Biology subjects

Mabilleau, G.

Publications and source records attributed to Mabilleau, G..

8 recordsLinked to original sources

bioRxiv2026

GL-0001, a first-in-class dual GIP/GLP-2 analogue, reduces bone fragility by enhancing bone material properties in a murine model of type III osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a severe heritable skeletal disorder characterized by bone fragility, short stature, and increased fracture risk. Currently, no pharmacological treatment has been approved for OI, and bisphosphonates are commonly used off label. While bisphosphonates increase bone mass, their effects on bone quality and fracture reduction remain limited. GL-0001, a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-2 (GLP-2) compound that targets bone material properties, may offer alternative skeletal benefits. We evaluated the effects of 9 weeks of GL-0001 treatment in the oim/oim murine model of severe OI, a well-established model carrying a homozygous Col1a2 mutation resulting in abnormal type I collagen formation and compared outcomes with zoledronic acid (100 g/kg) or saline. Analyses included longitudinal growth, fracture incidence, bone biomechanics, microarchitecture, turnover markers, and bone material properties. OI mice exhibited reduced body weight, impaired femoral growth, severe trabecular and cortical deficits, altered bone turnover, and compromised biomechanical properties compared with WT controls. GL-0001 increased femur length by 5% (p=0.015) and reduced spontaneous fracture incidence by 90% (p=0.004), whereas zoledronic acid had no significant effect on fracture burden. Bone microarchitecture was not significantly altered by GL-0001, whereas zoledronic acid improved trabecular and cortical parameters. At the tissue level, GL-0001 improved bone strength, increasing ultimate stress (+26%, p=0.022) and yield stress (+30%, p=0.014), and reducing brittleness (-32%, p=0.002). These changes were associated with increased collagen maturity (+12%, p<0.001). In contrast, zoledronic acid had limited effects on bone material properties. These findings demonstrate that GL-0001 improves skeletal fragility in the oim/oim murine model of severe OI through mechanisms primarily involving enhancement of bone material properties and longitudinal growth, rather than changes in bone mass or microarchitecture. GL-0001 may therefore represent a novel therapeutic strategy targeting bone quality in OI.

physiology↗

bioRxiv2026

Bone Material Properties Distributions from quantitative Raman analysis: a distribution-based approach to human bone matrix characterization

Background: Bone mechanical competence depends not only on bone mass but also on the spatial organization of mineral and organic matrix properties. Whereas quantitative backscattered electron imaging (qBEI) characterizes mineral heterogeneity using Bone Mineral Density Distributions (BMDDs), no equivalent framework currently exists for describing the biochemical heterogeneity of the bone matrix by Raman microspectroscopy. Methods: We developed a quantitative Raman analysis (qRA) workflow to generate Bone Material Properties Distributions (BMPDs). Raman spectra were acquired along full-thickness line scans crossing successive bone structural units in human trabecular and cortical bone. Pixel-wise Raman-derived biochemical parameters describing collagen organization, advanced glycation end-products, glycosaminoglycans, mineral-to-matrix ratios, carbonate substitution, and mineral crystallinity were converted into normalized frequency distributions and modeled using gaussian functions. BMPDs were generated from undecalcified pMMA-embedded iliac biopsies (n=38) and routinely processed decalcified paraffin-embedded osteomedullary biopsies (n=21). The analytical framework was validated against conventional two-dimensional Raman mapping, and reproducibility, interindividual variability, and demographic influences were evaluated. Results: BMPDs were consistently well described by gaussian functions (typically R2 > 0.95), allowing extraction of three descriptors for each biochemical parameters: Mean, Peak, and Width. One-dimensional line scans showed excellent agreement with conventional two-dimensional Raman mapping while reducing acquisition time approximately 100-fold. Technical variability remained substantially lower than biological variability for all parameters, and a single trabecular line scan provided reliable estimates of BMPD descriptors for nearly all Raman-derived indices. Cortical bone exhibited narrower BMPDs than trabecular bone, indicating lower biochemical heterogeneity. Comparable BMPDs were obtained from undecalcified and routinely decalcified specimens, demonstrating robustness to tissue processing. No significant associations with age or sex were observed after correction for multiple testing. Reference BMPDs further enabled visualization and standardized quantification of deviations in representative pathological bone biopsies. Conclusions: Quantitative Raman analysis introduces BMPDs as a novel framework for assessing the spatial heterogeneity of bone extracellular matrix composition. By extending Raman microspectroscopy beyond conventional mean measurements, BMPDs provide robust, reproducible descriptors of bone material organization and establish a methodological foundation for investigating alterations of bone quality in metabolic bone diseases.

