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Effects of glucocorticoids on chondrocytes and cartilageWallace, Chelsey 24 July 2018 (has links)
OBJECTIVE: Osteoarthritis (OA) is a leading cause of disability worldwide. This disease is characterized by the inflammation and degradation of the cartilage and surrounding tissue in a joint. The disease manifests as either a result of years of wear and tear or after a joint injury. Post-traumatic osteoarthritis, as this latter case is named, is frequently studied since the exact trigger of the disease is known. In addition to several changes within the joint space, a significant alteration is the degradation of cartilage caused primarily by the release of inflammatory cytokines including interleukin-1 and 6 and tumor necrosis factor α. One current pharmacological treatment for the pain caused by OA is an intra-articular injection of glucocorticoids such as dexamethasone. As this is a common treatment, the goal of this research was to determine if, at the cellular level, this treatment impacts cell viability in the presence of pro-inflammatory cytokines. Another goal was to investigate how such treatment affects the progression of cartilage degradation caused by cytokines. OA results in the loss of the key extracellular matrix molecule, aggrecan, which contains negatively charged glycosaminoglycan (GAG) chains. Measurement of the amount of GAGs lost is an early indicator of cartilage degradation. In addition, biosynthesis of GAG chains can be measured to estimate the overall metabolic health of the cells. We hypothesized that dexamethasone blunts the harmful effects of proinflammatory cytokines and improves GAG biosynthesis and chondrocyte viability.
METHODS: Cylindrical cartilage explants were collected from bovine knee joints and trimmed to a uniform 3 millimeters in diameter and 1 millimeter thick. Each treatment group consisted of n=6 explants from the same knee joint. In one set of experiments, these explants were subjected to two different doses of interleukin-1α (1 ng/mL and 10 ng/mL) with and without dexamethasone at 100 nM. In another set of experiments, explants were subjected to both interleukin-1α and tumor necrosis factor-α (1 ng/mL and 25 ng/mL respectively). The explants were cultured in medium for 6 days and were digested for outcome measurements on the final day. On day 4, 35S-sulfate was added to the explant medium for later measurement of radiolabel incorporation as a measure of GAG biosynthesis. Cell viability was measured on day 5 using red/green fluorescent viability dyes fluorescein diacetate (FDA) which stains live cells green and propidium iodide (PI) which stains dead cells red.
RESULTS: Compared with untreated controls, explants subjected to the pro-inflammatory cytokines interleukin-1α and tumor necrosis factor-α exhibited greater glycosaminoglycan loss and a decrease in GAG biosynthesis. These treatments also decreased cell viability. Addition of dexamethasone improved cell viability compared to treatment with the cytokines. In addition, dexamethasone prevented glycosaminoglycan loss and increased GAG biosynthesis in the presence of interleukin-1α. However, dexamethasone did not prevent tumor necrosis factor-α mediated loss of GAGs.
CONCLUSION: These studies demonstrated that dexamethasone inhibited specific aspects of cartilage degradation associated with inflammation in early OA. This therapeutic counteracts the degradative changes initiated by inflammatory cytokines such as interleukin-1α without compromising cell viability. Future studies are needed to identify the mechanisms of dexamethasone action and the ideal concentration to use if it is to be used as a treatment for OA following acute joint injury.
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Virtual pre-operative reconstruction planning for comminuted articular fracturesThomas, Thaddeus Paul 01 January 2010 (has links)
Highly comminuted intra-articular fractures are complex and difficult injuries to treat. Once emergent care is rendered, the definitive treatment objective is to restore the original anatomy while minimizing surgically induced trauma. Operations that use limited or percutaneous approaches help preserve tissue vitality, but reduced visibility makes reconstruction more difficult. A pre-operative plan of how comminuted fragments would best be re-positioned to restore anatomy helps in executing a successful reduction. The objective of this work was to create new virtual fracture reconstruction technologies that would deliver that information for a clinical series of severe intra-articular fractures. As a step toward clinical application, algorithmic development benefits from the availability of more precise and controlled data. Therefore, this work first developed 3D puzzle solving methods in a surrogate platform not confounded by various in vivo complexities. Typical tibial plafond fracture fragmentation/dispersal patterns were generated with five identical replicas of human distal tibia anatomy that were machined from blocks of high-density polyetherurethane foam (bone fragmentation surrogate). Replicas were fractured using an instrumented drop tower and pre- and post-fracture geometries were obtained using laser scans and CT. A semi-automatic virtual reconstruction computer program aligned fragment native surfaces to a pre-fracture template. After effective reconstruction algorithms were created for the surrogate tibias, the next aim was to develop new algorithms that would accommodate confounding biologic factors and puzzle solve clinical fracture cases. First, a novel image analysis technique was developed to segment bone geometries from pre- and post-surgical reduction CT scans using a modified 3D watershed segmentation algorithm. Next, 3D puzzle solving algorithms were advanced to obtain fracture reconstructions in a series of highly comminuted tibial plafond fracture cases. Each tibia was methodically reconstructed by matching fragment native (periosteal and articular) surfaces to an intact template that was created from a mirror image of the healthy contralateral limb. Virtual reconstructions obtained for ten tibial plafond fracture cases had average alignment errors of 0.39±0.5 mm. These novel 3D puzzle solving methods are a significant advancement toward improving treatment by providing a powerful new tool for planning the surgical reconstruction of comminuted articular fractures.
