Skeletal muscle plasticity is reflected by a dynamic balance between protein synthesis and breakdown, with basal muscle tissue protein synthesis rates ranging between 0.02 and 0.09%/h. Though it is ...evident that other musculoskeletal tissues should also express some level of plasticity, data on protein synthesis rates of most of these tissues in vivo in humans is limited. Six otherwise healthy patients (62±3 y), scheduled to undergo unilateral total knee arthroplasty, were subjected to primed continuous intravenous infusions with L-ring-13C6-Phenylalanine throughout the surgical procedure. Tissue samples obtained during surgery included muscle, tendon, cruciate ligaments, cartilage, bone, menisci, fat, and synovium. Tissue-specific fractional protein synthesis rates (%/h) were assessed by measuring the incorporation of L-ring-13C6-Phenylalanine in tissue protein and were compared with muscle tissue protein synthesis rates using a paired t test. Tendon, bone, cartilage, Hoffa's fat pad, anterior and posterior cruciate ligament, and menisci tissue protein synthesis rates averaged 0.06±0.01, 0.03±0.01, 0.04±0.01, 0.11±0.03, 0.07±0.02, 0.04±0.01, and 0.04±0.01%/h, respectively, and did not significantly differ from skeletal muscle protein synthesis rates (0.04±0.01%/h; P>0.05). Synovium derived protein (0.13±0.03%/h) and intercondylar notch bone tissue protein synthesis rates (0.03±0.01%/h) were respectively higher and lower compared to skeletal muscle protein synthesis rates (P<0.05 and P<0.01, respectively). Basal protein synthesis rates in various musculoskeletal tissues are within the same range of skeletal muscle protein synthesis rates, with fractional muscle, tendon, bone, cartilage, ligament, menisci, fat, and synovium protein synthesis rates ranging between 0.02 and 0.13% per hour in vivo in humans. Clinical trial registration: NTR5147.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cartilage defects in the knee are often seen in young and active patients. There is a need for effective joint preserving treatments in patients suffering from cartilage defects, as untreated defects ...often lead to osteoarthritis. Within the last two decades, tissue engineering based techniques using a wide variety of polymers, cell sources, and signaling molecules have been evaluated. We start this review with basic background information on cartilage structure, its intrinsic repair, and an overview of the cartilage repair treatments from a historical perspective. Next, we thoroughly discuss polymer construct components and their current use in commercially available constructs. Finally, we provide an in-depth discussion about construct considerations such as degradation rates, cell sources, mechanical properties, joint homeostasis, and non-degradable/hybrid resurfacing techniques. As future prospects in cartilage repair, we foresee developments in three areas: first, further optimization of degradable scaffolds towards more biomimetic grafts and improved joint environment. Second, we predict that patient-specific non-degradable resurfacing implants will become increasingly applied and will provide a feasible treatment for older patients or failed regenerative treatments. Third, we foresee an increase of interest in hybrid construct, which combines degradable with non-degradable materials.
We aimed to evaluate the prevalence of hip and knee osteoarthritis (HOA and KOA) according to American College of Rheumatology (ACR) criteria among participants with suspected early symptomatic ...osteoarthritis (OA) in the CHECK cohort. We also assessed whether participants not fulfilling ACR criteria at baseline develop ACR-defined OA at 2-year and/or 5-year follow up, and which baseline factors are associated with this development.
The CHECK cohort included 1002 subjects with first presentation of knee and/or hip complaints. The primary outcome was onset of HOA and/or KOA according to the ACR criteria, including the clinical classification criteria and the combined clinical and radiographic classification criteria at 2-year and/or 5-year follow up.
Of the participants with hip complaints, 63% (n = 370) were classified as having HOA at baseline according to the ACR criteria. Of those not classified with HOA at baseline, 40% developed HOA according to the clinical or combined clinical/radiographic ACR criteria after 2 and/or 5 years. Up to 92% of participants (n = 829) with knee complaints were classified as having KOA at baseline; of those not classified with KOA at baseline, 55% developed KOA according to the clinical ACR criteria or the clinical/radiographic ACR criteria after 2 and/or 5 years. The following factors were associated with development of HOA: morning stiffness (OR 2.39; 95% CI 1.14-4.98), painful internal rotation (OR 2.53; 95% CI 1.23-5.19), hip flexion < 115° (OR 2.33; 95% CI 1.17-4.64) and erythrocyte sedimentation rate (ESR) < 20 mm/h (OR 2.94; 95% CI 1.13-7.61). No variables were associated with development of KOA at 2-year and/or 5-year follow up.
A large proportion of persons with hip complaints not fulfilling the ACR criteria at baseline develop HOA after 2 and/or 5 years of follow up. Almost all persons with knee complaints already fulfill the clinical and/or radiographic ACR criteria for OA, and half of the persons not fulfilling criteria at baseline will do so after 5 years of follow up. Several individual ACR criteria for HOA at baseline were associated with the development of HOA at follow up. This association was not proven for KOA, probably because of the small number of subjects developing KOA in this study.
