MSCs lineage commitment regulated by CUL4B

Dysregulation of mesenchymal stem cells (MSCs) lineage specification contributes to reduced bone mass and increased marrow adipose tissue (MAT) in skeletal aging and osteoporosis. Cell intrinsic mechanisms that regulates the age-related switch in MSC commitment remains to be elucidated. Here, we identify Cullin 4B (CUL4B) as a critical switch of cell fate decisions of MSCs. CUL4B expression decreased with aging in mouse and human bone marrow MSCs (BMSCs). Loss of CUL4B promoted adipogenic differentiation of BMSCs at the expense of osteogenic differentiation. Mice depleted of CUL4B in MSCs exhibited increased age-related bone loss, MAT accumulation and decreased bone strength.