RNA-binding protein OTUD1 maintains skeletal homeostasis by determining mesenchymal stem cell lineage commitment.

Mesenchymal stem cells (MSCs) maintain bone homeostasis through osteogenic differentiation. During aging, MSCs undergo a fate shift toward adipogenesis rather than osteogenesis, but the post-transcriptional mechanisms remain unclear. Here, we identify ovarian tumor domain-containing protein 1 (OTUD1) as an RNA-binding protein that controls MSC fate by stabilizing osteogenic transcripts. OTUD1 directly binds and stabilizes BMP2 mRNA, thereby supporting osteogenic differentiation. In vivo, OTUD1 deficiency does not affect early skeletal development but progressively impairs bone homeostasis during aging and exacerbates bone loss in ovariectomy- and glucocorticoid-induced osteoporosis models. Structure-function analyses reveal that N-terminal intrinsically disordered region of OTUD1 mediates RNA binding and osteogenic activity, whereas its deubiquitinase catalytic domain is dispensable. Multi-omics profiling demonstrates that OTUD1 coordinates the stability of transcripts involved in collagen remodeling and extracellular matrix organization, thereby maintaining MSC stemness and activation. Together, these findings define a mechanism linking RNA stability control to MSC lineage commitment and skeletal homeostasis during aging and disease.