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Study of fucoidans as natural biomolecules for therapeutical applications in osteoarthritis.
Vaamonde-García, C, Flórez-Fernández, N, Torres, MD, Lamas-Vázquez, MJ, Blanco, FJ, Domínguez, H, Meijide-Faílde, R
Carbohydrate polymers. 2021;:117692
Abstract
Osteoarthritis (OA) is the most prevalent articular chronic disease. Although, to date there is no cure for OA. Fucoidans, one of the main therapeutic components of brown algae, have emerged as promising molecules in OA treatment. However, the variability between fucoidans makes difficult the pursuit of the most suitable candidate to target specific pathological processes. By an in vitro experimental approach in chondrocytes and fibroblast-like synoviocytes, we observed that chemical composition of fucoidan, and specifically the phlorotannin content and the ratio sulfate:fucose, seems critically relevant for its biological activity. Nonetheless, other factors like concentration and molecular weight of the fucoidan may influence on its beneficial effects. Additionally, a cell-type dependent response was also detected. Thus, our results shed light on the potential use of fucoidans as natural molecules in the treatment of key pathological processes in the joint that favor the development of rheumatic disorders as OA.
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A low cartilage formation and repair endotype predicts radiographic progression of symptomatic knee osteoarthritis.
Luo, Y, Samuels, J, Krasnokutsky, S, Byrjalsen, I, Kraus, VB, He, Y, Karsdal, MA, Abramson, SB, Attur, M, Bay-Jensen, AC
Journal of orthopaedics and traumatology : official journal of the Italian Society of Orthopaedics and Traumatology. 2021;(1):10
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Abstract
BACKGROUND Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation. MATERIALS AND METHODS The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width. RESULTS In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4-8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011). CONCLUSION Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug. LEVEL OF EVIDENCE Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.
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Bioinformatics analysis of differentially expressed genes in subchondral bone in early experimental osteoarthritis using microarray data.
Wang, Z, Ji, Y, Bao, HW
Journal of orthopaedic surgery and research. 2020;(1):310
Abstract
BACKGROUND Osteoarthritis (OA) is the most common arthritic disease in humans, affecting the majority of individuals over 65 years of age. The aim of this study is to identify the gene expression profile specific to subchondral bone in OA by comparing the different expression profiles in experimental and sham-operation groups. METHODS Gene expression profile GSE30322 was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were obtained by limma package. And Database for Annotation, Visualization and Integrated Discovery (DAVID) databases were further used to identify the potential gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Furthermore, a protein-protein interaction (PPI) network was constructed and significant modules were extracted. RESULTS Totally, 588 DEGs were identified including 199 upregulated DEGs and 389 downregulated DEGs screened in OA and sham-operation. GO showed that DEGs were significantly enhanced for ribosomal subunit export from nucleus and molting cycle. KEGG pathway analysis revealed that target genes were enriched in thiamine metabolism. CONCLUSION These key candidate DEGs that affect the progression of OA, and these genes might serve as potential therapeutic targets for OA.
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Current status of functional MRI of osteoarthritis for diagnosis and prognosis.
Juras, V, Chang, G, Regatte, RR
Current opinion in rheumatology. 2020;(1):102-109
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PURPOSE OF REVIEW Osteoarthritis is a major source of disability, pain and socioeconomic cost worldwide. The epidemiology of the disorder is multifactorial including genetic, biological and biomechanical components, some of them detectable by MRI. This review provides the most recent update on MRI biomarkers which can provide functional information of the joint structures for diagnosis, prognosis and treatment response monitoring in osteoarthritis trials. RECENT FINDINGS Compositional or functional MRI can provide clinicians with valuable information on glycosaminoglycan content (chemical exchange saturation transfer, sodium MRI, T1ρ) and collagen organization (T2, T2, apparent diffusion coefficient, magnetization transfer) in joint structures. Other parameters may also provide useful information, such as volumetric measurements of joint structures or advanced image data postprocessing and analysis. Automated tools seem to have a great potential to be included in these efforts providing standardization and acceleration of the image data analysis process. SUMMARY Functional or compositional MRI has great potential to provide noninvasive imaging biomarkers for osteoarthritis. Osteoarthritis as a whole joint condition needs to be diagnosed in early stages to facilitate selection of patients into clinical trials and/or to measure treatment effectiveness. Advanced evaluation including machine learning, neural networks and multidimensional data analysis allow for wall-to-wall understanding of parameter interactions and their role in clinical evaluation of osteoarthritis.
