Epigenetic Patterns in Musculoskeletal Disease: Methylation of DKK1, RHOJ, and SOX6 Genes in Osteoarthritis and Osteoporosis

Osteoarthritis (OA) and osteoporosis (OP) are prevalent conditions with a complex relationship, yet their shared epigenetic mechanisms remain poorly understood. While genes like DKK1, RHOJ, and SOX6 have been implicated in both diseases, the specific role of individual CpG sites has not been fully characterized. We investigated CpG methylation in these genes using bisulfite pyrosequencing of peripheral blood DNA from n = 96 postmenopausal women: n = 24 with comorbid OA and OP, n = 34 with OA, and n = 38 healthy controls. Methylation differences were analyzed using statistical tests and logistic regression. Comorbid patients showed significant hypermethylation at two DKK1 CpG sites compared to the OA-only group (padj = 0.0007 and padj = 0.042). Conversely, one DKK1 site was hypomethylated in the OA-only group relative to controls (padj = 0.03). A regression model combining three DKK1 sites and one SOX6 site demonstrated predictive value for comorbid disease, with an AUC of 0.696. These findings identify site-specific methylation of DKK1 and SOX6 as a molecular signature associated with comorbid OA and OP, offering new insights into their shared etiology.