Scientists at the Children’s Medical Center Research Institute at UT Southwestern (CRI) have identified a new mechanism by which exercise strengthens bones and immune function. Their studies in laboratory-grown cells and in mice, highlighted a specialized bone marrow niche where new bone and immune cells are produced, and demonstrated that movement-induced stimulation is required for the maintenance of the niche and the bone and immune-forming cells that it contains. They suggest the results point to the potential development of new therapeutic strategies that might increase bone formation and immune responses, particularly in the elderly.
“Past research has shown exercise can improve bone strength and immune function, and our study discovered a new mechanism by which this occurs,” said research lead Sean Morrison, PhD, CRI director, and a Howard Hughes Medical Institute investigator. Morrison and colleagues reported their findings in Nature, in a paper titled, “A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis.”
The Morrison laboratory had previously discovered the skeletal stem cells that give rise to most of the new bone cells that form during adulthood in the bone marrow. These Leptin receptor+ (LepR+) cells line the outside of blood vessels in the bone marrow and form critical growth factors for the maintenance of blood-forming cells. “Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of hematopoietic stem cells and early restricted progenitors,” the authors wrote in the newly released Nature paper.
The research had also demonstrated that a subset of LepR+ cells synthesize a previously undiscovered bone-forming growth factor called osteolectin, which promotes maintenance of the adult skeleton by causing LepR+ to form new bone cells.
The new studies collectively indicate that forces created from walking or running are transmitted from bone surfaces along arteriolar blood vessels into the marrow inside bones. The bone-forming cells that line the outside of the arterioles sense these forces and are induced to proliferate. This not only allows the formation of new bone cells, which helps to thicken bones, but the bone-forming cells also secrete a growth factor that increases the frequency of cells that form the immune system lymphocytes—B and T cells—around the arterioles.
But when the ability of the bone-forming cells to sense pressure caused by movement—mechanical forces—is inactivated, it reduces the formation of new bone cells and lymphocytes, causing bones to become thinner and, in the reported mouse experiments, reducing the ability of animals to clear a bacterial infection.
The research, by first author Bo Shen, PhD, a postdoctoral fellow in the Morrison laboratory, focused on the subset of LepR+ cells that make osteolectin. The researchers found that these cells reside exclusively around arteriolar blood vessels in the bone marrow and that they maintain nearby lymphoid progenitors by synthesizing SCF—a growth factor on which those cells depend. Further studies in experimental mice showed that deleting SCF from osteolectin-positive cells depleted lymphoid progenitors and undermined the ability of animals to mount an immune response to bacterial infection.
The investigators also found that the number of osteolectin-positive cells and lymphoid progenitors decreased with age. To see if this trend could be reversed, the researchers put running wheels in the cages so that the mice could exercise. The bones of these mice became stronger with exercise, while the number of osteolectin-positive cells and lymphoid progenitors around the arterioles increased. This result gave the team the first indication that mechanical stimulation regulates a niche in the bone marrow.
Shen and colleagues also found that osteolectin-positive cells expressed a receptor—known as Piezo1—on their surfaces, which signals inside the cell in response to mechanical forces. When Piezo1 was deleted from osteolectin-positive cells of mice, these cells and the lymphoid progenitors they support became depleted, weakening bones and impairing immune responses. “Deletion of the mechanosensitive ion channel PIEZO1 from osteolectin+ cells depleted osteolectin+ cells and common lymphoid progenitors,” the team wrote. “These results show that a peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during aging.”
Shen noted, “Together with our previous work, the findings in this study show osteolectin-positive cells create a specialized niche for bone-forming and lymphoid progenitors around the arterioles. Therapeutic interventions that expand the number of osteolectin-positive cells could increase bone formation and immune responses, particularly in the elderly.”
“As we age, the environment in our bone marrow changes and the cells responsible for maintaining skeletal bone mass and immune function become depleted,” Morrison noted. “We know very little about how this environment changes or why these cells decrease with age,” said Morrison. “We think we’ve found an important mechanism by which exercise promotes immunity and strengthens bones, on top of other mechanisms previously identified by others.”