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

Area of Science:

• Bone biology and mechanobiology
• Skeletal adaptation and aging
• Molecular regulation of bone remodeling

Background:

• Bone adapts to mechanical forces, but this ability diminishes with age, increasing fracture risk.
• Identifying molecular regulators is crucial for developing therapies to preserve bone health.
• Aging impairs bone's adaptive capacity, necessitating research into its underlying mechanisms.

Purpose of the Study:

• To identify key genes regulating bone's response to mechanical loading using spatial transcriptomics.
• To functionally investigate the role of Slc13a5 in bone mechanoadaptation.
• To explore Slc13a5 as a potential therapeutic target for bone fragility.

Main Methods:

• Spatial transcriptomics (GeoMx, NanoString) on murine tibia under mechanical loading.
• Validation with bulk RNA-seq and laser-capture microdissection data.
• Conditional deletion of Slc13a5 in osteolineage cells (Slc13a5 cKO mice) for functional analysis.

Main Results:

• Identified 12 genes consistently regulated by mechanical loading across platforms.
• Slc13a5 deletion in osteolineage cells enhanced loading-induced mineralization in tensile regions.
• Slc13a5 cKO mice showed reduced bone resorption around the neutral axis after loading.

Conclusions:

• Slc13a5 regulates bone adaptation, particularly in areas with low mechanical stimulation.
• Slc13a5 is a potential therapeutic target for improving bone mechanoadaptation.
• Spatial transcriptomics is a valuable tool for discovering novel targets in bone biology.