Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Objective. Osteoarthritis (OA) is accompanied by subchondral bone sclerosis. The present study was undertaken to determine whether osteoblast-like cells in patients with OA show an abnormal phenotype that could contribute to this sclerosis. Methods. Explants and primary in vitro osteoblast-like cell cultures were prepared from sub-chondral bone specimens from OA patients or from bone removed at autopsy from individuals showing no signs of OA or metabolic bone disease. We measured the abundance and activity of urokinase plasminogen acti-vator (uPA), and the levels of PA inhibitor (PAI-1) and insulin-like growth factor 1 (IGF-1) in conditioned media from both explants and osteoblast-like cells. The expression of osteoblast phenotypic biomarkers was also evaluated. Results. OA explants showed increased levels and activity of uPA, no changes in PAI-1 abundance, and increases in IGF-1 release, as compared with preparations from normal individuals. In vitro primary osteoblast-like cells showed results similar to the ex vivo findings for uPA, PAI-1, and IGF-1. Primary OA osteoblast-like cells also expressed higher alkaline phosphatase activity and osteocalcin release than normal cells, both under basal conditions and with 1,25(OH),D, (1,25-dihydroxyvitamin D) stimulation. Conversely, OA osteoblast-like cells showed blunted CAMP synthesis in response to human parathyroid hormone and prostaglandin E, in contrast to the finding with normal osteoblast-like cells, a result that could not be attributed to altered adenylate cyclase activity. Conclusion. Ex vivo and in vitro results indicate similar altered activities of OA osteoblasts as compared with normal cells. This suggests that an altered phenotype of subchondral osteoblasts may be a contributing factor in human OA. Osteoarthritis (OA) is the leading cause of disability among persons over 65 in the general population (1). Although major progress has been made in the last few years (2,3), we still have much to learn about the etiology, pathogenesis, and progression of this disease. Factors such as the slow progression and the multifac-torial nature of the disease have limited our comprehension of OA. However, we do know that it involves changes in articular cartilage and surrounding bone, and an imbalance between loss of cartilage (due to matrix degradation) and an attempt to repair this matrix (4 3. The specific interaction between bone and cartilage is still not clearly defined, nor do we know why chondro-cytes cannot adequately repair the cartilage matrix. OA can be described as the degradation and loss of articular cartilage, accompanied by hypertrophic bone changes
BackgroundRehabilitation provided through home visits is part of the continuum of care after discharge from hospital following total knee arthroplasty (TKA). As demands for rehabilitation at home are growing and becoming more difficult to meet, in-home telerehabilitation has been proposed as an alternate service delivery method. However, there is a need for robust data concerning both the effectiveness and the cost of dispensing in-home telerehabilitation.ObjectiveThe objective of this study was to document, analyze, and compare real costs of two service delivery methods: in-home telerehabilitation and conventional home visits.MethodsThe economic analysis was conducted as part of a multicenter randomized controlled trial (RCT) on telerehabilitation for TKA, and involved data from 197 patients, post-TKA. Twice a week for 8 weeks, participants received supervised physiotherapy via two delivery methods, depending on their study group allocation: in-home telerehabilitation (TELE) and home-visit rehabilitation (VISIT). Patients were recruited from eight hospitals in the province of Quebec, Canada. The TELE group intervention was delivered by videoconferencing over high-speed Internet. The VISIT group received the same intervention at home. Costs related to the delivery of the two services (TELE and VISIT) were calculated. Student’s t tests were used to compare costs per treatment between the two groups. To take distance into account, the two treatment groups were compared within distance strata using two-way analyses of variance (ANOVAs).ResultsThe mean cost of a single session was Can $93.08 for the VISIT group (SD $35.70) and $80.99 for the TELE group (SD $26.60). When comparing both groups, real total cost analysis showed a cost differential in favor of the TELE group (TELE minus VISIT: -$263, 95% CI -$382 to -$143). However, when the patient’s home was located less than 30 km round-trip from the health care center, the difference in costs between TELE and VISIT treatments was not significant (P=.25, .26, and .11 for the <10, 10-19, and 20-29 km strata, respectively). The cost of TELE treatments was lower than VISIT treatments when the distance was 30 km or more (30-49 km: $81<$103, P=.002; ≥50 km: $90<$152, P<.001).ConclusionsTo our knowledge, this is the first study of the actual costs of in-home telerehabilitation covering all subcosts of telerehabilitation and distance between the health care center and the patient’s home. The cost for a single session of in-home telerehabilitation compared to conventional home-visit rehabilitation was lower or about the same, depending on the distance between the patient’s home and health care center. Under the controlled conditions of an RCT, a favorable cost differential was observed when the patient was more than 30 km from the provider. Stakeholders and program planners can use these data to guide decisions regarding introducing telerehabilitation as a new service in their clinic.Trial RegistrationInternational Standard Registered Clinical Study Number (ISRCTN): 66285945; ...
