Maximum recovery after knee replacement - the MARKER study rationale and protocol

Background There is little scientific evidence to support the usual practice of providing outpatient rehabilitation to patients undergoing total knee replacement surgery (TKR) immediately after discharge from the orthopaedic ward. It is hypothesised that the lack of clinical benefit is due to the low exercise intensity tolerated at this time, with patients still recovering from the effects of major orthopaedic surgery. The aim of the proposed clinical trial is to investigate the clinical and cost effectiveness of a novel rehabilitation strategy, consisting of an initial home exercise programme followed, approximately six weeks later, by higher intensity outpatient exercise classes. Methods/Design In this multicentre randomised controlled trial, 600 patients undergoing primary TKR will be recruited at the orthopaedic pre-admission clinic of 10 large public and private hospitals in Australia. There will be no change to the medical or rehabilitative care usually provided while the participant is admitted to the orthopaedic ward. After TKR, but prior to discharge from the orthopaedic ward, participants will be randomised to either the novel rehabilitation strategy or usual rehabilitative care as provided by the hospital or recommended by the orthopaedic surgeon. Outcomes assessments will be conducted at baseline (pre-admission clinic) and at 6 weeks, 6 months and 12 months following randomisation. The primary outcomes will be self-reported knee pain and physical function. Secondary outcomes include quality of life and objective measures of physical performance. Health economic data (health sector and community service utilisation, loss of productivity) will be recorded prospectively by participants in a patient diary. This patient cohort will also be followed-up annually for five years for knee pain, physical function and the need or actual incidence of further joint replacement surgery. Discussion The results of this pragmatic clinical trial can be directly implemented into clinical practice. If beneficial, the novel rehabilitation strategy of utilising outpatient exercise classes during a later rehabilitation phase would provide a feasible and potentially cost-effective intervention to optimise the physical well-being of the large number of people undergoing TKR.

Aggravation of ADAMTS and MMP production and ERK1/2 pathway in the interaction of osteoarthritic subchondral bone osteoblasts and articular cartilage chondrocytes : a possible pathogenic role in osteoarthritis

Introduction: Degradative enzymes, such as A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinases (MMPs), play key roles in osteoarthritis (OA) development. The aim of the present study was to investigate if cross-talk between subchondral bone osteoblasts (SBOs) and articular cartilage chondrocytes (ACCs) in OA alters the expression and regulation of ADAMTS5, ADAMTS4, MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13, and also to test the possible involvement of mitogen activated protein kinase (MAPK) signaling pathway during this process. Methods: ACCs and SBOs were isolated from normal and OA patients. An in vitro co-culture model was developed to study the regulation of ADAMTS and MMPs under normal and OA joint cross-talk conditions. MAPK-ERK inhibitor, PD98059 was applied to delineate the involvement of specific pathway during this interaction process. Results: Indirect co-culture of OA SBOs with normal ACCs resulted in significantly increased expression of ADAMTS5, ADAMTS4, MMP-2, MMP-3 and MMP-9 in ACCs, whereas co-culture of OA ACCs led to increased MMP-1 and MMP-2 expression in normal SBOs. The upregulation of ADAMTS and MMPs under these conditions was correlated with activation of the MAPK-ERK1/2 signaling pathway and the addition of the MAPK-ERK inhibitor, PD98059, reversed the overexpression of ADAMTS and MMPs in co-cultures. Conclusion: In summary, we believe, these results add to the evidence that in human OA, altered bi-directional signals transmitted between SBOs and ACCs significantly impacts the critical features of both cartilage and bone by producing abnormal levels of ADAMTS and MMPs. Furthermore, we have demonstrated for the first time that this altered cross-talk was mediated by the phosphorylation of MAPK-ERK1/2 signaling pathway.

The Biodex Isokinetic Dynamometer for knee strength assessment in children : advantages and limitations

Objective: To critically appraise the Biodex System 4 isokinetic dynamometer for strength assessment of children. Methods: Appraisal was based on experiences from two independent laboratories involving testing of 213 children. Issues were recorded and the manufacturer was consulted regarding appropriate solutions. Results: The dynamometer had insufficient height adjustment for alignment of the knee for some children, requiring the construction of padding to better fit the child within the dynamometer. Potential for entrapment of the non-testing leg was evident in the passive and eccentric modes and a leg bracket restraint was constructed. Automated gravity correction did not operate when protocols were linked or data was exported to an external device. Conclusions: Limitations were noted, some of which were applicable to knee strength testing in general and others which were specific to use with children. However, most of these obstacles could be overcome, making the Biodex System 4 suitable for assessment of knee strength in children.

Effects of cold water immersion on knee joint position sense in healthy volunteers

The purpose of this study was to determine the effects of cryotherapy, in the form of cold water immersion, on knee joint position sense. Fourteen healthy volunteers, with no previous knee injury or pre-existing clinical condition, participated in this randomized cross-over trial. The intervention consisted of a 30-min immersion, to the level of the umbilicus, in either cold (14 ± 1°C) or tepid water(28 ± 1°C). Approximately one week later, in a randomized fashion, the volunteers completed the remaining immersion. Active ipsilateral limb repositioning sense of the right knee was measured, using weight-bearing and non-weight bearing assessments, employing video-recorded 3D motion analysis. These assessments were conducted immediately before and after a cold and tepid water immersion. No significant differences were found between treatments for the absolute (P = 0.29), relative (P = 0.21) or variable error (P = 0.86). The average effect size of the outcome measures was modest (range –0.49 to 0.9) and all the associated 95% confidence intervals for these effect sizes crossed zero. These results indicate that there is no evidence of an enhanced risk of injury, following a return to sporting activity, after cold water.

