A Bone-Protective Role for IFN-γ? Evidence from Genetic Association and Osteoblast Functional Assays in Postmenopausal Osteoporosis

: Osteoporosis (OP) is a complex disease in which several immune-related genes have been identified as contributing to susceptibility and disease progression. Despite efforts to achieve functional validation, many of these genes, such as interferon-gamma (IFNG), remain the subject of unresolved mechanisms. The present study aimed to examine whether the IFNG -1616 (G>A, rs2069705) polymorphism was associated with postmenopausal OP. A total of 251 OP patients and 115 healthy controls were genotyped to assess the association between the IFNG -1616 (G>A, rs2069705) polymorphism and osteoporosis. To further investigate the biological role of IFN-γ in bone metabolism, human SaOs-2 osteosarcoma cells were treated with recombinant IFN-γ (2 and 100 U/mL), and calcification and cell viability were evaluated using Alizarin Red staining and the MTT assay, respectively. We found that the IFNG rs2069705 G allele was associated with an increased risk of OP (OR = 1.45, 95% CI = 1.03-2.05, p = 0.03). Furthermore, serum IFN-γ levels did not differ significantly between genotype groups. In SaOs-2 cells, IFN-γ (2 U/mL) significantly increased viability (p = 0.017) and enhanced calcification in a dose-dependent manner. The IFNG rs2069705 G allele may confer susceptibility to postmenopausal OP. IFN-γ promotes osteoblast viability and mineralization at low concentrations, suggesting a potential anabolic role that warrants further investigation in human primary osteoblasts.