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1.
Magn Reson Imaging ; 97: 91-101, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36610648

RESUMO

Degeneration of cartilage can be studied non-invasively with quantitative MRI. A promising parameter for detecting early osteoarthritis in articular cartilage is T1ρ, which can be tuned via the amplitude of the spin-lock pulse. By measuring T1ρ at several spin-lock amplitudes, the dispersion of T1ρ is obtained. The aim of this study is to find out if the dispersion contains diagnostically relevant information complementary to a T1ρ measurement at a single spin-lock amplitude. To this end, five differently acquired dispersion parameters are utilized; A, B, τc, T1ρ/T2, and R2 - R1ρ. An open dataset of an equine model of post-traumatic cartilage was utilized to assess the T1ρ dispersion parameters for the evaluation of cartilage degeneration. Firstly, the parameters were compared for their sensitivity in detecting degenerative changes. Secondly, the relationship of the dispersion parameters to histological and biomechanical reference parameters was studied. Parameters A, T1ρ/T2, and R2 - R1ρ were found to be sensitive to lesion-induced changes in the cartilage within sample. Strong correlations of several dispersion parameters with optical density, as well as with collagen fibril angle were found. Most of the dispersion parameters correlated strongly with individual T1ρ values. The results suggest that dispersion parameters can in some cases provide a more accurate description of the biochemical composition of cartilage as compared to conventional MRI parameters. However, in most cases the information given by the dispersion parameters is more of a refinement than complementary to conventional quantitative MRI.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Cavalos , Imageamento por Ressonância Magnética/métodos , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Osteoartrite/diagnóstico por imagem
2.
Arthritis Res Ther ; 25(1): 7, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635774

RESUMO

BACKGROUND: Hypertension is a common comorbidity of osteoarthritis (OA) with known autonomic dysregulation; thus, the autonomic nervous system may provide a shared underlying mechanism. The objective of this study was to examine the role of the autonomic nervous system in a preclinical model of OA and hypertension. METHODS: Experiments were conducted in spontaneously hypertensive rats and a normotensive control strain, including male and female rats. OA was surgically induced via medial meniscus transection with skin incision used as a sham control (n = 7-8/strain/sex/surgery). Tactile sensitivity, anxiety-related behavior, and serum corticosterone were measured at baseline then bi-weekly across 8 weeks. At weeks 9-10, cardiovascular responses to a chemical vagal nerve agonist were determined to indirectly evaluate vagus nerve function. The joint structure was assessed via grading of histological sections. RESULTS: In males, OA resulted in thinner cartilage in both hypertensive (OA vs. non-OA p < 0.001) and normotensive (OA vs. non-OA p < 0.001). Only females with comorbid hypertension and OA displayed thinner cartilage (p = 0.013). Male hypertensive OA animals had increased calcified subchondral bone compared to normotensive OA animals (p = 0.043) while female hypertensive OA animals had increased calcified subchondral bone compared to hypertensive sham animals (p < 0.001). All MCLT+MMT groups developed low-grade synovitis; interestingly, hypertensive OA females had higher synovitis scores than normotensive OA females (p = 0.046). Additionally, hypertension led to larger drops in blood pressure with vagal activation in both OA (hypertensive vs. normotensive p = 0.018) and sham (hypertensive vs. normotensive p < 0.001) male animals. In females, this trend held true only in OA animals (normotensive vs. hypertensive p = 0.005). CONCLUSION: These data provide preliminary evidence that hypertension influences OA progression and encourages further study into the autonomic nervous system as a possible mechanism.


Assuntos
Cartilagem Articular , Hipertensão , Osteoartrite , Sinovite , Ratos , Masculino , Feminino , Animais , Osteoartrite/patologia , Meniscos Tibiais , Osso e Ossos , Sinovite/patologia , Modelos Animais de Doenças , Cartilagem Articular/patologia
3.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675010

RESUMO

Loose bodies (LBs) from patients with osteochondritis dissecans (OCD) are usually removed and discarded during surgical treatment of the defect. In this study, we address the question of whether these LBs contain sufficient viable and functional chondrocytes that could serve as a source for autologous chondrocyte implantation (ACI) and how the required prolonged in vitro expansion affects their phenotype. Chondrocytes were isolated from LBs of 18 patients and compared with control chondrocyte from non-weight-bearing joint regions (n = 7) and bone marrow mesenchymal stromal cells (BMSCs, n = 6) obtained during primary arthroplasty. No significant differences in the initial cell yield per isolation and the expression of the chondrocyte progenitor cell markers CD44 + /CD146+ were found between chondrocyte populations from LBs (LB-CH) and control patients (Ctrl-CH). During long-term expansion, LB-CH exhibited comparable viability and proliferation rates to control cells and no ultimate cell cycle arrest was observed within 12 passages respectively 15.3 ± 1.1 mean cumulative populations doublings (CPD). The chondrogenic differentiation potential was comparable between LB-CH and Ctrl-CH, but both groups showed a significantly higher ability to form a hyaline cartilage matrix in vitro than BMSC. Our data suggest that LBs are a promising cell source for obtaining qualitatively and quantitatively suitable chondrocytes for therapeutic applications, thereby circumventing donor site morbidity as a consequence of the biopsies required for the current ACI procedure.