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Associations Between Vitamins C and D Intake and Cartilage Composition and Knee Joint Morphology Over 4 Years: Data From the Osteoarthritis Initiative.
Joseph, GB, McCulloch, CE, Nevitt, MC, Neumann, J, Lynch, JA, Lane, NE, Link, TM
Arthritis care & research. 2020;(9):1239-1247
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OBJECTIVE To determine the cross-sectional and longitudinal associations of vitamin C and D intake with magnetic resonance imaging (MRI) measures of cartilage composition (T2) and joint structure (cartilage, meniscus, and bone marrow) using data from the Osteoarthritis Initiative (OAI) cohort. METHODS A total of 1,785 subjects with radiographic Kellgren/Lawrence knee grades 0-3 in the right knee were selected from the OAI database. Vitamins C and vitamin D intake (diet, supplements, and total) were assessed using the Block Brief 2000 Food Frequency Questionnaire at baseline. The MRI analysis protocol included 3T cartilage T2 quantification and semiquantitative joint morphology gradings (Whole-Organ Magnetic Resonance Imaging Score [WORMS]) at baseline and 4 years. Linear regression was used to assess the association between standardized baseline vitamin intake and both baseline WORMS scores and standardized cartilage T2 values. RESULTS Higher vitamin C intake was associated with lower average cartilage T2 values, medial tibia T2 values, and medial tibia WORMS scores (standardized coefficient range -0.07 to -0.05, P < 0.05). Higher vitamin D intake was associated with a lower cartilage WORMS sum score and medial femur WORMS score (standardized coefficient range -0.24 to -0.09, P < 0.05). Consistent use of vitamin D supplements of 400 IU at least once a week over 4 years was associated with significantly less worsening of cartilage, meniscus, and bone marrow abnormalities (odds ratio range 0.40-0.56, P < 0.05). CONCLUSION Supplementation with vitamin D over 4 years was associated with significantly less progression of knee joint abnormalities. Given the observational nature of this study, future longitudinal randomized controlled trials of vitamin D supplementation are warranted.
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Characterization of synovial fluid metabolomic phenotypes of cartilage morphological changes associated with osteoarthritis.
Carlson, AK, Rawle, RA, Wallace, CW, Brooks, EG, Adams, E, Greenwood, MC, Olmer, M, Lotz, MK, Bothner, B, June, RK
Osteoarthritis and cartilage. 2019;(8):1174-1184
Abstract
OBJECTIVE Osteoarthritis (OA) is a multifactorial disease with etiological heterogeneity. The objective of this study was to classify OA subgroups by generating metabolomic phenotypes from human synovial fluid. DESIGN Post mortem synovial fluids (n = 75) were analyzed by high performance-liquid chromatography mass spectrometry (LC-MS) to measure changes in the global metabolome. Comparisons of healthy (grade 0), early OA (grades I-II), and late OA (grades III-IV) donor populations were considered to reveal phenotypes throughout disease progression. RESULTS Global metabolomic profiles in synovial fluid were distinct between healthy, early OA, and late OA donors. Pathways differentially activated among these groups included structural deterioration, glycerophospholipid metabolism, inflammation, central energy metabolism, oxidative stress, and vitamin metabolism. Within disease states (early and late OA), subgroups of donors revealed distinct phenotypes. Synovial fluid metabolomic phenotypes exhibited increased inflammation (early and late OA), oxidative stress (late OA), or structural deterioration (early and late OA) in the synovial fluid. CONCLUSION These results revealed distinct metabolic phenotypes in human synovial fluid, provide insight into pathogenesis, represent novel biomarkers, and can move toward developing personalized interventions for subgroups of OA patients.
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Functional MRI for evaluation of hyaline cartilage extracelullar matrix, a physiopathological-based approach.
