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Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

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The retinoblastoma protein family is intimately involved in the regulation of tissue specific gene expression during mesenchymal stem cell differentiation. The role of these proteins, pRB, p107 and p130, is particularly significant in differentiation to the osteoblast lineage, as human germ-line mutations of RB1 greatly increase susceptibility to osteosarcoma. During differentiation, pRB directly targets certain osteogenic genes for activation, including the alkaline phosphatase-encoding gene Alpl. Chromatin immunoprecipitation (ChIP) assays indicate Alpl is targeted by p107 in differentiating osteoblasts selectively during activation with the same dynamics as pRB, which suggests that p107 helps promote Alpl activation. Mouse models indicate overlapping roles for pRB and p107 in bone and cartilage formation, but very little is known about direct tissue-specific gene targets of p107, or the consequences of targeting by p107. Here, the roles of p107 and pRB were compared using shRNA-mediated knockdown genetics in an osteoblast progenitor model, MC3T3-E1 cells. The results show that p107 has a distinct role along with pRB in induction of Alpl. Deficiency of p107 does not impede recruitment of transcription factors recognized as pRB co-activation partners at the promoter; however, p107 is required for efficient recruitment of an activating SWI/SNF chromatin-remodeling complex, an essential event in Alpl induction.