of contact forces slightly altered by changes in the adduction moment but a larger adduction rotation hugely increased this ratio from 8.8 to a 90 while in contrast a smaller adduction rotation yielded a more uniform distribution. If the aim in an intervention is to diminish the medial contact force and medial/lateral load ratio, a drop of 1.5° in adduction angle is much more effective (causing respectively 12% and 80% decreases) than a reduction of 50% in the adduction moment (causing respectively 4% and 13% decreases). Substantial role of changes in adduction angle is due to the associated alterations in joint nonlinear passive resistance. These findings explain the poor correlation between knee adduction moment and tibiofemoral compartment loading during gait suggesting that the internal load partitioning is dictated by the joint adduction angle.     

Evaluation of knee functional calibration with and without the effect of soft tissue artefact

Functional calibration methods were devised to improve repeatability and accuracy of the knee flexion–extension axis, which is used to define the medio-lateral axis of the femur coordinate system in gait analysis. Repeatability of functional calibration methods has been studied extensively in healthy individuals, but not accuracy in the absence of a benchmark knee axis. We captured bi-plane fluoroscopy data of the knee joint in 17 subjects with unilateral total knee arthroplasty during treadmill walking. The prosthesis provided a benchmark knee axis to evaluate the functional calibration methods. Stereo-photogrammetry data of thigh and shank marker clusters were captured simultaneously to investigate the effect of soft tissue artefact (STA). Three methods were tested, the Axis Transformation Technique (ATT) finds the best single fixed axis of rotation, 2DofKnee finds the axis that minimises knee varus–valgus and trajAJC finds the axis perpendicular to the trajectory, in the transverse plane of the femur, of a point located on the longitudinal axis of the tibia. Using fluoroscopy data, functional axes formed an angle of less than 2° in the transverse plane with the benchmark axis. True internal–external range of movement was correlated with decreased accuracy for ATT, while varus–valgus range of movement was correlated with decreased accuracy for 2DofKnee and trajAJC. STA had negative impact on accuracy and variability. Using stereo-photogrammetry data, the accuracy of 2DofKnee was 1.7°(SD: 5.1°), smaller than ATT 2.9°(SD: 5.1°) but not to trajAJC 1.7°(SD: 5.2°). Our results confirm that of previous studies, which utilised the femur condylar axis as reference.     

Biomechanical mechanism of lateral trunk lean gait for knee osteoarthritis patients

The biomechanical mechanism of lateral trunk lean gait employed to reduce external knee adduction moment (KAM) for knee osteoarthritis (OA) patients is not well known. This mechanism may relate to the center of mass (COM) motion. Moreover, lateral trunk lean gait may affect motor control of the COM displacement. Uncontrolled manifold (UCM) analysis is an evaluation index used to understand motor control and variability of the motor task. Here we aimed to clarify the biomechanical mechanism to reduce KAM during lateral trunk lean gait and how motor variability controls the COM displacement. Twenty knee OA patients walked under two conditions: normal and lateral trunk lean gait conditions. UCM analysis was performed with respect to the COM displacement in the frontal plane. We also determined how the variability is structured with regards to the COM displacement as a performance variable. The peak KAM under lateral trunk lean gait was lower than that under normal gait. The reduced peak KAM observed was accompanied by medially shifted knee joint center, shortened distance of the center of pressure to knee joint center, and shortened distance of the knee–ground reaction force lever arm during the stance phase. Knee OA patients with lateral trunk lean gait could maintain kinematic synergy by utilizing greater segmental configuration variance to the performance variable. However, the COM displacement variability of lateral trunk lean gait was larger than that of normal gait. Our findings may provide clinical insights to effectively evaluate and prescribe gait modification training for knee OA patients.     

