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The identification of the molecular mechanisms controlling the degradation of regulatory proteins in mesenchymal stromal cells (MSC) may provide clues to promote MSC osteogenic differentiation and bone regeneration. Ubiquitin ligase‐dependent degradation of proteins is an important process governing cell fate. In this study, we investigated the role of the E3 ubiquitin ligase c‐Cbl in MSC osteoblast differentiation and identified the mechanisms involved in this effect. Using distinct shRNA targeting c‐Cbl, we showed that c‐Cbl silencing promotes osteoblast differentiation in murine and human MSC, as demonstrated by increased alkaline phosphatase activity, expression of phenotypic osteoblast marker genes (RUNX2, ALP, type 1 collagen), and matrix mineralization in vitro. Coimmunoprecipitation analyses showed that c‐Cbl interacts with the transcription factor STAT5, and that STAT5 forms a complex with RUNX2, a master transcription factor controlling osteoblastogenesis. Silencing c‐Cbl decreased c‐Cbl‐mediated STAT5 ubiquitination, increased STAT5 protein level and phosphorylation, and enhanced STAT5 and RUNX2 transcriptional activity. The expression of insulin like growth factor‐1 (IGF‐1), a target gene of STAT5, was increased by c‐Cbl silencing in MSC and in bone marrow stromal cells isolated from c‐Cbl deficient mice, suggesting that IGF‐1 contributes to osteoblast differentiation induced by c‐Cbl silencing in MSC. Consistent with these findings, pharmacological inhibition of STAT5 activity, or neutralization of IGF‐1 activity, abrogated the positive effect of c‐Cbl knockdown on MSC osteogenic differentiation. Taken together, the data provide a novel functional mechanism by which the ubiquitin ligase c‐Cbl regulates the osteoblastic differentiation program in mesenchymal cells by controlling Cbl‐mediated STAT5 degradation and activity. S TEM  C ells  2013;31:1340–1349

Promotion of Osteoblast Differentiation in Mesenchymal Cells Through Cbl‐Mediated Control of STAT5 Activity