Development of a first-in-class unimolecular dual GIP/GLP-2 analogue, GL-0001, for the treatment of bone fragility

ABSTRACT Due to ageing of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone ECM material properties, i.e. the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual GIP/GLP-2 analogues, GL-0001, that activate simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cAMP-LOX pathway to enhance collagen maturity. Furthermore, in mice with ovariectomy-induced bone fragility, GL-0001 prevented excess trabecular bone degradation at the appendicular skeleton and also enhanced bone ECM material properties through reduction of the degree of mineralization and augmentation in enzymatic collagen crosslinking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering of bone fragility

L'ostéoporose chez l'homme (évolution de la densité osseuse chez 72 patients traités)

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

ETUDE DE LA MICRO-ARCHITECTURE OSSEUSE TRABECULAIRE DANS L'OSTEOPOROSE MASCULINE PRIMITIVE ET SECONDAIRE (DES RHUMATOLOGIE)

ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Oestradiol biodisponible, sex hormone binding globulin, et marqueurs du remodelage osseux au cours de l'ostéoporose chez l'homme

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Le traitement des spondylodiscites infectieuses en France

ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

[Gly²]-GLP-2, But Not Glucagon or [D-Ala²]-GLP-1, Controls Collagen Crosslinking in Murine Osteoblast Cultures

International audienceBone tissue is organized at the molecular level to resist fracture with the minimum of bone material. This implies that several modifications of the extracellular matrix, including enzymatic collagen crosslinking, take place. We previously highlighted the role of several gut hormones in enhancing collagen maturity and bone strength. The present study investigated the effect of proglucagon-derived peptides on osteoblast-mediated collagen post-processing. Briefly, MC3T3-E1 murine osteoblasts were cultured in the presence of glucagon (GCG), [D-Ala²]-glucagon-like peptide-1 ([D-Ala²]-GLP-1), and [Gly²]-glucagon-like peptide-2 ([Gly²]-GLP-2). Gut hormone receptor expression at the mRNA and protein levels were investigated by qPCR and Western blot. Extent of collagen postprocessing was examined by Fourier transform infrared microspectroscopy. GCG and GLP-1 receptors were not evidenced in osteoblast cells at the mRNA and protein levels. However, it is not clear whether the known GLP-2 receptor is expressed. Nevertheless, administration of [Gly²]-GLP-2, but not GCG or [D-Ala²]-GLP-1, led to a dose-dependent increase in collagen maturity and an acceleration of collagen post-processing. This mechanism was dependent on adenylyl cyclase activation. In conclusion, the present study highlighted a direct effect of [Gly²]-GLP-2 to enhance collagen post-processing and crosslinking maturation in murine osteoblast cultures. Whether this effect is translatable to human osteoblasts remains to be elucidated

New laboratory tools in the assessment of bone quality

International audienceBone quality is a complex set of different factors that are interdependent. The bone matrix organization can be described at five different levels of anatomical organization: nature (organic and mineral), texture (woven or lamellar), structure (osteons in the cortices and arch-like packets in trabecular bone), microarchitecture and macroarchitecture. Any change in one of these levels can alter bone quality. An altered bone remodeling can affect bone quality by influencing one or more of these factors. Here, we have reviewed the main methods that can be used in the laboratory to explore bone quality on bone samples. Bone remodeling can be evaluated by histomorphometry, microarchitecture is explored in 2D on histological sections and in 3D by microCT or synchrotron. Microradiography and scanning electron microscopy in the backscattered electron mode can measure the mineral distribution; Raman and Fourier transformed infra-red spectroscopy and imaging can simultaneously explore the organic and mineral phase of the matrix on multispectral images; scanning acoustic microscopy and nanoidentation provide biomechanical informations on individual trabeculae. Finally, some histological methods (polarization, surface staining, fluorescence, osteocyte staining) may also be of interest in the undestanding of quality as a component of bone fragility. Conclusion. A growing number of laboratory techniques are now available. Some of them have been described many years ago and can find a new youth, others having benefit from improvements in physical and computer techniques are now available

Sex hormone-binding globulin in osteoporosis

International audienceSex hormone-binding globulin (SHBG) is a plasma glycoprotein that binds with high affinity to sex steroids, most notably 5α-dihydrotestosterone, testosterone, and 17β-estradiol, thereby regulating their bioavailability and access to target cells. SHBG modulates the sex-steroid signaling system by binding to a specific membrane receptor (SHBG-R). Plasma SHBG levels vary in health and disease due to the effects of multiple regulation factors (age, body weight, sex steroids, insulin, and others). SHBG is involved in a number of diseases, including osteoporosis. Several studies found an inverse correlation between serum SHBG levels and bone mineral density in both males and females. SHBG levels may predict a number of macro-architectural characteristics of cortical bone. Weaker links have been reported between SHBG and bone turnover markers. Finally, high SHBG levels predict the occurrence of osteoporotic fractures of the vertebras and peripheral bones, most notably the proximal femur. Together with estradiol, SHBG plays a key role in the genesis of bone loss and osteoporotic fractures. Given that serum SHBG elevation is associated with the occurrence of multiple fractures, determination of the serum SHBG level, which can be readily performed in everyday clinical practice, may constitute a useful new marker for predicting the severity of osteoporosis.</p