Collaboration entre recherche académique et industrie dans l'étude d'un nouveau médicament anti-ostéoporotique

L'activité de l'ostéoclaste, cellule en charge de la résorption osseuse, est soumise à différents facteurs de régulation. Parmi eux, ceux issus de la matrice, en particulier les minéraux qui en sont libérés, comme le calcium, sont déterminants. Nous avons montré que la variation de concentration en calcium dans le milieu régulait l'activité de résorption et la durée de vie des ostéoclastes. Le développement d'une nouvelle thérapeutique, le ranélate de strontium, a montré des effets cliniques très intéressants reposant sur une stimulation des activités de formation de l'os par les ostéoblastes et une modulation des activités de résorption osseuse. Sur la base de nos connaissances de la physiologie de l'ostéoclaste, en particulier des voies de signalisation calcique, et de la maîtrise de différents modèles cellulaires ostéoclastiques, une collaboration logique s'est créée entre notre laboratoire et Servier afin d'approfondir les mécanismes à l'origine des effets du ranélate de strontium sur les ostéoclastes. En quelques années, cette collaboration s'est progressivement enrichie d'autres intervenants scientifiques afin de mieux éclairer ces mécanismes. Il a ainsi été montré que le strontium interagissait probablement avec le récepteur sensible au calcium et que les voies de signalisation intracellulaires activées par le calcium et le ranélate de strontium via ce récepteur étaient différentes. Dans le cadre de cette coopération avec Servier, des échanges avec d'autres laboratoires universitaires ont été initiés, telles que la mise en commun de techniques et de connaissances. Ainsi, il a été possible de confirmer la présence du récepteur sensible au calcium sur les ostéoclastes et de montrer son rôle dans les effets du ranélate de strontium sur l'ostéoclaste.The activity of the osteoclast, the cell responsible for bone resorption, is subjected to different regulation factors. Amongst these, those issued from the matrix, particularly released minerals such as calcium, are determinants. We have shown that variations in calcium concentration in the medium regulates resorption activity and duration of the osteoclast lifespan. The development of a new therapeutic agent, strontium ranelate, has shown very interesting clinical effects reliant on the stimulation of bone formation activity by osteoblasts and modulation of bone resorption activity. From our knowledge regarding osteoclast physiology, in particular calcium signaling pathways, and the control of different osteoclast cellular models, a consequent collaboration was formed between our laboratory and Servier in order to elaborate on the effects of strontium ranelate on the osteoclast. In several years, this collaboration has been further enriched by other collaborators in order to better understand this mechanism. It has also been shown that strontium likely interacts with the calcium-sensing receptor and that the pathways of intracellular signaling pathways activated by calcium and strontium ranelate via this receptor are different. In fact, within the scope of this collaboration with Servier, exchanges with other academic laboratories were initiated and collaboration on numerous techniques became possible. Then, it has been possible to confirm the presence of the calcium-sensing receptor on the osteoclasts and to demonstrate its role in the molecular events associated with strontium ranelate's effects on the osteoclast

Bone health in children with severe cerebral palsy

AimTo describe bone health and associated factors in children with severe cerebral palsy.MethodIn a retrospective, single-centre study, we performed a comprehensive bone evaluation (including clinical, densitometric and bone biomarker assessments) of children with severe cerebral palsy.ResultsNone of the 19 included children had a normal BMCTBLH Z score, and only one had a BMDTBLH Z score greater than −2. Six children had a BMDLS Z score greater than −2. The bone biomarker data were suggestive of excessive bone remodelling. Levels of bone remodelling markers factors and densitometric variables were not significantly related. Age, weight and pubertal stage were significantly related to bone mass.DiscussionOur results highlights the insufficient increase in bone mass with age (probably due to excessive bone remodelling) and confirms the high prevalence of low bone mineral density in children with severe cerebral palsy. Possible preventive measures might include calcium + vitamin D supplementation and the systematic management of underweight and delayed puberty. Bone remodelling markers might be of value for follow-up

The Association between 25-Hydroxyvitamin D and Hemoglobin A1c Levels in Patients with Type 2 Diabetes and Stage 1–5 Chronic Kidney Disease

Aim. To examine the relationship between plasma 25-hydroxyvitamin D (25(OH)D) levels and blood hemoglobin A1c (HbA1c) levels in diabetic patients at various stages of chronic kidney disease (CKD). Methods. We screened for data collected between 2003 and 2012. The correlation between 25(OH)D and HbA1c levels was studied in patients categorized according to the severity of CKD and their vitamin D status. A multivariate linear regression model was used to determine whether 25(OH)D and HbA1c levels were independently associated after adjustment for a number of covariates (including erythrocyte metformin levels). Results. We identified 542 reports from 245 patients. The mean HbA1c value was 6.7±1.0% in vitamin D sufficiency, 7.3±1.5% in insufficiency, and 8.4±2.0% in deficiency (P<0.0001). There was a negative correlation between 25(OH)D and HbA1c levels for the population as a whole (r=-0.387, P<0.0001) and in the CKD severity subgroups (r=-0.384, P<0.0001 and r=-0.333, P<0.0001 for CKD stages 1–3 and 4-5, resp.). In the multivariate analysis, the 25(OH)D level was the only factor associated with HbA1c (P<0.0001). Conclusion. 25(OH)D levels were negatively correlated with HbA1c levels independently of study covariates

Association between metformin use and below-the-knee arterial calcification score in type 2 diabetic patients.

