The building blocks of a structure consist of load-bearing elements that rarely change despite renovations or repairs. They remain intact and consistent over time, but in the human body, our building blocks do just the opposite.
Our bones are dynamic: they constantly break down and rebuild to become the strongest versions of themselves.
A mutation in this bone regeneration process can lead to weak and fragile bones, and if the mutation is related to the generated amount of collagen – a protein found in bone, connective tissue, skin and cartilage – it leads to brittle bone disease.
Brittle bone disease, also known as osteogenesis imperfecta, currently affects 20,000-50,000 people in the United States but is also the most commonly inherited bone disease. It often begins in utero, and in many cases, physicians can see fractures in the baby’s limbs before they are even born. And these infants are likely to break multiple bones during birth as well. Meenal Mehrotra, M.D., Ph.D., is an assistant professor in the department of pathology and laboratory medicine at MUSC. She says physicians and researchers focus on treating the symptoms of brittle bones, but her goal is to find the root cause of the disease.
In a recent paper in Cell Press, Mehrotra and her team look at regulatory T cells, or Treg cells, as a previously uninvestigated source of brittle bone disease. The internal environment of people with this disease is often hyperinflamed, and since Treg cells suppress the body’s immune response, Mehrotra thought that treating Treg levels in patients with brittle bone disease could lead to untapped treatment options.
Through Treg transplantations in mice, the research team proved that the presence of Tregs enhances bone remodeling, which in turn will be helpful in developing immunotherapy-based treatments for people with brittle bone disease.
Treg cells help maintain balance and homeostasis in the body. Mehrotra describes their effects as a cascade, but instead of treating the symptoms that come from various steps along that cascade, she goes back to the beginning.
When activated, T cells release cytokines, which in turn lead to inflammation. But when enough Treg cells are present, T cells aren’t as highly activated, which means there are fewer cytokines and less inflammation.
Healthy bone constantly experiences and remodels its own microfractures, according to Mehrotra. “Bone-resorbing cells known as osteoclasts chew away at the affected area,” she said. “And then osteoblasts, which are bone-forming cells, come and rebuild that portion of the bone.”
There are medications called bisphosphonates that influence osteoclast levels. By reducing osteoclasts and thus bone breakdown, osteoblasts can better address microfractures. But Mehrotra says this doesn’t fix the root problem: osteoblast levels can’t keep up with osteoclast levels in patients with brittle bone disease.
In other words, bones are being broken down faster than they can be rebuilt.
Mehrotra and her team tested Treg cell transplantation with both the affected mouse’s own T cells (autotransplantation) and a donor mouse’s T cells (allotransplantation) and compared the results. While both methods resulted in higher levels of Treg cells, she found that by extracting the subject’s own Treg cells and increasing those levels before transplanting them back, treatment results actually lasted longer.
With both transplantations, Mehrotra saw increased osteoblast numbers and decreased osteoclast numbers. There was more of a balance. “It’s very exciting,” she said. “We saw better bone architecture and better bone mechanics. Bones were stiffer.”
The most exciting part to her is that while allotransplantation and autotransplantation both worked, autotransplantation lasted a full year, while allotransplantation lasted only 6 months. Projecting toward a potential clinical perspective, using a patient’s own cells would allow for less donor rejection and no use of immunosuppressants. “It would be easier on our patients,” she said.
After studying hematopoietic stem cells and brittle bone disease in a previous study, Mehrotra had the idea to look at Treg cells. And when she started researching the topic, she realized no one had yet looked at Treg cell transplantation as an immunotherapy treatment option for patients with this disease. She is looking forward to continuing this promising line of research in the future.
She next wants to look at why a genetic disease which seemingly has no relationship to immunity or collagen mutation has an immunological deficit in it.
And then she wants to look at T cells. “I want to know why my patients’ T cells are unable to develop into Treg cells. That’s the other part of the puzzle for me.”
Answering both questions will help bring Treg cell transplantation closer to clinics for people with brittle bone disease.