Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

International audienceHistone modifications are important for maintaining the transcription program. BET proteins, an important class of " histone reading proteins " , have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro. Moreover, we show that treated non-resorbing osteoclasts could still activate osteoblast differentiation. In addition, specific inhibition of BRD4 using RNA interference inhibits osteoclast differentiation but strongly activates osteoblast mineralization activity. Mechanistically, JQ1 inhibits expression of the master osteoclast transcription factor NFATc1 and the transcription factor of osteoblast Runx2. These findings strongly support that targeting epigenetic chromatin regulators such as BET proteins may offer a promising alternative for the treatment of bone-related disorders such as osteoporosis

Lattice worldline representation of correlators in a background field

We use a discrete worldline representation in order to study the continuum limit of the one-loop expectation value of dimension two and four local operators in a background field. We illustrate this technique in the case of a scalar field coupled to a non-Abelian background gauge field. The first two coefficients of the expansion in powers of the lattice spacing can be expressed as sums over random walks on a d-dimensional cubic lattice. Using combinatorial identities for the distribution of the areas of closed random walks on a lattice, these coefficients can be turned into simple integrals. Our results are valid for an anisotropic lattice, with arbitrary lattice spacings in each direction.Comment: 54 pages, 14 figure

Ewing sarcoma from molecular biology to the clinic

In Europe, with an incidence of 7.5 cases per million, Ewing sarcoma (ES) is the second most common primary malignant bone tumor in children, adolescents and young adults, after osteosarcoma. Since the 1980s, conventional treatment has been based on the use of neoadjuvant and adjuvant chemotherapeutic agents combined with surgical resection of the tumor when possible. These treatments have increased the patient survival rate to 70% for localized forms, which drops drastically to less than 30% when patients are resistant to chemotherapy or when pulmonary metastases are present at diagnosis. However, the lack of improvement in these survival rates over the last decades points to the urgent need for new therapies. Genetically, ES is characterized by a chromosomal translocation between a member of the FET family and a member of the ETS family. In 85% of cases, the chromosomal translocation found is (11; 22) (q24; q12), between the EWS RNA-binding protein and the FLI1 transcription factor, leading to the EWS-FLI1 fusion protein. This chimeric protein acts as an oncogenic factor playing a crucial role in the development of ES. This review provides a non-exhaustive overview of ES from a clinical and biological point of view, describing its main clinical, cellular and molecular aspects

Diverse perspectives on interdisciplinarity from the Members of the College of the Royal Society of Canada

Various multiple-disciplinary terms and concepts (although most commonly “interdisciplinarity”, which is used herein) are used to frame education, scholarship, research, and interactions within and outside academia. In principle, the premise of interdisciplinarity may appear to have many strengths; yet, the extent to which interdisciplinarity is embraced by the current generation of academics, the benefits and risks for doing so, and the barriers and facilitators to achieving interdisciplinarity represent inherent challenges. Much has been written on the topic of interdisciplinarity, but to our knowledge there have been few attempts to consider and present diverse perspectives from scholars, artists, and scientists in a cohesive manner. As a team of 57 members from the Canadian College of New Scholars, Artists, and Scientists of the Royal Society of Canada (the College) who self-identify as being engaged or interested in interdisciplinarity, we provide diverse intellectual, cultural, and social perspectives. The goal of this paper is to share our collective wisdom on this topic with the broader community and to stimulate discourse and debate on the merits and challenges associated with interdisciplinarity. Perhaps the clearest message emerging from this exercise is that working across established boundaries of scholarly communities is rewarding, necessary, and is more likely to result in impact. However, there are barriers that limit the ease with which this can occur (e.g., lack of institutional structures and funding to facilitate cross-disciplinary exploration). Occasionally, there can be significant risk associated with doing interdisciplinary work (e.g., lack of adequate measurement or recognition of work by disciplinary peers). Solving many of the world’s complex and pressing problems (e.g., climate change, sustainable agriculture, the burden of chronic disease, and aging populations) demand thinking and working across long-standing, but in some ways restrictive, academic boundaries. Academic institutions and key support structures, especially funding bodies, will play an important role in helping to realize what is readily apparent to all who contributed to this paper—that interdisciplinarity is essential for solving complex problems; it is the new norm. Failure to empower and encourage those doing this research will serve as a great impediment to training, knowledge, and addressing societal issues

Safety Concern between Autologous Fat Graft, Mesenchymal Stem Cell and Osteosarcoma Recurrence

Background: Osteosarcoma is the most common malignant primary bone tumour in young adult treated by neo adjuvant chemotherapy, surgical tumor removal and adjuvant multidrug chemotherapy. For correction of soft tissue defect consecutive to surgery and/or tumor treatment, autologous fat graft has been proposed in plastic and reconstructive surgery. Principal Findings: We report here a case of a late local recurrence of osteosarcoma which occurred 13 years after the initial pathology and 18 months after a lipofilling procedure. Because such recurrence was highly unexpected, we investigated the possible relationship of tumor growth with fat injections and with mesenchymal stem/stromal cell like cells which are largely found in fatty tissue. Results obtained in osteosarcoma pre-clinical models show that fat grafts or progenitor cells promoted tumor growth. Significance: These observations and results raise the question of whether autologous fat grafting is a safe reconstructive procedure in a known post neoplasic context

Ciblage thérapeutique des tumeurs osseuses primitives par transfert de gène

L'ostéosarcome est la plus fréquente des tumeurs osseuses primitives affectant principalement une population jeune. Bien que les traitements actuels aient contribué à la progression de la survie des patients, ils montrent désormais leurs limites d'où la nécessité de développer de nouvelles thérapies. L'hypothèse biologique de l ostéosarcome repose sur l'existence d un cercle vicieux s'instaurant entre la prolifération tumorale et la résorption osseuse. Récemment découverte, la triade moléculaire Receptor Activator of NF B (RANK) / RANK ligand / Ostéoprotégérine (RANK/RANKL/OPG) est fortement impliquée dans la régulation de la résorption osseuse et du développement tumoral, ainsi l inhibition de l interaction RANK/RANKL représente une cible thérapeutique majeure. L'objectif de cette thèse a été de développer de nouvelles approches thérapeutiques dans des modèles expérimentaux d'ostéosarcomes afin de rompre ce cercle vicieux, notamment par l'utilisation de l'OPG ou de RANK-Fc, molécules anti-résorption osseuse, libérés par transfert de gène non viral, puis de tenter de comprendre le rôle de l OPG et de RANKL dans le microenvironnement tumoral osseux.Osteosarcoma is the most frequent primary bone tumor that affects mainly young patients. Despite current treatments have contributed to increase the survival rate, they show now their limitations with the need to develop new therapeutic approaches. The biological hypothesis of osteosarcoma is based on the existence of a vicious cycle between tumor proliferation and bone resorption. Recently discovered, the molecular triad Receptor Activator of NF B (RANK) / RANK ligand / Osteoprotegerin (RANK / RANKL / OPG) is strongly implicated in the regulation of bone resorption and tumor development, and the inhibition of the interaction RANK / RANKL represents a major therapeutic approach. The objectives of this thesis were to develop new therapeutic approaches in experimental models of osteosarcoma in order to break this vicious cycle, including the use of OPG and RANK-Fc, anti-bone resorption molecules, released by non-viral gene transfer, and then to try to understand the place of OPG and RANKL in the tumor bone microenvironment.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF