Hox11 function in Region-Specific Adult Mesenchymal Stem/Stromal Cells is Required for Fracture Repari.

Abstract

The mammalian skeleton boasts a remarkable capacity to completely restore the original structure and function of a bone following injury. Interestingly, the biological processes of fracture repair recapitulate many of the mechanisms of embryonic skeletal development. The Hox genes are critical regulators of skeletal development, yet the function of these genes during adult fracture repair is largely unknown. Ongoing research in the Wellik lab is focused on understanding the role(s) of these genes in this context.

The Hox genes encode evolutionarily conserved transcription factors that are imperative for patterning of the axial and limb skeleton in the developing embryo. Specifically, Hox11 genes function to instruct growth and morphology of the lumbar elements of the axial skeleton and the zeugopod elements (radius/ulna and tibia/fibula) of the limbs. Previous work using a Hoxa11eGFP allele showed that Hox11 is expressed through the latest stages of embryonic development. We have now discovered that Hox11 genes continue to be expressed in the adult skeleton and are largely restricted to the previously characterized PDGFRα+/CD51+/Leptin Receptor(LepR)+ mesenchymal stem/stromal cell (MSC) population in bone marrow. These Hox11-expressing MSCs expand in response to fracture injury and are maintained throughout repair. Loss of Hox11 function results in a significantly reduced ability to generate cartilage early in repair, and at late stages, the hard callus persists and is incompletely remodeled. Together, our data suggests that Hox11 functions in MSCs at multiple stages of repair, first, for endochondral ossification and later for bone remodeling. In addition, we show more generally that the Hox expression pattern established during embryonic development is maintained in the adult skeleton. Overall, this research provides novel evidence that Hox genes have critical roles beyond embryonic patterning and that these genes are expressed and function in adult MSCs.