Sex-determining region Y (SRY) attributes to gender differences in RANKL expression and incidence of osteoporosis

Abstract

Receptor activator of nuclear factor κB ligand (RANKL) plays a crucial role in bone metabolism. RANKL gene misregulation has been implicated in several bone and cancer diseases. Here, we aimed to identify novel transcription regulators of RANKL expression. We discovered that transcription factors, sex-determining region Y (SRY) and c-Myb, regulate RANKL expression. We demonstrated that c-Myb increases and male-specific SRY decreases RANKL expression through direct binding to its 5’-proximal promoter. These results are corroborated by the gene expression in human bone samples. In osteoporotic men, expression of RANKL is 17-fold higher, which correlates with the drastically reduced expression (200-fold) of Sry, suggesting that in osteoporotic men, the upregulation of RANKL is caused by a decrease of Sry. In healthy men, the expression of RANKL is 20% higher than that in healthy women. Our data suggest that gender differences in RANKL expression and bone quality could be due to the sex-specific transcription factor SRY. A male-specific gene offers clues to diagnosis and treatment of age-related osteoporosis. Osteoporosis was known to be linked to higher expression levels of RANKL, a gene that induces bone resorption, but the details were poorly understood. Nika Lovsin at the University of Ljubljana in Slovenia and co-workers searched for the genetic switches that control RANKL levels. They found that SRY, a gene on the male-specific Y chromosome, was a strong repressor of RANKL. In bone samples from osteoporotic men, expression levels of SRY levels were low and those of RANKL were high, suggesting that in men, when SRY fails to keep the bone-resorbing RANKL in check, osteoporosis results. SRY shows promise as an osteoporosis marker in men, or for development of treatment for both genders. Future research could address what triggers decreased SRY expression in men.