Uridine Attenuates Osteoclastogenesis and Ovariectomy Induced Bone Loss by Modulating the PI3K/Akt–FoxO ROS Signaling Axis

ABSTRACT:

Osteoporosis is a metabolic bone disorder characterized by aberrant osteoclast activation, leading 

to excessive bone resorption and microarchitectural deterioration. Although the interconnection 

between osteoclast differentiation and cellular energy metabolism has been increasingly appreciated, 

the contribution of pyrimidine metabolism to this process remains largely undefined. Here, 

integrative transcriptomic and metabolomic profiling delineated a distinct metabolic remodeling 

during osteoclastogenesis and identified uridine as a pivotal metabolite exhibiting a pronounced 

decline upon RANKL stimulation. Functional and mechanistic studies demonstrated that exogenous 

uridine supplementation effectively restrained osteoclast formation and bone resorptive activity, 

concomitant with the downregulation of NFATc1 and CTSK expression. In OVX mice, uridine 

administration ameliorated trabecular microarchitecture, reduced osteoclast burden, and mitigated 

bone loss. Mechanistically, uridine inhibited PI3K/Akt phosphorylation, facilitated FoxO nuclear 

translocation, and suppressed ROS accumulation, thereby preventing NFATc1 activation and 

nuclear import. Collectively, this study uncovers a previously uncharacterized metabolic–signaling 

coupling mechanism linking pyrimidine metabolism to osteoclastogenesis and establishes uridine 

as a potential metabolic modulator for the prevention and treatment of osteoporosis. 

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13394 | MetaboLights | 2026-04-09

REPOSITORIES: MetaboLights