Assuntos
Cartilagem Articular , Condrócitos , Procedimentos Ortopédicos , Cartilagem , Cartilagem Articular/patologia , Diferenciação Celular , Condrócitos/metabolismo , Condrócitos/transplante , Células-Tronco Mesenquimais/metabolismo , Procedimentos Ortopédicos/métodos , Transplante Autólogo/métodos
4.
Am J Sports Med ; 51(1): 237-249, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36592016

RESUMO

BACKGROUND: Chondrocyte-based cell therapy to repair cartilage has been used for >25 years despite current limitations. This work presents a new treatment option for cartilage lesions. HYPOTHESIS: High-quality hyaline cartilage microtissues called Cartibeads are capable of treating focal chondral lesions once implanted in the defect, by complete fusion of Cartibeads among themselves and their integration with the surrounding native cartilage and subchondral bone. STUDY DESIGN: Controlled laboratory study. METHODS: Cartibeads were first produced from human donors and characterized using histology (safranin O staining of glycosaminoglycan [GAG] and immunohistochemistry of collagen I and II) and GAG dosage. Cartibeads from 6 Göttingen minipigs were engineered and implanted in an autologous condition in the knee (4 or 5 lesions per knee). One group was followed up for 3 months and the other for 6 months. Feasibility and efficacy were measured using histological analysis and macroscopic and microscopic scores. RESULTS: Cartibeads revealed hyaline features with strong staining of GAG and collagen II. High GAG content was obtained: 24.6-µg/mg tissue (wet weight), 15.52-µg/mg tissue (dry weight), and 35 ± 3-µg GAG/bead (mean ± SD). Histological analysis of Göttingen minipigs showed good integration of Cartibeads grafts at 3 and 6 months after implantation. The Bern Score of the histological assay comparing grafted versus empty lesions was significant at 3 months (grafted, n = 10; nongrafted, n = 4; score, 3.3 and 5.3, respectively) and 6 months (grafted, n = 11; nongrafted, n = 3; score, 1.6 and 5.1). CONCLUSION: We developed an innovative 3-step method allowing, for the first time, the use of fully dedifferentiated adult chondrocytes with a high number of cell passage (owing to the extensive amplification in culture). Cartibeads engineered from chondrocytes hold potential as an advanced therapy medicinal product for treating cartilage lesions with established efficacy. CLINICAL RELEVANCE: This successful preclinical study, combined with standardized manufacturing of Cartibeads according to good manufacturing practice guidelines, led to the approval of first-in-human clinical trial by the ethics committee and local medical authority. The generated data highlighted a promising therapy to treat cartilage lesions from a small amount of starting biopsy specimen. With our innovative cell amplification technology, very large lesions can be treated, and older active patients can benefit from it.


Assuntos
Cartilagem Articular , Cartilagem Hialina , Humanos , Adulto , Suínos , Animais , Cartilagem Articular/patologia , Condrócitos/transplante , Porco Miniatura , Engenharia Tecidual/métodos , Colágeno , Glicosaminoglicanos , Modelos Animais , Transplante Autólogo
5.
Sci Rep ; 13(1): 1690, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36717645

RESUMO

In this study, Brillouin and Raman micro-Spectroscopy (BRamS) and Machine Learning were used to set-up a new diagnostic tool for Osteoarthritis (OA), potentially extendible to other musculoskeletal diseases. OA is a degenerative pathology, causing the onset of chronic pain due to cartilage disruption. Despite this, it is often diagnosed late and the radiological assessment during the routine examination may fail to recognize the threshold beyond which pharmacological treatment is no longer sufficient and prosthetic replacement is required. Here, femoral head resections of OA-affected patients were analyzed by BRamS, looking for distinctive mechanical and chemical markers of the progressive degeneration degree, and the result was compared to standard assignment via histological staining. The procedure was optimized for diagnostic prediction by using a machine learning algorithm and reducing the time required for measurements, paving the way for possible future in vivo characterization of the articular surface through endoscopic probes during arthroscopy.