BACKGROUND Vascular calcification (VC) is common in type 2 diabetes, and is associated with cardiovascular complications. Recent preclinical data suggest that metformin inhibits VC both in vitro and in animal models. However, metformin's effects in patients with diabetic VC have not previously been characterized. The present study investigated the association between metformin use and lower-limb arterial calcification in patients with type 2 diabetes and high cardiovascular risk. METHODS The DIACART cross-sectional cohort study included 198 patients with type 2 diabetes but without severe chronic kidney disease. Below-the-knee calcification scores were assessed by computed tomography and supplemented by colour duplex ultrasonography. Data on anti-diabetic drugs were carefully collected from the patients' medical records and during patient interviews. Biochemical and clinical data were studied as potential confounding factors. RESULTS Metformin-treated patients had a significantly lower calcification score than metformin-free patients (mean ± standard deviation: 2033 ± 4514 and 4684 ± 9291, respectively; p = 0.01). A univariate analysis showed that metformin was associated with a significantly lower prevalence of severe below-the-knee arterial calcification (p = 0.02). VC was not significantly associated with the use of other antidiabetic drugs, including sulfonylureas, insulin, gliptin, and glucagon like peptide-1 analogues. A multivariate logistic regression analysis indicated that the association between metformin use and calcification score (odds ratio [95% confidence interval] = 0.33 [0.11-0.98]; p = 0.045) was independent of age, gender, tobacco use, renal function, previous cardiovascular disease, diabetes duration, neuropathy, retinopathy, HbA1c levels, and inflammation. CONCLUSIONS In patients with type 2 diabetes, metformin use was independently associated with a lower below-the-knee arterial calcification score. This association may contribute to metformin's well-known vascular protective effect. Further prospective investigations of metformin's potential ability to inhibit VC in patients with and without type 2 diabetes are now needed to confirm these results

Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer

International audienc

Positionnement du ranelate de strontium dans le traitement de l'ostéoporose post-ménopausique

Depuis les années 1960, l arsenal thérapeutique permettant de lutter contre l ostéoporose post-ménopausique s est considérablement enrichi. Si l on met à part l épisode malheureux des sels de fluor dans les années 1990, tous les traitements mis en place au cours des deux dernières décennies (biphosphonates, raloxifène, hormones parathyroïdiennes) ont fait la preuve de leur capacité à réduire rapidement le risque de fractures chez les patientes traitées. Le ranélate de strontium (RS), à la posologie de 2 g/j, offre de nouvelles perspectives thérapeutiques à long terme dans le traitement de l ostéoporose post-ménopausique, en traitement de première intention, quels que soient l âge de la patiente ou le stade de gravité de la maladie. Il agit sur le risque fracturaire selon un mécanisme d action original, le différenciant nettement des thérapeutiques antirésorptives ou purement ostéoblastiques actuellement en usage. Il est ainsi, à ce jour, le seul agent thérapeutique capable à la fois d inhiber la résorption osseuse et de stimuler la formation, permettant un rééquilibre du métabolisme osseux en faveur d un gain de masse osseuse. Chez les femmes ostéopéniques n ayant pas de fracture prévalente mais ayant au moins un facteur additionnel de risque de fracture, il réduit le risque de première fracture vertébrale. Au cours de l ostéoporose post-ménopausique, il prévient les fractures vertébrales, qu il y ait ou non un antécédent de fracture, ainsi que les fractures non vertébrales, en particulier les fractures de hanche. Le traitement de l ostéoporose devant désormais être envisagé dans une perspective à très long terme, l observance est appelée à devenir une priorité dans l élaboration des stratégies thérapeutiques de demain. La bonne tolérance et le bénéfice en termes de qualité de vie démontrés avec le ranélate de strontium semble favoriser son observance à long termeAMIENS-BU Santé (800212102) / SudocSudocFranceF

Agonists and allosteric modulators of the calcium-sensing receptor and their therapeutic applications. Mol Pharmacol 76

ABSTRACT The calcium-sensing receptor (CaR) belongs to the G proteincoupled receptor superfamily, with a characteristic structure consisting of seven transmembrane helices, an intracellular C-terminal and an extracellular N terminal domain