In this study, we investigated the potential of celecoxib-loaded polyester amide (PEA) microspheres as an auto-regulating drug delivery system for the treatment of pain associated with knee ...osteoarthritis (OA). Celecoxib release from PEA microspheres and inflammation responsive release of a small molecule from PEA was investigated in vitro. Inflammation responsive release of a small molecule from PEA was observed when PEA was exposed to cell lysates obtained from a neutrophil-like Hl-60 cell line. Following a short initial burst release of ~15% of the total drug load in the first days, celecoxib was slowly released throughout a period of >80days. To investigate biocompatibility and degradation behavior in vivo, celecoxib-loaded PEA microspheres were injected in OA-induced (ACLT+pMMx) or contralateral healthy knee joints of male Lewis rats. Bioactivity of celecoxib from loaded PEA microspheres was confirmed by PGE2 measurements in total rat knee homogenates. Intra-articular biocompatibility was demonstrated histologically, where no cartilage damage or synovial thickening and necrosis were observed after intra-articular injections with PEA microspheres. Degradation of PEA microspheres was significantly higher in OA induced knees compared to contralateral healthy knee joints, while loading the PEA microspheres with celecoxib significantly inhibited degradation, indicating a drug delivery system with auto regulatory behavior. In conclusion, this study suggests the potential of celecoxib-loaded PEA microspheres to be used as a safe drug delivery system with auto regulatory behavior for treatment of pain associated with OA of the knee.
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Tissue Regeneration
The anterior cruciate ligament is characterized by its zonal structure. Electrospinning enables the fabrication of triphasic scaffolds that mimic the structure of the native ...ligament; with aligned and flattened extremes and an aligned and wavy core. In article 2203023 by Lorenzo Moroni and co‐workers, the different phases of the scaffold lead to distinct cellular arrangements and the formation of a coherent tissue in vitro and in vivo.
Background:
Focal cartilage defects are often debilitating, possess limited potential for regeneration, are associated with increased risk of osteoarthritis, and are predictive for total knee ...arthroplasty. Cartilage repair studies typically focus on the outcome in younger patients, but a high proportion of treated patients are 40 to 60 years of age (ie, middle-aged). The reality of current clinical practice is that the ideal patient for cartilage repair is not the typical patient. Specific attention to cartilage repair outcomes in middle-aged patients is warranted.
Purpose:
To systematically review available literature on knee cartilage repair in middle-aged patients and include studies comparing results across different age groups.
Study Design:
Systematic review; Level of evidence, 4.
Methods:
A systematic search was performed in EMBASE, MEDLINE, and the Cochrane Library database. Articles were screened for relevance and appraised for quality.
Results:
A total of 21 articles (mean Coleman Methodology Score, 64 points) were included. Two out of 3 bone marrow stimulation (BMS) studies, including 1 using the microfracture technique, revealed inferior clinical outcomes in middle-aged patients in comparison with younger patients. Nine cell-based studies were included showing inconsistent comparisons of results across age groups for autologous chondrocyte implantation (ACI). Bone marrow aspirate concentrate showed age-independent results at up to 8 years of follow-up. A negative effect of middle age was reported in 1 study for both ACI and BMS. Four out of 5 studies on bone-based resurfacing therapies (allografting and focal knee resurfacing implants FKRIs) showed age-independent results up to 5 years. One study in only middle-aged patients reported better clinical outcomes for FKRIs when compared with biological repairs.
Conclusion:
Included studies were heterogeneous and had low methodological quality. BMS in middle-aged patients seems to only result in short-term improvements. More research is warranted to elucidate the ameliorating effects of cell-based therapies on the aging joint homeostasis. Bone-based therapies seem to be relatively insensitive to aging and may potentially result in effective joint preservation. Age subanalyses in cohort studies, randomized clinical trials, and international registries should generate more evidence for the large but underrepresented (in terms of cartilage repair) middle-aged population in the literature.
Knee osteoarthritis (OA) is a condition mainly characterized by cartilage degradation. Currently, no effective treatment exists to slow down the progression of OA-related cartilage damage. Selective ...COX-2 inhibitors may, next to their pain killing properties, act chondroprotective in vivo. To determine whether the route of administration is important for the efficacy of the chondroprotective properties of selective COX-2 inhibitors, a systematic review was performed according to the PRISMA guidelines. Studies investigating OA-related cartilage damage of selective COX-2 inhibitors in vivo were included. Nine of the fourteen preclinical studies demonstrated chondroprotective effects of selective COX-2 inhibitors using systemic administration. Five clinical studies were included and, although in general non-randomized, failed to demonstrate chondroprotective actions of oral selective COX-2 inhibitors. All of the four preclinical studies using bolus intra-articular injections demonstrated chondroprotective actions, while one of the three preclinical studies using a slow release system demonstrated chondroprotective actions. Despite the limited evidence in clinical studies that have used the oral administration route, there seems to be a preclinical basis for considering selective COX-2 inhibitors as disease modifying osteoarthritis drugs when used intra-articularly. Intra-articularly injected selective COX-2 inhibitors may hold the potential to provide chondroprotective effects in vivo in clinical studies.