Correlation between translational and rotational kinematic abnormalities and osteoarthritis-like damage in two in vivo sheep injury models

The relations between kinematic abnormalities and post traumatic osteoarthritis have not yet been clearly elucidated. This study was conducted to determine the finite helical axes parameters and the tibiofemoral translation vector in the knee joints of two surgically induced injury sheep models: anterior cruciate ligament and medial collateral ligament transection (ACL/MCL Tx) (n = 5) and lateral meniscectomy (n = 5). We hypothesized that morphological damage in the experimental joints would be correlated to alterations in these kinematic variables. There was no strong evidence that morphological damage to the joints 20 weeks post ACL/MCL transection or meniscectomy was correlated with alterations in the finite helical axes variables. Nevertheless, significant correlations were found between the morphological damage to the joints and the magnitude of the change in the translation vectors after ACL/MCL transection (significant correlations (p = 0.005) during stance and trends (p < 0.1) at all points analyzed during swing). It can be concluded that: (1) osteoarthritic-like morphological damage after ACL/MCL transection is more critically correlated to the absolute tibiofemoral translational change and (2) alterations in analyzed kinematic variables cannot solely define osteoarthritis risk after meniscal injuries. From a clinical perspective, our results suggest that the magnitude of the change in the translation vector, which is independent of the coordinate system and combines the effects of the three translational degrees of freedom, i.e. medial–lateral, anterior-posterior and inferior-superior, would be an osteoarthritis risk factor after ligament injury, and requires validation in humans.     

Quantified in vitro tibiofemoral contact during bodyweight back squats

Squats are a common lower extremity task used in strength and conditioning, balance training, and rehabilitation. It is important to understand how slight alterations in lower extremity kinematics during a squat affect the internal joint loading of the knee. This study directly quantified tibiofemoral contact throughout the in vitro simulation of a bodyweight back squat performed two ways: a heel squat (knees in line with toes) and a toe squat (knees anterior to the toes) at peak knee flexion. Three cadaveric right lower extremities were instrumented and positioned into the University of Texas Joint Load Simulator. Kinematics, kinetics, and predicted muscle forces from a 20-year-old athletic male performing the two back squats were used as inputs for the in vitro simulations. The quantified tibiofemoral contact area, peak pressure, net force, and center of pressure location were significantly different between squat types (p > 0.05). Net contact area on the tibial plateau at peak knee flexion was significantly larger in the heel versus toe squat (599 ± 80 mm² vs. 469 ± 125 mm²; p < 0.05). Peak lateral pressure was significantly higher in the heel versus toe squat (2.73 ± 0.54 MPa vs. 0.87 ± 0.56 MPa; p < 0.05). Results suggest the heel squat generates an even load distribution, which is less likely to affect joint degeneration. Future in vitro simulations should quantify the effects lower extremity kinematics, kinetics, and individual muscle forces have on tibiofemoral contact parameters during common athletic tasks.     

Validation of method for analysing mechanics of unloader brace for medial knee osteoarthritis

Unloader braces are one non-invasive treatment of knee osteoarthritis, which primarily function by applying an external abduction moment to the joint to reduce loads in the medial compartment of the knee. We developed a novel method using brace deflection to estimate the mechanical effect of valgus braces and validated this model using strain gauge instrumentation.Three subjects performed static and walking trials, in which the moment applied by an instrumented brace was calculated using the deflection and strain methods. The deflection method predicted average brace moments of 8.7 Nm across static trials; mean error between the deflection model predictions and the gold-standard strain gauge measurements was 0.32 Nm. Mean brace moment predictions throughout gait ranged from 7.1 to 8.7 Nm using the deflection model. Maximum differences (MAE) over the gait cycle in mean and peak brace moments between methods were 1.50 Nm (0.96) and 0.60 Nm (0.42).Our proposed method enables quantification of brace abduction moments without the use of custom instrumentation. While the deflection-based method is similar to that implemented by Schmalz et al. (2010), the proposed method isolates abduction deflection from the 3 DOF angular changes that occur within the brace. Though the model should be viewed with more caution during swing (MAE = 1.16 Nm), it was shown that the accuracy is influenced by the uncertainty in angle measurement due to cluster spacing. In conclusion, the results demonstrate that the deflection-based method developed can predict comparable brace moments to those of the previously established strain method.