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FABP4 as a critical mediator in osteoporosis: inhibition strategies and therapeutic potential

ABSTRACT: Fatty acid-binding protein 4 (FABP4), a key lipid protein in metabolism and inflammation, has been suggested to be linked to osteoporosis (OP), though direct evidence is scarce. Here, we present the first clear evidence of FABP4's significant role in OP, supported by clinical data and comprehensive in vivo and in vitro experiments. Elevated serum FABP4 in OP patients inversely correlates with bone mineral density (BMD), with similar trends observed in OVX mice. While FABP4 does not influence osteoblast differentiation, it promotes osteoclast formation and bone resorption. The FABP4 inhibitor BMS309403, with an IC50 of 0.89 μM, inhibits osteoclast differentiation by modulating calcium ions and suppressing the Ca2+-Calcineurin-NFATc pathway. Oral BMS309403 increased BMD in OVX mice, albeit less effectively than alendronate, whereas bone-targeted PLGA nanoparticles showed comparable efficacy to alendronate. This research identifies FABP4 as a promising therapeutic target for OP, with significant clinical implications.

ORGANISM(S): Mus musculus

PROVIDER: GSE273951 | GEO | 2025/02/01

REPOSITORIES: GEO

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	GSE273951_core_table_gene.txt.gz	Txt

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Project description:Purpose: Using RNA-sequencing technology to screen the effect of moderate-intensity treadmill exercise on the key genes that affect bone mass in the peripheral blood mononuclear cells (PBMCs) of ovariectomized (OVX) rats. Methods: Three-month-old female Sprague–Dawley rats of Specific Pathogen Free (SPF) grade were randomly divided into the sham operation (SHAM) group, OVX group, and OVX combined exercise (OVX+EX) group. The OVX+EX group performed moderate-intensity treadmill exercise for 17 weeks. Upon completion of these exercises, the body composition and bone mineral density (BMD) were measured using dual-energy X-ray absorptiometry, and the bone microstructure of the femur was observed using micro-computed tomography scanning. PBMCs were collected from the abdominal aorta, and the differential genes were analyzed by transcriptome sequencing. The Metascape software was used for gene ontology and pathway enrichment analysis to further screen key genes. Results: 1. In the OVX group, the body weight and body fat content were significantly higher than in the SHAM group and the body muscle content and BMD were significantly lower. 2. The trabecular bone parameters in the OVX group were significantly lower than in the SHAM group, and they were significantly higher in the OVX+EX group than in the OVX group. When compared with the SHAM group, the microstructure of the distal femur trabecular in the OVX group was severely damaged, the trabecular bones were sparse, and there was a large gap between the trabecular bones. The number and continuity of the trabecular bones were higher in OVX+EX group than in the OVX group. 3. A Venn diagram showed that there were 58 common differential genes, with a fold change ≥2 and p value <0.05. and the differential genes were mainly enriched in the PI3K-Akt signaling pathway. Five key genes were screened including CCL2, Nos3, Tgfb3, ITGb4, and LpL. Conclusion: Moderate-intensity treadmill exercise may improve the body composition and bone mass of the OVX group by upregulating CCL2 and other genes of the PBMC. The results also showed that the PBMCs in the peripheral blood can be a useful tool for monitoring the effect of exercise on bone health in postmenopausal osteoporosis.

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FABP4 as a critical mediator in osteoporosis: inhibition strategies and therapeutic potential

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