“Divergence between catabolic and anabolic senescence underlies sex dimorphism of osteoarthritis.”
COBRE for Skeletal Health and Repair
Sex dimorphism is an important property of aging-related diseases (ARDs). For example, women are more prone to erosive osteoarthritis (OA), with a female to male ratio of 12:1. However, the mechanism underlying sex dimorphism of ARDs is unknown. We show here that female and male OA patients present sex dimorphism in their stress-responsive microRNA, and catabolic and anabolic gene expression. Sex dimorphism manifests after sexual maturity during aging and results from the opposite responses to the stress signals in adulthood between male and females. Mimicking mechanical and pro-inflammatory stress, cartilage-specific transient expression of miR-365 results in joint degeneration in female mice while leading to more resistance to OA in male mice. Stress microRNA induces inflammaging and catabolic genes including MMP3 and 13, IL1ß in female while repressing them in male. Human OA patients present a striking divergence of catabolic and anabolic gene expression between female and male. While the SASP IL1ß and stress-responsive heat shock protein 70 are the top pathways activated in women, extra- and matri-cellular genes COL18A1 and LGALS3BP are the top pathways in men. Among seven cell populations identified in human OA cartilage, four are prevalent in female while three are prevalent in male. These sex-prevalent cell populations represent the diverging cell senescence pathways cultivating in catabolic senescence in female and anabolic senescence in male.
This study is supported by R61 AR076807 and P30 GM122732 to Qian Chen.