GPs have high consultation rates for symptoms related to knee osteoarthritis (OA). Many risk factors for symptomatic knee OA progression remain unknown.
To define distinct knee pain trajectories in ...individuals with early symptomatic knee OA and determine the risk factors for these pain trajectories.
Data were obtained from the multicentre prospective Cohort Hip and Cohort Knee study in the Netherlands. Participants with knee OA, according to the clinical criteria of the American College of Rheumatology, and a completed 5-year follow-up were included.
Baseline demographic, anamnestic, and physical examination characteristics were assessed. Outcome was annually assessed by the Numeric Rating Scale for pain. Pain trajectories were retrieved by latent class growth analysis. Multinomial logistic regression was used to calculate relative risk ratios.
In total, 705 participants were included. Six distinct pain trajectories were identified with favourable and unfavourable courses. Statistically significant differences were found in baseline characteristics, including body mass index (BMI), symptom severity, and pain coping strategies between the different trajectories. Higher BMI, lower level of education, greater comorbidity, higher activity limitation scores, and joint space tenderness were more often associated with trajectories characterised by more pain at first presentation and pain progression--compared with the reference group with a mild pain trajectory. No association was found for baseline radiographic features.
These results can help differentiate those patients who require more specific monitoring in the management of early symptomatic knee OA from those for whom a 'wait-and-see' policy seems justifiable. Radiography provided no additional benefit over clinical diagnosis of early symptomatic knee OA in general practice.
Anterior cruciate ligament (ACL) is the connective tissue providing mechanical stability to the knee joint. ACL reconstruction upon rupture remains a clinical challenge due to the high mechanical ...properties required for proper functioning. ACL owes its outstanding mechanical properties to the arrangement of the extracellular matrix (ECM) and to the cells with distinct phenotypes present along the length of the tissue. Tissue regeneration appears as an ideal alternative. In this study, a tri‐phasic fibrous scaffold that mimics the structure of collagen in the native ECM is developed, presenting a wavy intermediate zone and two aligned uncurled extremes. The mechanical properties of the wavy scaffolds present a toe region, characteristic of the native ACL, and an extended yield and ultimate strain compared to aligned scaffolds. The presentation of a wavy fiber arrangement affects cell organization and the deposition of a specific ECM characteristic of fibrocartilage. Cells cultured in wavy scaffolds grow in aggregates, deposit an abundant ECM rich in fibronectin and collagen II, and express higher amounts of collagen II, X, and tenomodulin as compared to aligned scaffolds. In vivo implantation in rabbits shows a high cellular infiltration and the formation of an oriented ECM compared to aligned scaffolds.
The anterior cruciate ligament is characterized by its zonal structure. Electrospinning enables the fabrication of triphasic scaffolds that mimic the structure of the native ligament; with aligned and flattened extremes and an aligned and wavy core. The different phases of the scaffold lead to distinct cellular arrangements and the formation of a coherent tissue in vitro and in vivo.
NF-κB/p65 has been reported to be involved in regulation of chondrogenic differentiation. However, its function in relation to key chondrogenic factor Sox9 and onset of chondrogenesis during ...endochondral ossification is poorly understood. We hypothesized that the early onset of chondrogenic differentiation is initiated by transient NF-κB/p65 signaling.
The role of NF-κB/p65 in early chondrogenesis was investigated in different in vitro, ex vivo and in vivo endochondral models: ATDC5 cells, hBMSCs, chicken periosteal explants and growth plates of 6 weeks old mice. NF-κB/p65 activation was manipulated using pharmacological inhibitors, RNAi and activating agents. Gene expression and protein expression analysis, and (immuno)histochemical stainings were employed to determine the role of NF-κB/p65 in the chondrogenic phase of endochondral development. Our data show that chondrogenic differentiation is facilitated by early transient activation of NF-κB/p65. NF-κB/p65-mediated signaling determines early expression of Sox9 and facilitates the subsequent chondrogenic differentiation programming by signaling through key chondrogenic pathways.
The presented data demonstrate that NF-κB/p65 signaling, as well as its intensity and timing, represents one of the transcriptional regulatory mechanisms of the chondrogenic developmental program of chondroprogenitor cells during endochondral ossification. Importantly, these results provide novel possibilities to improve the success of cartilage and bone regenerative techniques.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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