physiology↗

bioRxiv2025

Multimodal analysis of osteoarthritic chondrocytes reveals mitochondrial alterations and patient-specific OxPhos response to bezafibrate

BackgroundOsteoarthritis (OA) is the most common joint disease and is characterized by bone remodeling, cartilage degradation and synovial inflammation. To date, no effective treatment is available for this debilitating condition. Recent evidence suggests that mitochondrial dysfunction, including oxidative phosphorylation (OxPhos) failure, accumulates within OA chondrocytes and may contribute to pathogenesis. In this context, mitochondrial dysfunction may be associated with observable changes in mitochondrial number, size and shape. However, a comprehensive characterization of mitochondria-related features during OA, from tissue-to-cell level, is still lacking. Addressing these gaps could inform therapeutic strategies, such as the partial restoration of OxPhos, which has been proposed as a therapeutic approach. MethodsHere, we employed a multimodal approach that included Fourier-transform infrared spectroscopy (FTIR), scanning transmission electron microscopy (STEM) and real-time cellular metabolic assays (Seahorse technology) to better characterize mitochondrial parameters in cartilage during OA. Two types of experimental models were used using human cartilage: (1) undamaged versus damaged OA zones, and (2) non-OA versus OA samples. In addition, we investigated the potential of repurposing bezafibrate, an approved peroxisome proliferator-activated receptor (PPAR) agonist, as a mitochondria-based therapy to restore OxPhos in OA chondrocytes. ResultsWe identified that OA chondrocytes exhibit a decrease in glycogen deposits surface, and an increased number of mitochondria alongside an OxPhos dysfunction compared to non-OA chondrocytes. A similar trend toward glycogen storage deficiency and increased mitochondria number was observed in OA chondrocytes from damaged cartilage areas. Furthermore, multivariate analyses revealed that the clinical profiles of OA patients allowed OA chondrocytes to be separated into responders and non-responders to bezafibrate. ConclusionWe provide evidence that OA chondrocytes display decreased glycogen deposits surface, increased mitochondrial number and OxPhos dysfunction. Additionally, we identified that bezafibrate, a PPAR agonist, improved OxPhos function in a subgroup of OA chondrocytes derived from patients.

pathology↗

bioRxiv2024

The GLP-1 analogue, exendin-4, improves bone material properties and strength through a central relay in ovariectomized mice

Glucagon-like peptide-1 (GLP-1) has previously been shown to be indispensable for optimal bone strength by acting at the bone material level. However, it was not fully clear whether the effects of GLP-1 were mediated by direct or indirect actions on bone cells. In the present study, we were unable to demonstrate the expression of the GLP-1 receptor (GLP-1r) in bone tissue at the gene expression level using qPCR and in situ hybridization, or at the protein level. Furthermore, the peripheral administration of exendin-4, a specific GLP-1r agonist, in ovariectomized (OVX) BALB/c mice enhanced post-yield displacement (18%) and energy-to-fracture (24%), as well as bone volume/total volume (BV/TV) (11%), trabecular number (Tb.N) (6%), and collagen maturity (18%). These bone effects were still observed when exendin-4 was centrally administered into the lateral cerebral ventricle. On the other hand, the peripheral administration of exendin-4 coupled to bovine serum albumin, a GLP-1r agonist that cannot penetrate the brain, failed to replicate the positive effects on bone despite increased calcitonin secretion. Altogether, these data confirm that GLP-1r agonists represent an interesting approach for managing bone fragility due to ovariectomy, but also suggest that GLP-1r agonists require a central relay yet to be identified to exert positive effects on bone physiology. Further studies are needed to decipher the mechanisms of action of GLP-1 and GLP-1r agonists on bone physiology.

physiology↗

bioRxiv2024

Raman mineral-to-matrix ratios correlate with weight percentage mineral-to-matrix ratio determined by in-SEM Raman imaging of bone tissue