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Chondrogenic progenitor cell response to cartilage injury and its application for cartilage repairSeol, Dong Rim 01 July 2011 (has links)
Focal damage to cartilage sustained in serious joint injuries typically goes unrepaired and may progress to post-traumatic osteoarthritis. However, in a bovine explant model we found that cartilage damage provoked the emergence of highly migratory cells that homed to the site of injury and appeared to re-populate dead zones. We hypothesized that the migrating population were chondrogenic progenitor cells engaged in cartilage repair. The surfaces of bovine osteochondral explants injured by blunt impact were serially imaged to follow cell migration. Migrating cells harvested from cartilage surfaces were tested for clonogenic, side population, chemotactic activities and multipotency in in vitro assays. Gene expression in migrating cells was evaluated by microarray and their potential for spontaneous cartilage regeneration was assessed in a chondral defect model. Migrating cells emerged from superficial zone cartilage and efficiently repopulated areas where chondrocyte death had occurred. In confocal examination with high magnification, we could clearly observe the morphology of elongated progenitor cells which were migrating toward cartilage defect area and these cells were distinguishable from round chondrocytes. The cells were also activated to migrate in cartilage defect model. Most migrated cells in fibrin were morphologically elongated and a few cells were differentiating to chondrocyte-like cells with the deposit of proteoglycans. These cells proved to be highly clonogenic and capable of chondrogenesis and osteogenesis, but not adipogenesis. They were more active in chemotaxis assays than chondrocytes, showed a significantly larger side population, and over-expressed progenitor cell markers and genes involved in migration, chemotaxis, and proliferation. To active migration of chondrogenic progenitor cells (CPCs) short-term enzymatic method was used around edge of cartilage defect. Surprisingly, CPCs migrated into fibrin defect and were differentiating into chondrocytes with abundant deposit of proteoglycans. This result strongly supports that progenitor cells are activated in traumatic cartilage injury and have great potential for cartilage repair. In conclusion, migrating cells on injured explant surfaces are chondrogenic progenitors from the superficial zone that were activated by cartilage damage to attempt repair. Facilitating this endogenous process could allow repair of focal defects that would otherwise progress to post-traumatic osteoarthritis.
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<strong>Biomechanics and Mechanobiology of Impacted Cartilage: In-vitro and In-vivo Studies</strong>Hessam Noori Dokht (16682121) 02 August 2023 (has links)
<p>Osteoarthritis (OA) is one of the most prevalent diseases in the United States and also in the world. Cartilage plays a vital role in articular joints and its structural integrity and mechanical properties are diminished by OA. Post traumatic osteoarthritis (PTOA) is a prevalent type of OA and occurs after a significant joint injury. Currently, no treatments are available to prevent or delay the progression of any form of OA.</p><p>Collagen crosslinking improves the material properties of cartilage and has been proposed as a potential treatment for OA. The wear resistance of cartilage that had been crosslinked with CASPc, a light activated crosslinking agent, was tested. Results suggested that photo-initiated crosslinking improves the wear characteristics of cartilage.</p><p>Another treatment for PTOA is through biological intervention. Preliminary data from our lab showed that metformin rescues the chondrocyte response to injurious impact overloading in the initial 24 hours following impact. However, whether this treatment maintained cartilage integrity for an extended duration had not been investigated. Material properties of cartilage were analyzed with an indentation test at different time points post-impact to determine the functional effect of cartilage injury and metformin treatment. Changes in the composition of the cartilage were investigated through biochemical techniques.</p><p>Having an in vivo model for PTOA is key for testing any new therapeutic intervention. In this study a model was developed to deliver a consistent impact load to the posterior aspect of medial condyle of a rabbit knee. A drop tower was designed for impacting the rabbit knee, and load and acceleration were measured during the impact. A k-wire was passed through the condyles in the medial-lateral direction under the impact site to secure the condyle during the impact. Whether the impact parameters were affected by the location of the k-wire was evaluated. The location of the k-wire was varied in the anterior/posterior and proximal/distal directions in a knee joint of cadaveric rabbits and impact parameters were recorded. Multiple linear regression showed a correlation between the location of the k-wire and peak stress, loading rate, impact duration and work. Moreover a correlation was found between the damage induced to the cartilage and loading rate, impact duration and peak stress. This study indicated that k-wire location is critical to prevent fracture of the subchondral bone.</p><p>A pilot study was designed to investigate the in-vivo effect of the metformin treatment on PTOA. Impacted knee joints in rabbits were treated with intraarticular metformin or were untreated controls. At 12 weeks post-injury, the progression of OA in the rabbit knees was quantified by histology, and OA severity was assessed using OA Research Society International (OARSI) scoring. Although the number of animals in the study were limited, intraarticular metformin appeared to prevent the development of PTOA in the impacted rabbit knees.</p>