Martín Noguerol, T, Raya, JG, Wessell, DE, Vilanova, JC, Rossi, I, Luna, A
The British journal of radiology. 2019;(1103):20190443
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MRI of articular cartilage (AC) integrity has potential to become a biomarker for osteoarthritis progression. Traditional MRI sequences evaluate AC morphology, allowing for the measurement of thickness and its change over time. In the last two decades, more advanced, dedicated MRI cartilage sequences have been developed aiming to assess AC matrix composition non-invasively and detect early changes in cartilage not captured on morphological sequences. T2-mapping and T1ρ sequences can be used to estimate the relaxation times of water inside the AC. These sequences have been introduced into clinical protocols and show promising results for cartilage assessment. Extracelullar matrix can also be assessed using diffusion-weighted imaging and diffusion tensor imaging as the movement of water is limited by the presence of extracellular matrix in AC. Specific techniques for glycosaminoglycans (GAG) evaluation, such as delayed gadolinium enhanced MRI of cartilage or Chemical Exchange Saturation Transfer imaging of GAG, as well as sodium imaging have also shown utility in the detection of AC damage. This manuscript provides an educational update on the physical principles behind advanced AC MRI techniques as well as a comprehensive review of the strengths and weaknesses of each approach. Current clinical applications and potential future applications of these techniques are also discussed.
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The chondrocyte channelome: A narrative review.
Mobasheri, A, Matta, C, Uzielienè, I, Budd, E, Martín-Vasallo, P, Bernotiene, E
Joint bone spine. 2019;(1):29-35
Abstract
Chondrocytes are the main cells in the extracellular matrix (ECM) of articular cartilage and possess a highly differentiated phenotype that is the hallmark of the unique physiological functions of this specialised load-bearing connective tissue. The plasma membrane of articular chondrocytes contains a rich and diverse complement of membrane proteins, known as the membranome, which defines the cell surface phenotype of the cells. The membranome is a key target of pharmacological agents and is important for chondrocyte function. It includes channels, transporters, enzymes, receptors, and anchors for intracellular, cytoskeletal and ECM proteins and other macromolecular complexes. The chondrocyte channelome is a sub-compartment of the membranome and includes a complete set of ion channels and porins expressed in these cells. Many of these are multi-functional proteins with "moonlighting" roles, serving as channels, receptors and signalling components of larger molecular assemblies. The aim of this review is to summarise our current knowledge of the fundamental aspects of the chondrocyte channelome, discuss its relevance to cartilage biology and highlight its possible role in the pathogenesis of osteoarthritis (OA). Excessive and inappropriate mechanical loads, an inflammatory micro-environment, alternative splicing of channel components or accumulation of basic calcium phosphate crystals can result in an altered chondrocyte channelome impairing its function. Alterations in Ca2+ signalling may lead to defective synthesis of ECM macromolecules and aggravated catabolic responses in chondrocytes, which is an important and relatively unexplored aspect of the complex and poorly understood mechanism of OA development.
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Osteochondral Angiogenesis and Promoted Vascularization: New Therapeutic Target.
García-Fernández, L
Advances in experimental medicine and biology. 2018;:315-330
Abstract
The control of the different angiogenic process is an important point in osteochondral regeneration. Angiogenesis is a prerequisite for osteogenesis in vivo; insufficient neovascularization of bone constructs after scaffold implantation resulted in hypoxia and cellular necrosis. Otherwise, angiogenesis must be avoided in chondrogenesis; vascularization of the cartilage contributes to structural damage and pain. Finding a balance between these processes is important to design a successful treatment for osteochondral regeneration. This chapter shows the most important advances in the control of angiogenic process for the treatment of osteochondral diseases focused on the administration of pro- or anti-angiogenic factor and the design of the scaffold.
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[Cartilage/chondrocyte research and osteoarthritis. Mechanobiology for development of osteoarthritis.].
Ogawa, H, Akiyama, H
Clinical calcium. 2018;(6):789-795
Abstract
Articular cartilage is exquisitely sensitive to their mechanical environment, and mechanical loading may be the most important external factor regulating cartilage metabolism. Mechanical loading regulates chondrocyte activity, and pathological excessive loading leads to abnormal mechanotransduction, which in turn induces cartilage degradation. Several studies report that moderate levels of exercise exerts beneficial effects, such as improvements in pain and physical function, and also mitigates joint destruction through the down-regulation of the expression of matrix proteases. Calcium signaling is an initial step in chondrocyte mechanotransduction that has been linked to many cellular processes, and recent studies found that calcium ion channels distinctively mechanically activated by physiological or pathological mechanical loading through transient receptor potential vanilloid 4(TRPV4)or Piezo ion channels. We review here the recent progress on mechanotransduction of chondocytes, highlighting the calcium ion channels.