Discovery reveals the skeleton’s hidden repair system

How the fetal skeleton bounces back when growth goes off track

When things go wrong during growth, the body sometimes finds its own way to make things right again.

A new study, just published in Nature Communications, led by Dr Xinli (Cindy) Qu and Dr Ehsan Razmara in the Roselló-Díez Laboratory at the Australian Regenerative Medicine Institute (ARMI) has uncovered a natural self-repair system inside the developing skeleton that helps bones recover from early growth disturbances.

Before bones harden, they begin as a soft, flexible framework made of cartilage. This cartilage acts as a scaffold where new bone is built during development and throughout childhood. Growth is driven by special stem-like cells in a region called the growth plate, which add new layers of cartilage that later turn into bone. Keeping this process balanced is vital, and when it is disrupted, skeletal growth disorders can occur.

In this study, the team discovered that when cartilage growth is interrupted, a small population of stromal cells surrounding the cartilage can switch roles. Stromal cells are a type of connective tissue cell that usually provide structure and support, but here they act more like stem cells, transforming into cartilage-producing cells that restore normal bone growth.

These “repair cells,” marked by a gene called Gli1, then remain in the body as long-lived progenitors that continue supporting bone growth throughout childhood.

“The system is remarkably plastic, it’s like the skeleton has a built-in backup plan,” says senior author Associate Professor Alberto Roselló-Díez. “When growth goes off track, these cells step in to protect development.”

Peering inside growing bones

To uncover this repair process, Cindy, Ehsan and the team used advanced developmental models that allowed them to manipulate and track bone growth at the cellular level. By gently blocking cartilage growth in developing mice, they could see how the tissue responded to stress. Using sophisticated imaging and genetic techniques, Cindy tracked the behaviour of thousands of cells at multiple time points.

Her work revealed how these fetal cells not only give rise to the cartilage that eventually forms in juvenile animals, but also form part of the skeleton’s natural resilience system, capable of repairing cartilage and restoring normal growth.

To understand these patterns in greater depth, co-first author Ehsan Razmara led the computational analysis. Using high-resolution gene expression data, he examined which genes were active inside individual cells and how these patterns changed during repair. Genes such as Gli1 and Pdgfra act as molecular “markers” that tell scientists which cell types they are looking at and what roles those cells might be playing. By comparing these molecular signatures across thousands of cells, Ehsan was able to trace how certain stromal cells switched identity, moving from a supportive role outside the cartilage to an active, repair-focused role within it.

He also helped identify a key molecular switch called CCN2 or CTGF (Connective Tissue Growth Factor), which usually keeps these cells quiet. When growth slows and CCN2 levels fall, Gli1-positive cells activate and begin to repair.

Together, the imaging and computational work showed that the fetal skeleton contains a built-in mechanism to sense and respond to growth disturbances, ensuring bones can continue to form properly even when development falters.

Behind the microscope

For Cindy, this project represents nearly two decades of dedication to science at Monash University, from her early days at the Biomedical Discovery Institute to the seven years she has spent at ARMI.

Cindy still remembers the first moment that set her path: a Friday afternoon in the lab, peering through a microscope at living cells for the first time.

 “I found the exact cell we were looking for,” she recalls with a smile. “It was so exciting. I couldn’t wait for Monday to come so I could get back into the lab.”

That same curiosity has driven her through every challenge of this technically demanding project. Working at this early stage of development required the team to rethink standard methods and adapt their approach to suit the much smaller, more fragile tissues. The result was a new way of visualising how the skeleton forms and repairs itself during growth.

Why it matters

Understanding how the fetal skeleton repairs itself could transform approaches to treating childhood growth disorders, growth-plate injuries, and even cartilage loss in adults. In fact, the growth suppressor that the team used to slow down cartilage growth is abnormally abundant in the cartilage of people with achondroplasia (short-limb dwarfism), suggesting that the discovered repair mechanism could be used to treat this condition.

“If we can learn how to reactivate these pathways in a non-invasive way, we might one day repair cartilage without transplants,” Alberto says.

The study, Gli1-expressing stromal cells are highly reparative precursors of long-lived chondroprogenitors in the fetal murine limb, has just been published in Nature Communications.

About ARMI
The Australian Regenerative Medicine Institute (ARMI), based at Monash University in Melbourne, is a world leader in regenerative biology and stem cell research. ARMI works at the frontier of science, translating discovery into hope for people living with conditions like cancer, arthritis, dementia, neurodegenerative disease, rare disease and injury.

Media Contact:
Penny Fannin, Communications Consultant, ARMI
M: +61 (0) 417125700
E: penny.fannin@monash.edu