Single-cell sequencing reveals TBXA2R–ACSL1 axis amplifies RANKL-driven osteoclast differentiation in rheumatoid arthritis

Joint destruction in rheumatoid arthritis (RA) has long been attributed to inflammation itself, but how activated platelets convert inflammatory signals into bone erosion remained unclear: the peer-reviewed paper states that activated platelets contribute to inflammation in RA, yet how platelet-derived signals promote bone erosion was poorly understood [C]. TXA2, a major mediator released by activated platelets, promotes the formation of bone-resorbing osteoclasts through the thromboxane A2 receptor, and markers of TXA2 biosynthesis are increased in RA patients [C]. This study, published on October 15, 2026 in Nature Communications (Nat Commun 17, 10610) by the team of Huang Runyue and Wang Maojie at the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, shows that urinary 11-dehydro-TXB2 and synovial TXB2 levels are significantly elevated in RA patients; in vitro, the TBXA2R agonist U46619 alone cannot replace RANKL but enhances RANKL-induced TRAP-positive multinucleated osteoclast formation and expression of Acp5, Ctsk, Nfatc1, and Car2, while antagonists STD, SQ or siRNA knockdown of Tbx2r suppress this process (needs verification).

The core advance lies in using single-cell sequencing to pinpoint where TBXA2R inhibition acts: scRNA-seq of BMMs cultured for 4 days under control, RANKL, and RANKL+STD conditions retained 124,369 cells after quality control and identified 7 major cell populations; the osteoclast differentiation subpopulation was re-clustered into 9 clusters, and cluster 8 was further resolved into 6 subclusters, of which subcluster 4, specifically expressing Mmp9, Acp5, and Ctsk, was annotated as mature osteoclasts. This subpopulation was significantly enriched in the RANKL group and markedly reduced in the RANKL+STD group, but STD did not reduce the overall proportion of cluster 8, indicating that TBXA2R inhibition selectively lowers the probability of cells entering terminal maturation rather than eliminating a cell population. Pathway enrichment showed that cluster 8 and subcluster 4 enriched osteoclast differentiation, OXPHOS, and TCA cycle programs under RANKL, which were coordinately downregulated after STD. Mechanistically, TBXA2R maintains ACSL1 expression via the PGC-1β/PPARγ axis, supporting fatty acid oxidation-derived acetyl-CoA supply needed for mitochondrial energy metabolism [C]; Seahorse assays confirmed that STD or SQ significantly weakened RANKL-induced maximal respiration and spare respiratory capacity, and the ACSL inhibitor triacsin C mimicked this effect.

In vivo, STD or SQ treatment in CIA mice alleviated joint inflammation and bone destruction, reduced TRAP-positive osteoclasts and lowered joint expression of PGC-1β, PPARγ, and ACSL1; germline Tbx2r knockout mice showed no obvious skeletal abnormalities at baseline, but after CIA induction displayed milder pathology, fewer osteoclast accumulations, and better bone microstructure, consistent with the paper's conclusion that receptor inhibition or genetic deletion reduces osteoclast accumulation and bone destruction in mice [C].

Information not yet disclosed includes whether STD or SQ have any clinical translation plans, related patent and licensing arrangements, and validation of this mechanism in female mice or RA patients; these await confirmation in subsequent studies.