Objective To determine the effects of peroxisome proliferator–activated receptor γ (PPARγ) agonists on interleukin‐1 (IL‐1) induction of nitric oxide (NO) and matrix metalloproteinase 13 (MMP‐13) in human chondrocytes. Methods PPARγ expression and synthesis in human chondrocytes were determined by reverse transcriptase–polymerase chain reaction (RT‐PCR) and immunohistochemistry, respectively. Chondrocytes were cultured with IL‐1β, tumor necrosis factor α (TNFα), and IL‐17 in the presence or absence of PPARγ agonists, and NO and MMP‐13 synthesis and expression levels were measured. Transient transfection experiments were performed with the 7‐kb inducible NO synthase (iNOS) and 1.6‐kb MMP‐13 human promoters, as well as with the PPARγ expression vector and the activator protein 1 (AP‐1) and nuclear factor κB (NF‐κB) reporter constructs. Results RT‐PCR and immunohistochemical analysis revealed that human chondrocytes expressed and produced PPARγ. Treatment of chondrocytes with PPARγ ligands BRL 49653 and 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2), but not with PPARα ligand Wy 14643, decreased IL‐1β–induced NO and MMP‐13 production in a dose‐dependent manner. In addition, both iNOS and MMP‐13 messenger RNA were inhibited in the presence of 15d‐PGJ2. The inhibitory effect of PPARγ activation was not restricted to IL‐1β, since TNFα‐ and IL‐17–induced NO and MMP‐13 production were also inhibited by 15d‐PGJ2. In transient transfection experiments, we showed that a constitutively active form of mitogen‐activated protein kinase kinase kinase 1 (ΔMEKK‐1) induced the MMP‐13 and iNOS human promoter activity. This process was reduced by 15d‐PGJ2 and further inhibited by cotransfection with a PPARγ expression vector. Similarly, in a PPARγ‐dependent manner, 15d‐PGJ2 inhibited ΔMEKK‐1–induced AP‐1– and NF‐κB–luciferase reporter plasmid activation. Conclusion The findings of this study demonstrate that PPARγ agonists inhibit IL‐1β induction of both NO and MMP‐13 in human chondrocytes. The inhibition occurs at least at the transcriptional level through a PPARγ‐dependent pathway, probably by interfering with the activation of AP‐1 and NF‐κB.
Objective. The lipid peroxidation product 4-hydroxynonenal (HNE) is prominently produced in osteoarthritic (OA) synovial cells, but its specific contribution to cartilage destruction is not understood. This study was designed to test whether HNE signaling and binding are involved in OA cartilage degradation through type II collagen (CII) and matrix metalloproteinase 13 (MMP-13) modulation.Methods. HNE levels in synovial fluid and in isolated OA chondrocytes treated with free radical donors were determined by enzyme-linked immunosorbent assay. The formation of the HNE/CII adducts was measured in cartilage explants by immunoprecipitation. Levels of CII and MMP-13 messenger RNA and protein were determined by reverse transcription-polymerase chain reaction, Western blotting, and by the use of commercial kits.Results. Levels of HNE/protein adducts were higher in OA synovial fluid compared with normal synovial fluid and were higher in OA chondrocytes treated with free radical donors compared with untreated cells. In cartilage explants, HNE induced CII cleavage, as established by the generation of neoepitopes. The level of HNE/CII adducts was increased in OA cartilage explants incubated with free radical donors. Modification of CII by HNE accelerated its degradation by active MMP-13. In isolated OA chondrocytes, HNE inhibited the expression of CII and tissue inhibitor of metalloproteinases 1 and induced MMP-13 mainly through activation of p38 MAPK. In vitro, HNE binding to MMP-13 activated this enzyme at a molar ratio of 1:100 (MMP-13 to HNE).Conclusion. The increased level of HNE in OA cartilage and the ability of HNE to induce transcriptional and posttranslational modifications of CII and MMP-13 suggest that this aldehyde could play a role in OA.The deterioration and loss of articular cartilage that lead to the irreversible impairment of joint motion are the final pathogenic events common to osteoarthritis (OA). This progressive condition develops in response to mechanical and environmental stimuli and is orchestrated by growth factors and cytokines, which act through several signaling cascades (1-3).Cartilage extracellular matrix (ECM) consists of 2 major components: type II collagen (CII) and proteoglycan aggregates, which are composed of a noncovalent association between aggrecan, hyaluronate, and link protein (4,5). In OA, proteoglycan degradation is thought to be an early and reversible process, whereas the breakdown of the collagen network is believed to be irreversible (6-8). To maintain a healthy collagen network, chondrocytes continuously remodel the ECM, albeit slowly (9,10). Changes in the capacity of chondrocytes to maintain the collagen network are likely to
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