Matrix Gla protein suppresses osteoblast senescence and promotes osteogenic differentiation by the PI3K-AKT signaling pathway

Age-related bone loss in mice is associated with senescent cell accumulation and reduced bone formation by osteoblasts. Matrix Gla protein (MGP), secreted by osteoblasts, is pivotal in regulating the bone extracellular matrix mineralization.Previous research has demonstrated that Mgp null mice exhibit osteopenia and fractures, and ultimately die prematurely. To elucidate the mechanisms underlying MGPs role of MGP in bone metabolism, we generated osteoblast-specific Mgp knockout (Mgp cKO) mice by crossing Mgpfl/fl mice with Bglap-Cre mice. The study revealed that in 3-month-old Mgp cKO male mice, trabecular bone volume decreased, and the senescence marker protein p21 increased. Primary osteoblasts from Mgp cKO mice exhibited markers of DNA damage and senescence, such as increased rH2AX foci, p21, and senescence-associated b-galactosidase staining, as well as attenuated cellular proliferation and osteogenic differentiation abilities. Our results suggest that MGP is protective by suppressing osteoblast senescence, offering new insights into potential therapeutic strategies for age-related osteoporosis.