Assuntos
Cartilagem Articular , Osteoartrite , Humanos , Cartilagem Articular/patologia , Osteoartrite/diagnóstico por imagem , Osteoartrite/patologia , Análise Espectral Raman , Cabeça do Fêmur/patologia , Coloração e Rotulagem
6.
PLoS Comput Biol ; 19(1): e1010337, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36701279

RESUMO

Osteoarthritis (OA) is a common musculoskeletal disease that leads to deterioration of articular cartilage, joint pain, and decreased quality of life. When OA develops after a joint injury, it is designated as post-traumatic OA (PTOA). The etiology of PTOA remains poorly understood, but it is known that proteoglycan (PG) loss, cell dysfunction, and cell death in cartilage are among the first signs of the disease. These processes, influenced by biomechanical and inflammatory stimuli, disturb the normal cell-regulated balance between tissue synthesis and degeneration. Previous computational mechanobiological models have not explicitly incorporated the cell-mediated degradation mechanisms triggered by an injury that eventually can lead to tissue-level compositional changes. Here, we developed a 2-D mechanobiological finite element model to predict necrosis, apoptosis following excessive production of reactive oxygen species (ROS), and inflammatory cytokine (interleukin-1)-driven apoptosis in cartilage explant. The resulting PG loss over 30 days was simulated. Biomechanically triggered PG degeneration, associated with cell necrosis, excessive ROS production, and cell apoptosis, was predicted to be localized near a lesion, while interleukin-1 diffusion-driven PG degeneration was manifested more globally. Interestingly, the model also showed proteolytic activity and PG biosynthesis closer to the levels of healthy tissue when pro-inflammatory cytokines were rapidly inhibited or cleared from the culture medium, leading to partial recovery of PG content. The numerical predictions of cell death and PG loss were supported by previous experimental findings. Furthermore, the simulated ROS and inflammation mechanisms had longer-lasting effects (over 3 days) on the PG content than localized necrosis. The mechanobiological model presented here may serve as a numerical tool for assessing early cartilage degeneration mechanisms and the efficacy of interventions to mitigate PTOA progression.


Assuntos
Cartilagem Articular , Osteoartrite , Humanos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Proteoglicanas , Citocinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Qualidade de Vida , Osteoartrite/metabolismo , Interleucina-1/metabolismo , Interleucina-1/farmacologia , Necrose/metabolismo , Necrose/patologia , Apoptose
7.
Sci Rep ; 13(1): 1579, 2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36709358

RESUMO

The role of cardiac lymphatics in the pathogenesis of myocardial infarction (MI) is unclear. Lymphatic system regulates cardiac physiological processes such as edema and tissue fluid balance, which affect MI pathogenesis. Recently, MI and fibrosis have been assessed using endogenous contrast in magnetic resonance imaging (MRI) based on the relaxation along a fictitious field with rank n (RAFFn). We extended the RAFFn applications to evaluate the effects of lymphatic insufficiency on MI with comparison to longitudinal rotating frame (T1ρ) and T2 relaxation times. MI was induced in transgenic (TG) mice expressing soluble decoy VEGF receptor 3 that reduces lymphatic vessel formation and their wild-type (WT) control littermates for comparison. The RAFFn relaxation times with rank 2 (TRAFF2), and rank 4 (TRAFF4), T1ρ and T2 were acquired at time points 0, 3, 7, 21 and 42 days after the MI at 9.4 T. Infarct sizes were determined based on TRAFF2, TRAFF4, T1ρ and T2 relaxation time maps. The area of differences (AOD) was calculated based on the MI areas determined on T2 and TRAFF2, TRAFF4 or T1ρ relaxation time maps. Hematoxylin-eosin and Sirius red stained histology sections were prepared to confirm MI locations and sizes. MI was detected as increased TRAFF2, TRAFF4, T1ρ and T2 relaxation times. Infarct sizes were similar on all relaxation time maps during the experimental period. Significantly larger AOD values were found together with increased AOD values in the TG group compared to the WT group. Histology confirmed these findings. The lymphatic deficiency was found to increase cardiac edema in MI. The combination of TRAFF2 (or TRAFF4) and T2 characterizes MI and edema in the myocardium in both lymphatic insufficiency and normal mice without any contrast agents.


Assuntos
Cartilagem Articular , Vasos Linfáticos , Infarto do Miocárdio , Camundongos , Animais , Imageamento por Ressonância Magnética/métodos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Vasos Linfáticos/diagnóstico por imagem , Vasos Linfáticos/patologia , Espectroscopia de Ressonância Magnética , Edema , Cartilagem Articular/patologia
8.
Biomolecules ; 13(1)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36671508

