Hox Genes Found to be Essential for Bone Repair

A recent study led by researchers at NYU Langone Health has revealed that genes responsible for controlling neonatal bone formation also regulate bone healing later in life. Specifically, the study identified key Hox genes that control stem cells involved in both bone formation and repair. These Hox genes act like the body’s “zip code,” providing instructions for transcription factors that attach to DNA and influence gene action.

Hox genes guide immature stem cells as they mature in the womb, becoming heart muscle, nerves, and bones in the correct places. Bones and other tissues can reserve a pool of stem cells into adulthood that are ready to mature into needed replacement cells to maintain healthy and broken bones. During aging, stem cells become depleted, resulting in weaker bones that are more likely to fracture and slower to heal. 

To counter this loss in healing capacity, the research team increased the activity of a gene that directs the building of the Hoxa10 transcription factor in aging mice’s tibia. In turn, this caused a 32.5% restoration of fracture repair capacity.

A fundamental question in bone healing has been whether stem cells in the marrow in a bone’s center or those known to pool in the nearby periosteum, the outer bone layer made of tough connective tissue and cell-filled areas, are more important. Both types of stem cells can mature into osteoblasts, which lay down new bone in response to damage, but this study argues that stem cells in the periosteum, the periosteal stem and progenitor cells (PSPCs), are the essential contributors to bone repair.

The study’s results build on the understanding that stem cell pool maintenance relies on accurate signals to divide and multiply without maturing, maintaining their “stemness” until needed. The body regulates bone repair by controlling the degree to which stem cells stay immature, with the most primitive cells playing the most extensive role in healing due to their flexibility and ability to multiply quickly.

In this study, Hox deficiency increased the stem cells’ propensity to differentiate into mature bone cell types. Conversely, increasing Hoxa10 expression in tibia stem and progenitor cells reprogrammed them into a more stem-cell-like state, a needed step if they are to become new bone-making cells as part of healing.

According to the authors, PSPCs exist as a mixed stem cell population that includes those with the most stemness, naïve periosteal stem cells (PSCs), alongside more mature periosteal progenitor 1 (PP1s) and periosteal progenitor 2 (PP2s) cells.

The study authors found that Hoxa10 expression was most abundant in PSCs and was significantly reduced as cells progressed along the lineage hierarchy to PP1 and PP2. Increasing Hox gene activity in these more mature progenitors brought about a 3-fold increase of PSCs as cells were reprogrammed into a more primitive stem cell identity. These distinguishing characteristics of PSPCs could form the basis for future cell-based therapies, allowing researchers to help them regenerate bone more effectively in individuals with deficient bone-healing capacity.