Abstract
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.
Highlights
Fracture healing is a unique postnatal bone regeneration process that occurs as a cascade of well-orchestrated biological events leading to the restoration of bone tissue
Among the genes associated with bone/cartilage development and ossification, we identified 25 genes that were significantly suppressed at day 7 in the Cox-2 deficient cells (Fig. S3B), providing further evidence to show the disruption of bone morphogenetic pathway in micromass culture as a consequence of targeted Cox-2 gene deletion in periosteum-derived mesenchymal progenitor cells (PDMPCs)
During fracture healing mesenchymal progenitors residing in periosteum undergo osteogenic and chondrogenic differentiation to induce intramembranous and endochondral bone formation
Summary
Fracture healing is a unique postnatal bone regeneration process that occurs as a cascade of well-orchestrated biological events leading to the restoration of bone tissue. Analogous to embryonic skeletal development, periosteum-initiated fracture repair implicates endochondral and intramembranous bone formation, which proceed in a sequential and organized manner [5,6]. While adult bone repair recapitulates some essential regulatory mechanisms that occur in early skeletal development, repair is a unique bone morphogenetic process, orchestrated by an ensemble of genes distinct from early skeletal development [7]. Due to an inability to directly target the periosteum, the molecular mechanisms and the implicated molecular pathway(s) that control the differentiation program of periosteal mesenchymal progenitor cells in bone fracture repair remains poorly understood. Identifying the critical genes in periosteum-initiated bone repair, establishing their spatiotemporal expression, and elucidating their integrated roles will be essential to understand bone regeneration and to develop useful therapeutics to improve skeletal repair and reconstruction
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