RESUMO

Osteoarthritis (OA), the most prevalent joint disease and the leading cause of disability, remains an incurable disease largely because the etiology and pathogenesis underlying this degenerative process are poorly understood. Low-grade inflammation within joints is a well-established factor that disturbs joint homeostasis and leads to an imbalance between anabolic and catabolic processes in articular cartilage; however, the complexity of the network between inflammatory factors that often involves positive and negative feedback loops makes current anti-cytokine therapy ineffective. MicroRNAs (miRNAs) have emerged as key regulators to control inflammation, and aberrant miRNAs expression has recently been linked to OA pathophysiology. In the present study, we characterized transcriptomic profiles of miRNAs in primary murine articular chondrocytes in response to a proinflammatory cytokine, IL-1ß, and identified miR-146a-5p as the most responsive miRNA to IL-1ß. miR-146a-5p was also found to be upregulated in human OA cartilage. We further demonstrated that knockdown of miR-146a-5p antagonized IL-1ß-mediated inflammatory responses and IL-1ß-induced catabolism in vitro, and silencing of miR-146a in chondrocytes ameliorated articular cartilage destruction and reduced OA-evoked pain in an injury-induced murine OA model. Moreover, parallel RNA sequencing revealed that differentially expressed genes in response to IL-1ß were enriched in pathways related to inflammatory processes, cartilage matrix homeostasis, and cell metabolism. Bioinformatic analyses of putative miR-146a-5p gene targets and following prediction of protein-protein interactions suggest a functional role of miR-146a-5p in mediating inflammatory processes and regulation of cartilage homeostasis. Our genetic and transcriptomic data define a crucial role of miR-146a-5p in OA pathogenesis and implicate modulation of miR-146a-5p in articular chondrocytes as a potential therapeutic strategy to alleviate OA.


Assuntos
Cartilagem Articular , MicroRNAs , Osteoartrite , Humanos , Camundongos , Animais , Osteoartrite/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Condrócitos , Inflamação/metabolismo , Cartilagem Articular/patologia , Apoptose
9.
Vet Surg ; 52(2): 284-298, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36523261

RESUMO

OBJECTIVE: To develop an in vivo experimental model for bone marrow lesions (BMLs) in ovine femorotibial joints. STUDY DESIGN: Randomized, prospective experimental study. ANIMALS: Eighteen healthy, skeletally-mature Dorper cross ewes. METHODS: One medial femoral condyle was penetrated with a 1.1 mm pin, and the contralateral medial femoral condyle was treated with transcutaneous extracorporeal shockwave (ESW) at 0.39 ± 0.04 mJ/mm2 . Clinical examination, magnetic resonance imaging (MRI), computed tomography (CT), and histopathological analyses were used to detect and characterize the development and progression of BMLs in the medial femoral condyle at 4, 8, and 12 weeks post-surgery. RESULTS: Pin penetration induced a BML detected on MRI within 2 weeks and lasted at least 12 weeks. BMLs were not observed in ESW-treated condyles. Histologically, BMLs were characterized by hemorrhage and inflammatory cellular infiltrate, and progressed to more dense fibrous tissue over time. Pathological changes were not observed in the articular cartilage overlying the region of BMLs. CONCLUSIONS: Direct, focal trauma to all layers of the osteochondral unit was sufficient to create an experimentally-induced BML which persisted for at least 90 days. The protocol used for ESW in this study did not induce BMLs. CLINICAL SIGNIFICANCE: Experimental induction of BMLs is possible and mimicked naturally occurring disease states. Volumetric imaging is a sensitive method for characterization of the dynamic nature of these lesions.


Assuntos
Doenças Ósseas , Doenças das Cartilagens , Cartilagem Articular , Osteoartrite do Joelho , Doenças dos Ovinos , Ovinos , Animais , Feminino , Medula Óssea/patologia , Osteoartrite do Joelho/patologia , Osteoartrite do Joelho/veterinária , Estudos Prospectivos , Articulação do Joelho/patologia , Fêmur/diagnóstico por imagem , Fêmur/patologia , Imageamento por Ressonância Magnética/veterinária , Imageamento por Ressonância Magnética/métodos , Cartilagem Articular/patologia , Doenças Ósseas/veterinária , Doenças das Cartilagens/veterinária , Carneiro Doméstico , Modelos Teóricos
10.
Tissue Eng Regen Med ; 20(1): 83-92, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36562983

RESUMO

BACKGROUND: The extracellular matrix (ECM) has many functions, such as segregating tissues, providing support, and regulating intercellular communication. Cartilage-derived ECM (CECM) can be prepared via consecutive processes of chemical decellularization and enzyme treatment. The purpose of this study was to improve and treat osteoarthritis (OA) using porcine knee articular CECM. METHODS: We assessed the rheological characteristics and pH of CECM solutions. Furthermore, we determined the effects of CECM on cell proliferation and cytotoxicity in the chondrocytes of New Zealand rabbits. The inhibitory effect of CECM on tumor necrosis factor (TNF)-α-induced cellular apoptosis was assessed using New Zealand rabbit chondrocytes and human synoviocytes. Finally, we examined the in vivo effects of CECM on inflammation control and cartilage degradation in an experimental OA-induced rat model. The rat model of OA was established by injecting monosodium iodoacetate into the intra-articular knee joint. The rats were then injected with CECM solution. Inflammation control and cartilage degradation were assessed by measuring the serum levels of proinflammatory cytokines and C-telopeptide of type II collagen and performing a histomorphological analysis. RESULTS: CECM was found to be biocompatible and non-immunogenic, and could improve cell proliferation without inducing a toxic reaction. CECM significantly reduced cellular apoptosis due to TNF-α, significantly improved the survival of cells in inflammatory environments, and exerted anti-inflammatory effects. CONCLUSION: Our findings suggest that CECM is an appropriate injectable material that mediates OA-induced inflammation.


