Fatty Acid Oxidation has Age-dependent Effects on Osteoblast Function

During skeletal aging, the bone remodeling cycle becomes dysregulated when bone resorption by osteoclasts outpaces bone formation by osteoblasts. Bone matrix mineralization by osteoblasts is an energy demanding process, and our lab seeks to better understand the fuel selectivity and utilization of energetic precursors by osteoblasts during age-related bone loss. Previous data from our lab underscored the importance of fatty acids as an energy source for bone formation in young (3 month) mice as mice deficient for carnitine palmitoyltransferase 2 (Cpt2 flox/flox ; Ocn-Cre), an obligate enzyme in mitochondrial long chain fatty acid beta-oxidation, exhibited lower trabecular bone volume than littermate controls. However, the impact of fatty acid catabolism during skeletal maturity and advanced aging remains unknown. To begin this study, we reanalyzed a publicly-available RNAseq dataset (GSE72815) comparing gene expression in human bone biopsies from young and geriatric female participants. A general pattern of increased expression of genes involved in fatty acid catabolism was evident in aged samples with the expression of SLC27a1, SLC27a5, and SLC27a6, involved in fatty acid uptake, being significantly up-regulated. These results were confirmed by qPCR analysis of RNA isolated from young (4 month) and aged (20 month) mouse femoral bone, and further supported by the increased fatty acid uptake in osteoblast cultures isolated from aged mice relative to young mice. To determine the significance of the shift towards increased fatty acid utilization in aging bone, we examined the skeletal phenotype of Cpt2 knockout mice and control littermates at 6 or 20 months of age. In contrast to the phenotype of 3-month-old Cpt2 knockout mice, bone mineral density was comparable to controls in male mutants at 6 months of age, then trended higher in the mutants at 20 months of age. MicroCT suggested the increase in BMD was due to a significant increase in cortical thickness at the femoral mid-diaphysis. In line with this finding, femurs from mutant mice exhibited increased bending rigidity and failure load. Because cellular senescence is a hallmark contributing to aging phenotypes, we examined the effect of senescent burden on the bone microenvironment in aged Cpt2 KO compared to controls. Reduced expression of cell cycle inhibitor CDKN2A, as well as senescent associated secretory phenotype (SASP) genes suggest an impact on senescent load in femoral bone due to the attenuation of lipid catabolism. These data suggest fatty acid oxidation has distinct age-dependent effects on osteoblast function and skeletal homeostasis, and disruption of this catabolic pathway could alter the senescent phenotype contributing to age-related bone loss. NIH DK099134 and NIH AR077533 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.