OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2

This study identified the deubiquitinase OTUB1 as a key regulator of osteogenesis by stabilizing fibroblast growth factor receptor 2 (FGFR2). Using global and osteoblast-specific Otub1 knockout mouse models, the authors demonstrated that OTUB1 deficiency results in severe bone mass loss, impaired mineralization, and reduced osteogenic differentiation. Mechanistically, OTUB1 inhibits SMURF1-mediated FGFR2 ubiquitination, preventing its lysosomal degradation and sustaining PI3K–AKT and MAPK pathway activation during bone formation. Restoration of FGFR2 expression via adeno-associated virus (AAV9)-mediated delivery rescued bone mass in knockout mice, and OTUB1 overexpression in ovariectomized (OVX) mice alleviated osteopenia. The findings reveal OTUB1 as a therapeutic target for age- and hormone-related osteoporosis.