Regulatory mechanism of transforming growth factor beta receptor type II degradation by interleukin-1 in primary chondrocytes.

International audienceInterleukin-1β (IL-1β), a key-cytokine in osteoarthritis, impairs TGFβ signaling through TβRII down-regulation by increasing its degradation. Here, we investigated the molecular mechanism that controls TßRII fate in IL-1ß treated cells. Chondrocytes were treated with IL-1ß in the presence of different inhibitors. TßRII and Cav-1 expression were assayed by Western blot and RT-PCR. We showed that IL-1ß-induced degradation of TßRII is dependent on proteasome and on its internalization in caveolae. In addition, IL-1ß enhances Cav-1 expression, a major constituent of lipid raft. In conclusion, we enlighten a new mechanism by which IL-1ß antagonizes TGFß pathway and propose a model of TßRII turnover regulation upon IL-1ß treatment

Tissue engineering of different cartilage types: a review of different approaches and recent advances

Cartilage is a connective tissue that serves as a structural support for maintaining the shape for specific appendices (nose, ear) and also helps for shock absorption when present in joints. Different types of cartilage coexist in the body: hyaline, elastic and fibrocartilage. Due to their different embryologic origin, they produce distinct extracellular matrix and therefore have specific functions according to their location. Cartilage is frequently subjected to many different lesions. Those include traumatic, metabolic and congenital forms, concerning all regions where this tissue is present: joints, head and neck area, intervertebral disks, etc. Increasing number of cancers also affects cartilage; especially in ear, nose and trachea. Unfortunately, this tissue has a poor regeneration ability. Few therapeutic options exist for cartilaginous lesions and most of them concern articular cartilage. They include micro fracture, autologous chondrocytes implantation, mosaicplasty, allograft and prosthesis. Ear and trachea are also targeted for reconstruction with lesser extent. Therefore, cartilage engineering highly addresses increasing number of pathologies associated to this tissue. In the last two decades, several trials were investigated using both progenitor cells and scaffolds. Even bone marrow derived stem cells were widely used and served as gold standard. Many progenitors from different areas are investigated for their capacity of chondrogenesis. On the other hand, biomaterials, natural and synthetic, are used to induce a 3D environment that allows proper growth and differentiation toward cartilage formation. Their characteristics depend on the location of the expected graft where porosity, biodegradability, ability to support strength and large scale use are the key points. Favorable environments are also needed to achieve appropriate chondrogenesis, including biochemical or mechanical stimuli and low oxygen tension. Bioprinting showed also encouraging outcomes in cartilage reconstruction with the investigation of several scaffolds

Development of a simple osteoarthritis model useful to predict in vitro the anti-hypertrophic action of drugs

International audienceOsteoarthritis (OA) is characterized by cartilage degradation, inflammation, and hypertrophy. Therapies are mainly symptomatic and aim to manage pain. Consequently, medical community is waiting for new treatments able to reduce OA process. This study aims to develop an in vitro simple OA model useful to predict drug ability to reduce cartilage hypertrophy. Human primary OA chondrocytes were incubated with transforming growth factor beta 1 (TGF-β1). Hypertrophy was evaluated by Runx2, type X collagen, MMP13, and VEGF expression. Cartilage anabolism was investigated by Sox9, aggrecan, type II collagen, and glycosaminoglycan expression. In chondrocytes, TGF-β1 increased expression of hypertrophic genes and activated canonical WNT pathway, while it decreased dramatically cartilage anabolism, suggesting that this treatment could mimic some OA features in vitro. Additionally, EZH2 inhibition, that has been previously reported to decrease cartilage hypertrophy and reduce OA development in vivo, attenuated COL10A1 and MMP13 upregulation and SOX9 downregulation induced by TGF-β1 treatment. Similarly, pterosin B (an inhibitor of Sik3), and DMOG (a hypoxia-inducible factor prolyl hydroxylase which mimicks hypoxia), repressed the expression of hypertrophy markers in TGF-β stimulated chondrocytes. In conclusion, we established an innovative OA model in vitro. This cheap and simple model will be useful to quickly screen new drugs with potential anti-arthritic effects, in complementary to current inflammatory models, and should permit to accelerate development of efficient treatments against OA able to reduce cartilage hypertrophy

Histone methylases as novel drug targets: developing inhibitors of EZH2.

