Deciphering the RSPO3-NFATC1 Switch in the Bone-Cartilage Paradox: Genetic Liability to Osteoporosis Protects Against Osteoarthritis by Modulating Subchondral Bone Compliance

Osteoarthritis Cartilage. 2026 May 30:S1063-4584(26)00921-0. doi: 10.1016/j.joca.2026.05.013. Online ahead of print.

ABSTRACT

BACKGROUND: The clinical “bone-cartilage paradox” between osteoporosis (OP) and osteoarthritis (OA) remains controversial. Deciphering their causal link and underlying molecular switches is crucial for the integrated management of concurrent musculoskeletal diseases.

OBJECTIVE: To investigate the OP-OA relationship and explore key regulatory nodes at tissue and single-cell resolutions.

METHODS: This computational study integrated bidirectional Mendelian randomization (MR) using large-scale GWAS summary statistics, GTEx eQTL mapping, and transcriptomic analyses of bulk (GSE114007, GSE176223) and single-cell (GSE196678) RNA-seq data.

RESULTS: Genetic predisposition to OP demonstrated evidence consistent with a protective association against OA development, particularly in weight-bearing joints: total OA (OR=0.96, 95% CI: 0.94-0.98), knee OA (OR=0.42, 95% CI: 0.28-0.63), and hip OA (OR=0.30, 95% CI: 0.09-0.98). Reverse MR analysis showed little evidence of a causal effect of OA on OP risk. Transcriptomic exploration revealed that NFATC1 was substantially downregulated while RSPO3 was upregulated in established OA cartilage. Single-cell analysis localized NFATC1 expression predominantly to osteoclasts and RSPO3 to stromal progenitor cells in the subchondral bone. Furthermore, NFATC1 expression positively correlated with chondroprotective markers ( COL2A1, ACAN) and negatively with catabolic enzymes ( MMP13).

CONCLUSIONS: OP may protect against OA by maintaining subchondral bone compliance, potentially through Wnt-mediated RSPO3 signaling and NFATC1 -driven remodeling. While functional experimental validation is required, these integrated multi-omics findings provide a novel theoretical framework for the bone-cartilage paradox, indicating that targeting the RSPO3-NFATC1 axis could be a potential strategy to decouple bone loss from joint degeneration.

PMID:42218990 | DOI:10.1016/j.joca.2026.05.013