Assuntos
Cartilagem Articular , Osteoartrite , Ratos , Humanos , Animais , Coelhos , Suínos , Cartilagem Articular/patologia , Osteoartrite/tratamento farmacológico , Condrócitos/metabolismo , Inflamação/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Matriz Extracelular/metabolismo
11.
Int Immunopharmacol ; 114: 109486, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36508923

RESUMO

BACKGROUND: The temporomandibular joint osteoarthritis (TMJ-OA) is characterized by progressive cartilage degradation, subchondral bone erosion, and chronic pain, leading to articular damage and chewing dysfunction. Studies have shown that interleukin-1ß (IL-1ß) plays a critical role in the development of TMJ-OA. Transglutaminase 2 (TG2) has been identified as a marker of chondrocyte hypertrophy and IL-1ß was able to increase TG2 expression in chondrocytes. Therefore, the aim of this study was to explore the ability of TG2 inhibitors to suppress TMJ-OA progression. METHODS: Firstly, toluidine blue staining, cell counting kit-8 assay, immunocytofluorescent staining and western blot were used to investigate the anti-inflammatory effects of TG2 inhibitors in IL-1ß-stimulated murine chondrocytes and the underlying mechanisms. Afterwards, micro-CT analysis, histological staining, immunohistochemical and immunohistofluorescent staining were used to evaluate the therapeutic efficacy of TG2 inhibitors in monosodium iodoacetate (MIA)-induced TMJ-OA in rats. RESULTS: TG2 inhibitors suppressed the IL-1ß-induced upregulation of COX-2, iNOS, MMP-13, and MMP-3 and reversed the IL-1ß-induced proteoglycan loss in chondrocytes through inhibiting NF-κB activation. Consistently, the MIA-induced upregulation of MMP-13 and MMP-3, and loss of structural integrity of the articular cartilage and subchondral bone were markedly reversed by TG2 inhibitors via inhibiting NF-κB activation. CONCLUSIONS: TG2 inhibitors demonstrated a potent therapeutic efficacy on cartilage and subchondral bone structures of TMJ-OA by reducing inflammation and cartilage degradation through suppressing NF-κB activation.


Assuntos
Cartilagem Articular , Osteoartrite , Ratos , Camundongos , Animais , NF-kappa B/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Proteína 2 Glutamina gama-Glutamiltransferase , Osteoartrite/metabolismo , Articulação Temporomandibular/patologia , Ácido Iodoacético , Condrócitos , Interleucina-1beta/metabolismo , Cartilagem Articular/patologia , Células Cultivadas
12.
Int J Nanomedicine ; 17: 6275-6287, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36536940

RESUMO

Partial-thickness cartilage defects (PTCDs) of the articular surface is the most common problem in cartilage degeneration, and also one of the main pathogenesis of osteoarthritis (OA). Due to the lack of a clear diagnosis, the symptoms are often more severe when full-thickness cartilage defect (FTCDs) is present. In contrast to FTCDs and osteochondral defects (OCDs), PTCDs does not injure the subchondral bone, there is no blood supply and bone marrow exudation, and the nearby microenvironment is unsuitable for stem cells adhesion, which completely loses the ability of self-repair. Some clinical studies have shown that partial-thickness cartilage defects is as harmful as full-thickness cartilage defects. Due to the poor effect of conservative treatment, the destructive surgical treatment is not suitable for the treatment of partial-thickness cartilage defects, and the current tissue engineering strategies are not effective, so it is urgent to develop novel strategies or treatment methods to repair PTCDs. In recent years, with the interdisciplinary development of bioscience, mechanics, material science and engineering, many discoveries have been made in the repair of PTCDs. This article reviews the current status and research progress in the treatment of PTCDs from the aspects of diagnosis and modeling of PTCDs, drug therapy, tissue transplantation repair technology and tissue engineering ("bottom-up").