Raman imaging combined with scanning electron microscopy (SEM) is a powerful technique that allows for topographical, chemical and structural correlative multi-scale imaging. It provides the perfect tool to determine which of the Raman mineral-to-matrix ratios represent the best parameter to accurately measure the degree of mineralization of the bone matrix using quantitative backscattered electron imaging (qBEI) as the reference methodology. Indeed, previous studies evidenced that the v2PO4 and v4PO4 vibrational modes were less sensitive to laser polarization than the v1PO4. However, using the v2PO4 or v4PO4 requires a longer acquisition time or lower spectral resolution. In the present study, we evaluated the correlation between mineral-to-matrix ratios computed from v1PO4 and v2PO4 in a human bone sample retrieved from orthopaedic surgery during hip replacement and wt% mineral / wt% organic matrix obtained from qBEI using the inLux SEM Raman interface. We reported here that all mineral-to-matrix ratios were significantly linearly correlated with wt% mineral / wt% organic matrix and that v1PO4/CH2 exhibited the strongest correlation coefficient (r=0.880). This study suggests that the v1PO4 is still a valid Raman peak to estimate the mineral-to-matrix ratio in bone samples and can be used to diagnose bone fragility disorders.

physiology↗

bioRxiv2024

Effects of vertical sleeve gastrectomy prior to pregnancy on bone mass, microarchitecture and material properties in the female rat

Obesity is a major public health issue worldwide. Despite various approaches to weight loss, the most effective technique for reducing obesity, as well as diabetes and associated diseases, is bariatric surgery. Increasingly, young women without children are undergoing bariatric surgery, vertical sleeve gastrectomy (VSG) being the most common procedure nowadays. However, despite several reports suggesting bone loss after VSG, little is known about the potential additive effects of gestation and lactation after VSG to bone health. This study investigated the combined effects of pre-gestational VSG and subsequent gestation/lactation on bone metabolism in a rat model fed a high fat high sugar (HFHS) diet, with a focus on bone biomechanics, mass, microarchitecture and material properties. Furthermore, bone mass and remodelling was followed longitudinally by microCT prior to surgery, 4 weeks post-surgery, after weaning and at sacrifice. Significant alterations in bone mass and microarchitecture, characterized by changes in trabecular thickness and number, as well as changes in bone formation and resorption were influenced by both surgery and reproductive demands. Mechanical testing at sacrifice demonstrated compromised long bone fragility, in rat with HFHS regardless of the surgical procedure (Sham or VSG). Furthermore, analysis of bone material properties highlighted potential disruptions in the pattern of bone mineralization in sham and VSG animals fed a HFHS diet. These findings underscore the complex interplay between pre-gestational VSG and subsequent gestation/lactation in modulating bone metabolism. Understanding these combined effects is essential for optimizing surgical strategies and developing targeted interventions to mitigate potential bone-related complications associated with VSG in reproductive-aged individuals.

physiology↗

bioRxiv2023

Validation of Fourier transform infrared microspectroscopy for the evaluation of enzymatic cross-linking of bone collagen

Enzymatic cross-linking of the bone collagen is important to resist to crack growth and to increased flexural strength. In the present study, we proposed a new method for assessment of enzymatic cross-link based on FTIR microspectroscopy that takes into account secondary structure of type I collagen. Briefly, femurs were collected from sham or ovariectomized mice and subjected either to LC-MS or embedded in polymethylmethacrylate, cut and analyzed by FTIR microspectroscopy. FTIR acquisition were recorded before and after UV exposure or acid treatment. In addition, femurs from a second animal study were used to compare gene expression of Plod2 and Lox enzymes and enzymatic cross-links determined by FTIR microspectroscopy. We evidenced here that intensities and areas of subbands located at [~]1660 cm-1, [~]1680 cm-1 and [~]1690 cm-1 were positively and significantly associated with the concentration of pyridinoline (PYD), deoxypyridinoline (DPD) or immature dihydroxylysinonorleucine (DHLNL) / hydroxylysinonorleucine (HLNL) cross-links. Seventy-two hours exposure to UV light significantly reduced by [~]86% and [~]89% the intensity and area of the [~]1660 cm-1 subband. Similarly, 24 hours of acid treatment significantly reduced by 78% and 76% the intensity and area of the [~]1690 cm-1 subband. Plod2 and Lox expression were also positively associated to the signal of the [~]1660 cm-1 and [~]1690 cm-1 subbands. In conclusion, our study provided a new method for decomposing the amide I envelope of bone section that positively correlates with PYD and immature collagen cross-links. This method allows for investigation of tissue distribution of enzymatic cross-links in bone section.

biochemistry↗

bioRxiv2022

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

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.

pharmacology and toxicology↗