Deciphering the RSPO3-NFATC1 switch in the bone-cartilage paradox: Genetic liability to osteoporosis protects against osteoarthritis by modulating subchondral bone compliance.

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.