Assuntos
Cartilagem Articular , Cartilagem Articular/patologia , Engenharia Tecidual/métodos , Medula Óssea , Células-Tronco , Células Cultivadas
13.
Stem Cells Transl Med ; 11(12): 1186-1195, 2022 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-36493381

RESUMO

Osteoarthritis is a common disease resulting in significant disability without approved disease-modifying treatment (other than total joint replacement). Stem cell-based therapy is being actively explored for the repair of cartilage lesions in the treatment and prevention of osteoarthritis. Embryonic stem cells are a very attractive source as they address many of the limitations inherent in autologous stem cells, such as variability in function and limited expansion. Over the past 20 years, there has been widespread interest in differentiating ESC into mesenchymal stem cells and chondroprogenitors with successful in vitro, ex vivo, and early animal studies. However, to date, none have progressed to clinical trials. In this review, we compare and contrast the various approaches to differentiating ESC; and discuss the benefits and drawbacks of each approach. Approaches relying on spontaneous differentiation are simpler but not as efficient as more targeted approaches. Methods replicating developmental biology are more efficient and reproducible but involve many steps in a complicated process. The small-molecule approach, arguably, combines the advantages of the above two methods because of the relative efficiency, reproducibility, and simplicity. To better understand the reasons for lack of progression to clinical applications, we explore technical, scientific, clinical, and regulatory challenges that remain to be overcome to achieve success in clinical applications.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Reprodutibilidade dos Testes , Transplante de Células-Tronco , Cartilagem , Osteoartrite/terapia , Osteoartrite/patologia , Células-Tronco Embrionárias , Cartilagem Articular/patologia
14.
PLoS One ; 17(12): e0275682, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36538560

RESUMO

Osteoarthritis (OA) is the most common joint disease in older adults and is characterized by a gradual degradation of articular cartilage due to decreased cartilage matrix gene expression and increased expression of genes involved in protein degradation, apoptosis and inflammation. Due to the high water content of cartilage, one of the main physical stimuli sensed by chondrocytes is hydrostatic pressure. We previously showed that high pressure above 20 MPa induced gene expression changes in chondrocyte precursor cells similar to what is observed in OA. Micro-RNAs are small non-coding RNAs essential to many physiological and pathological process including OA. As the micro-RNA miR-155 has been found increased in OA chondrocytes, we investigated the effects of high pressure on the expression of the miR-155 host gene Mir155hg. The chondrocyte progenitor cell line ATDC5 was pressurized under hydrostatic pressure up to 25 MPa and the expression of Mir155hg or the resulting micro-RNAs were measured; pharmacological inhibitors were used to identify the signaling pathways involved in the regulation of Mir155hg. We found that Mir155hg is strongly and rapidly up-regulated by high, but not moderate, pressure in chondrocyte progenitor cells. This up-regulation likely involves the membrane channel pannexin-1 and several intracellular signaling molecules including PKC and Src. MiR-155-5p and -3p were also up-regulated by pressure though somewhat later than Mir155hg, and a set of known miR-155-5p target genes, including Ikbke, Smarca4 and Ywhae, was affected by pressure, suggesting that Mir155hg may have important roles in cartilage physiology.


Assuntos
Cartilagem Articular , MicroRNAs , Osteoartrite , RNA Longo não Codificante , Humanos , Idoso , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Pressão Hidrostática , Condrócitos/metabolismo , MicroRNAs/metabolismo , Osteoartrite/patologia , Cartilagem Articular/patologia , Apoptose , DNA Helicases/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo
15.
Arthritis Res Ther ; 24(1): 286, 2022 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-36585687

RESUMO

Osteoarthritis (OA) is mainly characterized by the progressive destruction of articular cartilage. Mounting studies have revealed that disruption of extracellular matrix (ECM) homeostasis, aberrant chondrocyte metabolism, an increase in the number of senescent chondrocytes and abnormal activation of cell death such as chondrocyte apoptosis and autophagy, are the crucial steps in OA development. Additionally, mitochondrial dysfunction also participates in the abovementioned processes and is the key element of OA pathogenesis. Sirtuin (SIRT) is a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that can actively participate and primarily regulate chondrocyte function in OA pathophysiological processes. Some members of the SIRT family located in mitochondria can regulate mitochondrial function and mediate mitochondrial homeostasis via deacetylation to protect chondrocytes. In addition, SIRT can maintain ECM homeostasis, regulate chondrocyte metabolism, inhibit chondrocyte apoptosis and autophagy, and prevent chondrocyte senescence in cartilage by exerting its deacetylation activity. However, the molecular mechanism of the SIRT family against the onset and development of OA remains poorly elucidated. In this review, we will discuss the potential protective role of SIRT in the progression of OA and summarize several sirtuin-activating molecules as well as their potential therapeutic applications for OA.