International audiencePost-translational modifications of histones (so-called epigenetic modifications) play a major role in transcriptional control and normal development, and are tightly regulated. Disruption of their control is a frequent event in disease. In particular, the methylation of lysine 27 on histone H3 (H3K27), induced by the methylase EZH2, emerges as a key control of gene expression and a major regulator of cell physiology. The identification of driver mutations in EZH2 has already led to new prognostic and therapeutic advances, and new classes of potent and specific inhibitors for EZH2 show promising results in preclinical trials. This review examines the roles of histone lysine methylases and demethylases in cells and focuses on the recent knowledge and developments about EZH2

Posible origen de las excentricidades orbitales de las familias de Hirayama

Partiendo de la hipótesis cosmogónica, se analiza el posible origen no-gravitacional de la actual distribución de excentricidades de las familias de Hirayama. Para ello se utiliza un modelo muy sencillo basado en estudios realizados sobre formación de asteroides (Alfvén) y su posterior evolución debida a mecanismos de fricción (Greenberg). De esta manera se obtienen como resultados la tasa de formación de los asteroides y el tiempo de formación de Júpiter, con un valor para este último de aproximadamente 200 millones de años. Estudios realizados en forma independiente por Hiyashi (1981) y Horedt (1981) basados en modelos teóricos para la estructura interna de Júpiter han brindado tiempos de formación del mismo entre 100 y 500 millones de años. La similitud con nuestro valor nos permite aceptar el presente modelo y por lo tanto la hipótesis en la cual se basa (evolución gravitacional despreciable) como un mecanismo factible para la formación de la estructura actual del cinturón de asteroides.Asociación Argentina de Astronomí

Vers une généralisation multidimensionnelle de la notion de géodésiques sur les groupes de Lie (1ère partie).

L’utilisation des symétries pour simplifier la résolution d’un problème de mécanique remonte aux travaux d’Euler, Lagrange, Hamilton, Routh, Jacobi, Liouville, Poincaré ... Ils ont étudié la possibilité de réduire la taille de l’espace des phases en se servant de l’ensemble des symétries et des lois de conservation qui leurs sont associées. Cette procédure de réduction peut s’appliquer à une poutre de Reissner - modélisée sous la forme d’un assemblage de sections rigides. Ce système mécanique présente une symétrie dans la mesure où il est invariant sous l’action du groupe des rotations et des translations. La géométrisation de ce problème, envisagée sous une forme classique, consiste à déterminer l’évolution de la déformée de la poutre à chaque instant. Cette approche, appelée « dynamique », présente la difficulté de considérer un espace des configurations de dimension infinie. Les solutions sont les courbes géodésiques d’un espace de fonctions. L’alternative est de considérer non plus un unique paramètre d’évolution (le temps) mais plusieurs (le temps et l’espace). On parle alors d’approche « covariante » où l’espace des configurations est de dimension finie (celle du groupe de symétrie). Dans ce cas, les solutions sont des surfaces (plus généralement, des sections sur un fibré). Envisagée dans un premier temps par De Donder, Weyl, Caratheodory (~1930), cette théorie (field theory) a suscité de l’intérêt et a été utilisée pour différents types d’applications comme par exemple l’étude dynamique des brins d’ADN ou des systèmes articulés. On souhaite l’utiliser à des fins de synthèse sonore par modèles physiques d’une corde vue comme une poutre de Reissner. La théorie des champs nécessite une généralisation, parfois délicate, des outils de la géométrie. La mise en évidence de ces outils ainsi que des symétries et des lois de conservation régissant l’évolution d’une poutre de Reissner feront l’objet de la présentation

Antiproliferative effect of the histone demethylase inhibitor GSK-J4 in chondrosarcomas

International audienceChondrosarcoma (CS) is the second most common malignant bone sarcoma. Its treatment remains an issue, because this tumor is radio- and chemo-resistant. In the present study, we investigated the antitumoral potential of GSK-J4, a small molecule described as an inhibitor of histone demethylases UTX and JMJD3 (KDM6A and KDM6B), alone or in combination with cisplatin in CSs. Human CS-derived cell lines were treated with GSK-J4 in the presence or not of cisplatin. Survival curves were established and cell proliferation and cycle were evaluated by flow cytometry using dividing cell tracking technique utilizing carboxyfluorescein succinimidyl ester labeling, or DNA staining by propidium iodide. Apoptosis and senescence were also investigated. GSK-J4 decreased proliferation of CS cells. Additionally, it induced apoptosis in CH2879 and JJ012 cells, but not in SW1353 CSs. In addition, its association with cisplatin decreased cell proliferation more than drugs alone, whereas it did not increase apoptosis compared to cisplatin alone. Interestingly, GSK-J4 alone as well as in association with cisplatin did not affect chondrocyte survival or proliferation. In conclusion, this study suggests that demethylase inhibitors may be useful in improving therapy for CS in reducing its proliferation