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

Source:

			Action	DRS
	a_MTBLS13394_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13394_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13394_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13394_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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