Reactivation of Hox gene expression during bone regeneration

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Abstract
Previous studies have explored the link between bone regeneration and skeletogenesis. Although a great deal is known regarding tissue and cell based events, especially those involving ossification and chondrogenesis, much remains unknown about the molecular similarity of repair and development. Since the functional significance of Homeobox (Hox) genes in embryonic skeletogenesis has been well documented through knockout and deficiency studies, we chose to investigate whether members of this family are reactivated during fracture repair. Specifically, we examined the temporal and spatial expression of Msx-1, Msx-2, rHox, Hoxa-2 and Hoxd-9, because of their involvement in limb development. Utilizing quantitative reverse transcriptase RT-PCR (qPCR), mRNA levels from all five genes were shown to be upregulated during fracture repair at all times tested (post-fracture day 3-21), as compared to intact bone. Further, using in situ hybridization and immunohistochemistry, spatial expression of these genes was localized to osteoblasts, chondrocytes and periosteal osteoprogenitor cells found within the fracture callus, the foremost cells responsible for the reparative phase of the healing process. Given the contribution of Hox genes in skeletal development, our results suggest that these genes are involved in either the patterning or formation of the fracture callus, further supporting the notion that bone regeneration recapitulates skeletal development.