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Periosteum provides a major source of mesenchymal progenitor cells for bone fracture repair. Combining cell-specific targeted  Cox-2  gene deletion approaches with  in vitro  analyses of the differentiation of periosteum-derived mesenchymal progenitor cells (PDMPCs), here we demonstrate a spatial and temporal role for Cox-2 function in the modulation of osteogenic and chondrogenic differentiation of periosteal progenitors in fracture repair.  Prx1Cre -targeted  Cox-2  gene deletion in mesenchyme resulted in marked reduction of intramembraneous and endochondral bone repair, leading to accumulation of poorly differentiated mesenchyme and immature cartilage in periosteal callus. In contrast,  Col2Cre -targeted  Cox-2  gene deletion in cartilage resulted in a deficiency primarily in cartilage conversion into bone. Further cell culture analyses using  Cox-2  deficient PDMPCs demonstrated reduced osteogenic differentiation in monolayer cultures, blocked chondrocyte differentiation and hypertrophy in high density micromass cultures. Gene expression microarray analyses demonstrated downregulation of a key set of genes associated with bone/cartilage formation and remodeling, namely  Sox9 ,  Runx2 ,  Osx ,  MMP9 ,  VDR  and  RANKL . Pathway analyses demonstrated dysregulation of the HIF-1, PI3K-AKT and Wnt pathways in Cox-2 deficient cells. Collectively, our data highlight a crucial role for Cox-2 from cells of mesenchymal lineages in modulating key pathways that control periosteal progenitor cell growth, differentiation, and angiogenesis in fracture repair.

The Spatiotemporal Role of COX-2 in Osteogenic and Chondrogenic Differentiation of Periosteum-Derived Mesenchymal Progenitors in Fracture Repair