Assuntos
Cartilagem Articular , Osteoartrite , Sirtuínas , Humanos , Osteoartrite/terapia , Osteoartrite/tratamento farmacológico , Condrócitos/metabolismo , Cartilagem Articular/patologia , Matriz Extracelular/metabolismo , Sirtuínas/metabolismo , Sirtuínas/uso terapêutico , Sirtuína 1/metabolismo
16.
Osteoarthritis Cartilage ; 30(1): 147-159, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34547432

RESUMO

OBJECTIVE: There is a need to incorporate multiple tissues into in vitro OA models to evaluate novel therapeutics. This approach is limited by inherent donor variability. We present an optimized research tool: a human OA cartilage-synovium explant co-culture model (OA-EXM) that employs donor-matched lower and upper limit response controls combined with statistical approaches to address variability. Multiple rapid read-outs allow for evaluation of therapeutics while cataloguing cartilage-synovium interactions. DESIGN: 48-h human explant cultures were sourced from OA knee arthroplasties. An OA-like cartilage-synovium co-culture baseline was established relative to donor-matched upper limit supraphysiological pro-inflammatory cytokine and lower limit OA cartilage or synovium alone controls. 100 nM dexamethasone treatment validated possible "rescue effects" within the OA-EXM dual tissue environment. Gene expression, proteoglycan loss, MMP activity, and soluble protein concentrations were analyzed using blocking and clustering methods. RESULTS: The OA-EXM demonstrates the value of the co-culture approach as the addition of OA synovium increases OA cartilage proteoglycan loss and expression of MMP1, MMP3, MMP13, CXCL8, CCL2, IL6, and PTGS2, but not to the extent of supraphysiological stimulation. Conversely, OA cartilage does not affect gene expression or MMP activity of OA synovium. Dexamethasone shows dual treatment effects on synovium (pro-resolving macrophage upregulation, protease downregulation) and cartilage (pro-inflammatory, catabolic, and anabolic downregulation), and decreases soluble CCL2 levels in co-culture, thereby validating OA-EXM utility. CONCLUSIONS: The OA-EXM is representative of late-stage OA pathology, captures dual interactions between cartilage and synovium, and combined with statistical strategies provides a rapid, sensitive research tool for evaluating OA therapeutics.


Assuntos
Cartilagem Articular/patologia , Osteoartrite/patologia , Membrana Sinovial/patologia , Idoso , Idoso de 80 Anos ou mais , Técnicas de Cocultura , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada
17.
Exp Mol Med ; 54(11): 1979-1990, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36380018

RESUMO

The mitochondrial unfolded protein response (UPRmt) is a mitochondrial-to-nuclear signaling pathway that is activated to maintain mitochondrial function when there is an accumulation of misfolded proteins within mitochondria. Mitochondrial function is essential for chondrocyte homeostasis, and mitochondrial dysfunction is a characteristic of osteoarthritis (OA). However, the role of the UPRmt in OA remains unclear. In the present study, the level of the UPRmt was examined in primary mouse chondrocytes subjected to different stresses and in the articular cartilage of OA model mice and OA patients. The relationship between UPRmt activation and OA progression was studied. The UPRmt was induced in primary mouse chondrocytes subjected to diverse stresses and in the cartilage of OA mice. Enhancement of the UPRmt with nicotinamide riboside (NR) significantly improved mitochondrial function, reduced chondrocyte death, attenuated OA pain, and ameliorated OA progression, and the protective effects decreased significantly in chondrocyte-specific Atf5 knockout (ATF5f/fCol2a1-CreERT2) mice. UPRmt induction was also identified in the articular cartilage of OA patients and was associated with reduced chondrocyte death, less severe hip pain, and lower levels of inflammation in synovial fluid. These findings identify the induction of the UPRmt in primary mouse chondrocytes exposed to pathological stresses and in the articular cartilage of OA model mice and OA patients. Enhancement of the UPRmt ameliorates OA progression, suggesting that the UPRmt exerts a protective effect against OA and may be a potential diagnostic and therapeutic strategy for OA.


Assuntos
Cartilagem Articular , Osteoartrite , Camundongos , Animais , Resposta a Proteínas não Dobradas , Osteoartrite/patologia , Condrócitos/metabolismo , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Dor
18.
BMC Musculoskelet Disord ; 23(1): 988, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36397054

