Hox genes in the adult skeleton: Novel functions beyond embryonic development

Abstract

Hox genes encode evolutionarily conserved transcription factors that control skeletal patterning in the developing embryo. They are expressed in regionally restricted domains and function to regulate the morphology of specific vertebral and long bone elements. Recent work has provided evidence that Hox genes continue to be regionally expressed in adult tissues. Fibroblasts cultured from adult tissues show broadly maintained Hox gene expression patterns. In the adult skeleton, Hox genes are expressed in progenitor-enriched populations of mesenchymal stem/stromal cells (MSCs), and genetic loss-of-function analyses have provided evidence that Hox genes function during the fracture healing process. This review will highlight our current understanding of Hox expression in the adult animal and its function in skeletal regeneration. Developmental Dynamics 246:310-317, 2017. © 2016 Wiley Periodicals, Inc.

Keywords: Hox genes; adult mesenchymal stem/stromal cells; fracture repair and regeneration; skeletal development.

Fig. 1. Schematic of Hox gene clusters and regional expression in the embryo

Each line represents an area of a single chromosome. Color-coding of Hox genes show the conserved relationships between Drosophila and mammalian Hox genes, and the paralogous relationships within the mammalian cluster. The depiction of the mouse skeleton reflects the anterior to posterior patterning of the axial skeleton and the proximal to distal patterning of the limb skeleton.

Fig. 2. Expression of Hox11 during development and fracture repair

Hox11-expressing cells are expressed through embryonic development, postnatal, and adult stages, as well as during fracture healing. In the embryonic skeleton, Hox11-expressing cells are observed in the outer perichondrium surrounding the cartilage anlagen of the skeleton. During postnatal stages and adult stages, Hox11 continues to be expressed in the outer periosteum surrounding the limb skeleton. It is additionally expressed in the bone marrow at both of these stages, and very highly in the endosteum during postnatal growth. Following fracture injury, Hox11-expressing cells expand with the forming callus.

Fig. 3. Schematic of Hox gene expression in the adult skeleton

Recent data lead to a proposed model where Hox genes are expressed in adult bone marrow MSCs. The expression of Hox genes in these cells mirrors the regionally restricted pattern of expression and function during embryonic development.