The building blocks of a structure are load-bearing elements that rarely change, despite renovation or repair. They remain intact and consistent over time, but in the human body, our building blocks do exactly the opposite.
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 brittle bones, and when the mutation is related to the amount of collagen produced – 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 to 50,000 people in the United States, but is also the most commonly inherited bone disease. It often begins in the uterus, and in many cases doctors can see fractures in the baby’s limbs before they’re even born. And these patients are likely to fracture multiple bones over the course of their lives. Meenal Mehrotra, MD, Ph.D., is an assistant professor in the Department of Surgery at South Carolina Medical University, and she says there is currently no cure for the disease. She also points out that while doctors focus primarily on treating the symptoms of brittle bones, doing so can have its own unpleasant side effects.
Your goal is to find a safer way to treat this devastating disease.
According to Mehrotra, healthy bone constantly undergoes and remodels its own microfractures.
Bone-breaking cells known as osteoclasts eat away at the affected area. And then osteoblasts, which are bone-forming cells, come along and rebuild that part of the bone.”
Meenal Mehrotra, Assistant Professor, Department of Surgery, Medical University of South Carolina
There are drugs called bisphosphonates currently used to treat brittle bone disease that affect osteoclast levels. More bone is formed as a result of the breakdown of osteoclasts and thus bone loss. But Mehrotra says this doesn’t fix the root problem because the bone formed is also inherently flawed.
In a recent article in iScience, The team is studying regulatory T cells, or Treg cells, as a previously unstudied treatment for brittle bone disease. Treg cells help maintain balance and homeostasis in the body by keeping immune cell (T-cell) activity in check. When activated, T cells release cytokines, which in turn lead to inflammation. But when there are enough Treg cells, T cells aren’t activated as much, which means there are fewer cytokines and less inflammation.
They found that the internal environment of mice with this disease is hyperinflamed due to fewer Tregs. Mehrotra hypothesized that increasing these Treg levels in mice with brittle bone disease could lead to untapped treatment options.
Through Treg transplants, researchers proved that increasing the number of Tregs actually promotes bone remodeling, which in turn leads to stronger bones.
Mehrotra and her team tested Treg cell transplantation with both the affected mouse’s own T cells (autograft) and T cells from a donor mouse (allograft) and compared the results. While both methods resulted in higher Treg cells and stronger bones, she found that treatment results can last longer if the subject’s own Treg cells are extracted and those levels increased before transplanting them back.
In both transplants, Mehrotra saw an increased number of osteoblasts and a decreased number of osteoclasts. It was more of a balance. “It’s very exciting,” she said. “We saw better bone architecture and better bone mechanics. The bones were stiffer.”
But the most exciting thing for her is that although allograft and autograft both worked, the results with autograft were better than allograft. From a possible clinical perspective, the use of the patient’s own cells would allow for reduced donor rejection and the elimination of immunosuppressive drugs. “It would be easier for 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 found that no one had looked at Treg cell transplantation as an immunotherapeutic treatment option for patients with this disease. She looks forward to continuing this promising line of research in the future.
Next, she wants to investigate why a genetic disease of collagen mutation, which appears unrelated to immunity, is immunologically deficit.
And then she wants to look at how the increase in Tregs actually causes the positive changes in the bone. “That’s the other piece of the puzzle for me,” she said.
Answering both questions will help bring Treg cell transplantation to clinics for people with brittle bone disease.
Source:
Medical University of South Carolina
Magazine reference:
Kang, I.-H., et al. (2022) Quantitative increase in regulatory T cells enhances bone remodeling in osteogenesis imperfecta. iscience. doi.org/10.1016/j.isci.2022.104818.