RESUMO

BACKGROUND: The IMI-APPROACH cohort is an exploratory, 5-centre, 2-year prospective follow-up study of knee osteoarthritis (OA). Aim was to describe baseline multi-tissue semiquantitative MRI evaluation of index knees and to describe change for different MRI features based on number of subregion-approaches and change in maximum grades over a 24-month period. METHODS: MRIs were acquired using 1.5 T or 3 T MRI systems and assessed using the semi-quantitative MRI OA Knee Scoring (MOAKS) system. MRIs were read at baseline and 24-months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. In descriptive fashion, the frequencies of MRI features at baseline and change in these imaging biomarkers over time are presented for the entire sample in a subregional and maximum score approach for most features. Differences between knees without and with structural radiographic (R) OA are analyzed in addition. RESULTS: Two hundred eighty-nine participants had readable baseline MRI examinations. Mean age was 66.6 ± 7.1 years and participants had a mean BMI of 28.1 ± 5.3 kg/m2. The majority (55.3%) of included knees had radiographic OA. Any change in total cartilage MOAKS score was observed in 53.1% considering full-grade changes only, and in 73.9% including full-grade and within-grade changes. Any medial cartilage progression was seen in 23.9% and any lateral progression on 22.1%. While for the medial and lateral compartments numbers of subregions with improvement and worsening of BMLs were very similar, for the PFJ more improvement was observed compared to worsening (15.5% vs. 9.0%). Including within grade changes, the number of knees showing BML worsening increased from 42.2% to 55.6%. While for some features 24-months change was rare, frequency of change was much more common in knees with vs. without ROA (e.g. worsening of total MOAKS score cartilage in 68.4% of ROA knees vs. 36.7% of no-ROA knees, and 60.7% vs. 21.8% for an increase in maximum BML score per knee). CONCLUSIONS: A wide range of MRI-detected structural pathologies was present in the IMI-APPROACH cohort. Baseline prevalence and change of features was substantially more common in the ROA subgroup compared to the knees without ROA. TRIAL REGISTRATION: Clinicaltrials.gov identification: NCT03883568.


Assuntos
Doenças das Cartilagens , Cartilagem Articular , Osteoartrite do Joelho , Idoso , Humanos , Pessoa de Meia-Idade , Biomarcadores , Doenças das Cartilagens/patologia , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Seguimentos , Imageamento por Ressonância Magnética , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/patologia , Estudos Prospectivos
19.
J Transl Med ; 20(1): 515, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36348497

RESUMO

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the destruction of the articular cartilage, sclerosis of the subchondral bone, and joint dysfunction. Its pathogenesis is attributed to direct damage and mechanical destruction of joint tissues. Mesenchymal stem cells (MSCs), suggested as a potential strategy for the treatment of OA, have shown therapeutic effects on OA. However, the specific fate of MSCs after intraarticular injection, including cell attachment, proliferation, differentiation, and death, is still unclear, and there is no guarantee that stem cells can be retained in the cartilage tissue to enact repair. Direct homing of MSCs is an important determinant of the efficacy of MSC-based cartilage repair. Recent studies have revealed that the unique homing capacity of MSCs and targeted modification can improve their ability to promote tissue regeneration. Here, we comprehensively review the homing effect of stem cells in joints and highlight progress toward the targeted modification of MSCs. In the future, developments of this targeting system that accelerate tissue regeneration will benefit targeted tissue repair.


Assuntos
Cartilagem Articular , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Osteoartrite , Humanos , Cartilagem Articular/patologia , Osteoartrite/terapia , Osteoartrite/patologia , Diferenciação Celular
20.
Artigo em Russo | MEDLINE | ID: mdl-36440775

RESUMO

The dominant collagen of the cartilaginous matrix in adults is type II collagen. The amount of type II collagen in the intercellular matrix of cartilage is significantly reduced against the background of musculoskeletal system diseases. The basis of articular cartilage is hyaline cartilage tissue consisting of chondrocytes with tissue-specific antigens that induce the production of antibodies in patients with osteoarthritis (OA). Today, new approaches are being considered in the treatment of OA with the use of udenatured type II collagen (UC-II). Such molecular mechanisms of action of UC-II as the formation of a systemic response through oral tolerance are discussed, since the induction of tolerance is the immune pathway, by default, in the intestine. A number of experimental, preclinical (on volunteers) and clinical studies have shown the effectiveness and safety of the use of UC-II in OA. Standardized extracts of UC-II exhibit anti-inflammatory, immunoregulatory, chondroprotective effects, contributing to the reduction of pain symptoms of OA. Against the background of taking UC-II with induced OA, there is a statistically significant decrease in the level of proinflammatory cytokines, such as interleukin (IL-1ß, IL-6), tumor necrosis factor alpha (TNF), C-reactive protein (CRP) in serum and the level of max proteinases (MMP-3), nucleated factor «kappa-bi¼ (NF-κB) in the knee joint. UC-II significantly inhibits the production of prostaglandin E2 (by 20%) and the expression of genes encoding proinflammatory proteins. In experimental models and in OA patients, a decrease in the severity of pain syndrome, an increase in endurance, mobility and an improvement in the functional state of the joints were noted. Clinically, no changes in the structure of the muscle fiber were detected with increased physical exertion. With OA on the background of UC-II (10-40 mg/s), there was a statistically significant decrease in joint pain according to WOMAC. A promising direction of OA therapy is the combination of UC-II with chondroitin sulfate and glucosamine sulfate.


Assuntos
Cartilagem Articular , Dor Musculoesquelética , Osteoartrite , Adulto , Humanos , Colágeno Tipo II/uso terapêutico , Dor Musculoesquelética/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Glucosamina/uso terapêutico , Cartilagem Articular/patologia
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