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Biomarcadores do metabolismo da cartilagem e sua relação com as alterações morfológicas, inflamatórias e funcionais: um estudo sobre a lesão condral secundária em joelhos humanos / Biomarkers of cartilage metabolism and its relationship with morphological, inflammatory and functional changes: a study of secondary chondral injury in human kneesFranco, Renata Nogueron 28 February 2011 (has links)
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Previous issue date: 2011-02-28 / Osteoarthritis (OA), a degenerative joint disease, is one of the most frequent causes of pain in the musculoskeletal system and of the inability to work in Brazil and the world. It is a multifactor, chronic disease, leading to progressive functional inability. It can arise as a result of injuries to structures such as the anterior crossed ligament and/or meniscus (post-traumatic OA), which, in this case, can affect individuals in any age range. The development of osteoarthritis includes multiple changes in the extracellular cartilage matrix, altering the normal morphological configuration of the joint involved, leading to a lack of equilibrium between the synthesis and degradation of products in this matrix. Although OA is not considered primordially as an inflammatory disease, inflammation of the joint has been shown to be a potential amplifier of the degenerative process. Thus the objective of the present study was to analyze potential biological markers in the serum and synovial fluid, and then correlate them with one another and with the morphological, inflammatory and functional alterations found in individuals with chronic injury of the anterior crossed ligament (ACL). The following techniques were used in the study: zymography, to determine the activity of the metallopeptidases 2 and 9 (MMP-2 and MMP-9); an immune-enzymatic assay (ELISA) to determine the presence of systemic and local cytokines; and a manual count of inflammatory cells (mononuclear and polymorphonuclear) by optical microscopy and spectrophotometry, in order to analyze for sulfated glycosaminoglycans (GAGs). The results indicated joint and systemic inflammation in chronic injury of the ACL by the detection of systemic and local cytokines, by the activity of MMP-9 and by the inflow of neutrophils. There were interactions between systemic and local cytokines, in which a cytokine did not always exert the same function in the serum as in the synovial fluid. The interleucines (IL) connected to degradation of the cartilage in chronic injury of the ACL were IL-12, IL-6 and IL-8, and those connected to pain and loss of function were IL-6 and IL-9. In counterpart, MMP-2 showed a negative correlation with the damage to the cartilage. It was concluded that the molecules studied had potential as biomarkers, since alterations were suggestive of injury and degradation of the cartilage. In addition, after the traumatic event resulting in rupture of the ACL, the ambient remained chronically inflamed and this inflammation was crucial for the high index of posttraumatic OA. / A osteoartrite (OA), doença articular degenerativa, é uma das causas mais freqüentes de dor do sistema músculo-esquelético e de incapacidade para o trabalho no Brasil e no mundo. É uma doença crônica, multifatorial, que leva a uma incapacidade funcional progressiva. Pode surgir em decorrência de lesões em estruturas como ligamento cruzado anterior e/ou meniscos (OA pós-traumática), e neste caso, pode afetar indivíduos em qualquer faixa etária. O desenvolvimento da osteoartrite inclui múltiplas mudanças na matriz extracelular da cartilagem, o que altera a configuração morfológica normal da articulação envolvida, levando a um desequilíbrio entre a síntese e degradação dos produtos desta matriz. Apesar da OA não ser considerada primordialmente como uma doença inflamatória, a inflamação articular tem demonstrado um potencial amplificador do processo degenerativo. Sendo assim, o objetivo deste trabalho foi analisar potenciais marcadores biológicos no soro e no líquido sinovial, e em seguida correlacioná-los uns com os outros e com as alterações morfológicas, inflamatórias e funcionais encontradas em sujeitos com lesão crônica do ligamento cruzado anterior (LCA). Para este estudo foram utilizadas técnicas de: zimografia, para verificar a atividade das metalopeptidases 2 e 9 (MMP-2 e MMP-9); Ensaio imunoenzimático (ELISA), para constatar a presença das citocinas sistêmicas e locais; contagem manual de células inflamatórias (mononucleares e polimorfonucleares) por microscopia óptica e espectrofotometria para a análise dos glicosaminoglicanos sulfatados (GAGs). Os resultados apontaram para uma inflamação articular e sistêmica na lesão crônica do LCA, pela detecção de citocinas sistêmicas e locais, pela atividade das MMP-9 e pelo influxo de neutrófilos. Houve interações entre citocinas sistêmicas e locais, nas quais nem sempre uma citocina exerce a mesma função no soro e no líquido sinovial. As interleucinas (IL) ligadas à degradação da cartilagem na lesão crônica do LCA foram IL-12, IL-6 e IL-8 e as ligadas à dor e a perda de função foram IL-6 e IL-8. Em contrapartida, a MMP-2 apresentou correlação negativa com os danos na cartilagem. Conclui-se que, as moléculas estudadas apresentam potencial como biomarcadores, sendo suas alterações sugestivas de lesão e degradação da cartilagem. E ainda, que após o evento traumático responsável pelo rompimento do LCA, o ambiente permanece inflamado cronicamente e que esta inflamação é crucial para o alto índice de OA pós-traumática.
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