Effects of oxygen on zonal marker expression in human articular chondrocytes

Articular cartilage is organized in depth zones with phenotypically distinct subpopulations of chondrocytes that are exposed to different oxygen tensions. Despite growing evidence of the critical role for oxygen in chondrogenesis, little is known about its effect on chondrocytes from different zones. This study evaluates zonal marker expression of human articular chondrocytes from different zones under various oxygen tensions. Chondrocytes isolated from full-thickness, superficial, and middle/deep cartilage from knee replacement surgeries were expanded and redifferentiated under hypoxic (5% O 2) or normoxic (20% O 2) conditions. Differentiation under hypoxia increased expression of hypoxia-inducible factors 1alpha and 2alpha and accumulation of extracellular matrix, particularly in middle/deep chondrocytes, and favored re-expression of proteoglycan 4 by superficial chondrocytes compared with middle/deep cells. Zone-dependent expression of clusterin varied with culture duration. These results demonstrate that zonal chondrocytes retain important phenotypic differences during in vitro cultivation, and that these characteristics can be improved by altering the oxygen environment. However, transcript levels for pleiotrophin, cartilage intermediate layer protein, and collagen type X were similar between zones, challenging their reliability as zonal markers for tissue-engineered cartilage from osteoarthritis patients. Key factors including oxygen tension and cell source should be considered to prescribe zone-specific properties to tissue-engineered cartilage. © 2012, Mary Ann Liebert, Inc.

Dynamic compression improves biosynthesis of human zonal chondrocytes from osteoarthritis patients

Objective: We hypothesize that chondrocytes from distinct zones of articular cartilage respond differently to compressive loading, and that zonal chondrocytes from osteoarthritis (OA) patients can benefit from optimized compressive stimulation. Therefore, we aimed to determine the transcriptional response of superficial (S) and middle/deep (MD) zone chondrocytes to varying dynamic compressive strain and loading duration. To confirm effects of compressive stimulation on overall matrix production, we subjected zonal chondrocytes to compression for 2 weeks. Design: Human S and MD chondrocytes from osteoarthritic joints were encapsulated in 2% alginate, pre-cultured, and subjected to compression with varying dynamic strain (5, 15, 50% at 1 Hz) and loading duration (1, 3, 12 h). Temporal changes in cartilage-specific, zonal, and dedifferentiation genes following compression were evaluated using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). The benefits of long-term compression (50% strain, 3 h/day, for 2 weeks) were assessed by measuring construct glycosaminoglycan (GAG) content and compressive moduli, as well as immunostaining. Results: Compressive stimulation significantly induced aggrecan (ACAN), COL2A1, COL1A1, proteoglycan 4 (PRG4), and COL10A1 gene expression after 2 h of unloading, in a zone-dependent manner (P < 0.05). ACAN and PRG4 mRNA levels depended on strain and load duration, with 50% and 3 h loading resulting in highest levels (P < 0.05). Long-term compression increased collagen type II and ACAN immunostaining and total GAG (P < 0.05), but only S constructs showed more PRG4 stain, retained more GAG (P < 0.01), and developed higher compressive moduli than non-loaded controls. Conclusions: The biosynthetic activity of zonal chondrocytes from osteoarthritis joints can be enhanced with selected compression regimes, indicating the potential for cartilage tissue engineering applications. © 2012 Osteoarthritis Research Society International.

Non-destructive evaluation of articular cartilage defects using near-infrared (NIR) spectroscopy in osteoarthritic rat models and its direct relation to Mankin Score

Objective The aim of this study was to demonstrate the potential of near-infrared (NIR) spectroscopy for categorizing cartilage degeneration induced in animal models. Method Three models of osteoarthritic degeneration were induced in laboratory rats via one of the following methods: (i) menisectomy (MSX); (ii) anterior cruciate ligament transaction (ACLT); and (iii) intra-articular injection of mono-ido-acetete (1 mg) (MIA), in the right knee joint, with 12 rats per model group. After 8 weeks, the animals were sacrificed and tibial knee joints were collected. A custom-made nearinfrared (NIR) probe of diameter 5 mm was placed on the cartilage surface and spectral data were acquired from each specimen in the wavenumber range 4 000 – 12 500 cm−1. Following spectral data acquisition, the specimens were fixed and Safranin–O staining was performed to assess disease severity based on the Mankin scoring system. Using multivariate statistical analysis based on principal component analysis and partial least squares regression, the spectral data were then related to the Mankinscores of the samples tested. Results Mild to severe degenerative cartilage changes were observed in the subject animals. The ACLT models showed mild cartilage degeneration, MSX models moderate, and MIA severe cartilage degenerative changes both morphologically and histologically. Our result demonstrate that NIR spectroscopic information is capable of separating the cartilage samples into different groups relative to the severity of degeneration, with NIR correlating significantly with their Mankinscore (R2 = 88.85%). Conclusion We conclude that NIR is a viable tool for evaluating articularcartilage health and physical properties such as change in thickness with degeneration.