How the Body’s ‘Zip Code’ Proteins Help Heal Our Bones As We Age

The Context: Our bones keep specialized pools of stem cells on hand to aid in general upkeep and injury repair throughout our lives, but this process becomes less effective as we age, which is why our bones can start to degenerate. When we are developing in the womb, special proteins called HOX proteins act as zip codes for these stem cells, specifying where our limbs grow. These proteins are also suspected to play a role in bone healing, but how exactly they do this was not well understood. 

The Study: HOX proteins help direct bone-forming stem cells to regenerate the bones in which they reside, finds a new study in Development co-led by NYSCF – Druckenmiller Fellow Sophie Morgani, PhD, of NYU. Increasing activity of one particular HOX gene bolstered bone repair capacity in mice by one third.

The Importance: This study illuminates the process by which the body conducts bone repair, and points to HOX as a potential target scientists can leverage to promote more effective healing in aging and healing-compromised populations.

Anyone who has broken a bone is familiar with the healing process: you get a cast or a sling to keep it immobile, and your body does the rest. This is because our bones have an incredible ability to heal themselves thanks to the pool of stem cells they keep on hand to make healthy tissue and repair injuries. As we get older, however, this pool of stem cells depletes, and maintaining healthy bones becomes harder. The team set out to better understand how the process works, and how we might be able to intervene when it falters.

Stick and Stones May Break My Bones, But Stem Cells Will Heal Them

Our bones have two main reserves of stem cells to call upon when an injury occurs: one resides in the bone marrow (the spongy tissue at the center of our bones), and the other resides in the periosteum (the tough, outer layer of our bones). The team focused their attention on the periosteum stem cells, or ‘PSCPs’[RA1] .

Inside the stem cell pools, PSCSs exist on a spectrum of ‘stemness’: the youngest [RA2] ones are most primed to jump into action to heal wounds, whereas the ones who have matured a bit are more likely to take a backseat. To best heal wounds, there has to be enough of the young, eager, go-getter stem cells to lead the way, and this is what we lose as we age.

The team wondered if the HOX pathway’s role in bone development meant that it could influence how PSCSs behave and in turn their ability to heal bones. They started by decreasing HOX activity, which made the PSCSs more likely to mature faster, relegating them to the ‘too old and tired to help out’ crowd. Increasing HOX activity, however, helped keep them in an extended youthful state, perfect for wound healing.

Importantly, they found that increasing HOX activity doesn’t just keep young stem cells young — it helps turn back the clock on older PSCSs, reinvigorating them to chip in.

Excitingly, mice who had increased HOX activity showed a 32.5% better capacity to heal bone fractures. Altogether, these results suggest that the HOX system could be a prime target to leverage for interventions that promote bone healing.

“PSPCs have distinguishing characteristics that form the basis for future cell-based therapies, including their greater tendency to naturally regenerate bone than many related stem cell groups,” co-corresponding lead author Kevin Leclerc, a postdoctoral scholar in Dr. Leucht’s lab, told NYU. “By modifying Hox activity in these cells, we can help them regenerate bone more effectively in individuals with deficient bone-healing capacity.”

Sophie quote? Something like: “This study provides unique insights into how our bones heal, how the process becomes less effective as we age, and how we might be able to intervene via the HOX pathway to promote bone repair. This work was made possible in part by the NYSCF – Druckenmiller Fellowship, and I’m looking forward to building on it to help find innovative ways to keep our bones healthy as we age.”

Journal Article:

Hox genes are crucial regulators of periosteal stem cell identity

Kevin Leclerc, Lindsey H. Remark, Malissa Ramsukh, Anne Marie Josephson, Laura Palma, Paulo E. L. Parente, Margaux Sambon, Sooyeon Lee, Emma Muiños Lopez, Sophie M. Morgani, Philipp Leucht. Development. 2023. DOI: https://doi.org/10.1242/dev.201391

Photo credit: WILDPIXEL/GETTY, NYU