Biology subjects

Meslier, Q. A.

Publications and source records attributed to Meslier, Q. A..

4 recordsLinked to original sources

bioRxiv2026

Spatial transcriptomics for gene discovery identifies Slc13a5 as a modulator of bone mechanoadaptation

Bone is a dynamic tissue that continuously adapts its structure in response to mechanical loading, an essential process for maintaining skeletal health. However, this adaptive capacity declines with aging, contributing to increased fragility and fracture risk. Developing therapeutic strategies that preserve or restore bone mechanoadaptation in patients with increased bone fragility requires identifying key molecular regulators of this process. We applied spatial transcriptomics (GeoMx, NanoString) to characterize gene expression changes induced by mechanical loading in the murine tibia, focusing on periosteal and bone compartments in regions under tension and compression. Spatial data were validated and cross-compared with previously published bulk RNA-seq and laser-capture microdissection datasets, identifying a set of 12 genes consistently regulated by loading across independent platforms and laboratories. As part of a functional analysis, we selected Slc13a5, a citrate transporter implicated in bone mineralization and metabolism. Conditional deletion of Slc13a5 in osteolineage cells using Osteocalcin-Cre significantly increased the loading-induced mineralizing surface in tensile regions compared with Cre- Slc13a5fl/fl littermates. In addition, Slc13a5 cKO mice exhibited lower resorption around the neutral axis after loading compared to controls. Together, these findings identify Slc13a5 as a regulator of bone adaptation in regions experiencing low mechanical stimulation and suggest it as a potential therapeutic target for conditions characterized by impaired mechanoadaptive responses. This study highlights spatial transcriptomics as a powerful gene discovery framework for bone, enabling identification of novel targets to understand mechanisms and develop therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/711126v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@14fc0e9org.highwire.dtl.DTLVardef@1023a16org.highwire.dtl.DTLVardef@133aa0eorg.highwire.dtl.DTLVardef@e19c86_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Combined effects of mechanical loading and Piezo1 chemical activation on 22-months-old female mouse bone adaptation

With age, bones mechanosensitivity is reduced, which limits their ability to adapt to loading. The exact mechanism leading to this loss of mechanosensitvity is still unclear, making developing effective treatment challenging. Current treatments mostly focus on preventing bone mass loss (such as bisphosphonates) or promoting bone formation (such as Sclerostin inhibitors) to limit the decline of bones mass. However, treatments do not target the cause of bone mass loss which may be, in part, due to the bones inability to initiate a normal bone mechanapdatation response. In this work, we investigated the effects of 2 weeks of tibia loading, and Piezo1 agonist injection in vivo on 22-month-old mouse bone adaptation response. We used an optimized loading profile, which induced high fluid flow velocity and low strain magnitude in adult mouse tibia. We found that tibia loading and Yoda2 injection have an additive effect on increasing cortical bone parameters in 22-month-old mice. This combination of mechanical and chemical stimulation could be a promising treatment strategy to help promote bone formation in patients who have low bone mass due to aging.

bioengineering↗

bioRxiv2024

3D spatial distribution of Sost mRNA and Sclerostin expression in response to in vivo mechanical loading

Bones adapt to external mechanical loads through a process known as mechanoadaptation. Osteocytes are the bone cells that sense the mechanical environment and initiate a biological response. Investigating the changes in osteocyte molecular expression following mechanical loading has been instrumental in characterizing the regulatory pathways involved in bone adaptation. However, current methods for examining osteocyte molecular expression do not preserve the three-dimensional structure of the bone, which plays a critical role in the mechanical stimuli sensed by the osteocytes and their spatially controlled biological responses. In this study, we used WISH-BONE to investigate the spatial distribution of Sost-mRNA transcripts and its encoded protein, sclerostin, in 3D mouse tibia midshaft following in vivo tibia loading. Our findings showed a decrease in the percentage of Sost-positive osteocytes predominantly at 25% and 37% of the bone length, and in the posterior-lateral side of the tibia after loading. Sclerostin-positive osteocytes in the loaded legs were found to be similar to the contralateral legs after 2 weeks of loading. This work is the first to provide a 3D analysis of Sost and sclerostin distribution in loaded versus contralateral mouse tibia midshafts. It also highlights the importance of the bone region analyzed and the method utilized when interpreting mechanoadaptation results. WISH-BONE represents a powerful tool for further characterization of mechanosensitive genes regulation in bone and holds potential for advancing the development of new treatments targeting mechanosensitivity-related bone disorders.

bioengineering↗

bioRxiv2024

WISH-BONE: Whole-mount In Situ Histology, to label osteocyte mRNA and protein in 3D adult mouse bones

Bone is a three dimensional and highly dynamic tissue under constant remodeling. Commonly used tools to investigate bone biology require sample digestion for biomolecule extraction or only provide two-dimensional spatial information. There is a need for 3D tools to investigate spatially preserved biomarker expression in osteocytes. In this work, we present a new method, WISH-BONE, to label osteocyte mRNA and protein in whole-mount mouse bone. For mRNA labeling, we used Hybridization Chain Reaction - Fluorescence In Situ Hybridization to label genes of interest in osteocytes. For protein labeling, samples were preserved using an epoxy-based solution that protects tissue structure and biomolecular components. Then an enzymatic matrix permeabilization step was performed to enable antibody penetration. Immunostaining was used to label various proteins involved in bone homeostasis. We also demonstrate the use of customized fluorescent nanobodies to target and label proteins in the cortical bone. However, the relatively dim signal observed from nanobodies staining limited detection. In this study, we share protocols, highlight opportunities, and identify the challenges of this novel 3D labeling method. They are the first protocols for whole-mount osteocyte 3D labeling of mRNA and protein in mature mouse bones. WISH-BONE will allow the investigation of molecular signaling in bone cells in their 3D environment and could be applied to various bone-related fields of research.

bioengineering↗