You are hereSeptember 25, 2017
Mechanism behind age-associated bone loss described
Researchers have detailed an underlying mechanism that leads to a major health problem for older people, osteoporosis. When this mechanism malfunctions, progenitor cells stop creating bone-producing cells and instead create fat cells.
Osteoporosis is characterized by weak and brittle bones. According to the National Osteoporosis Foundation, studies suggest that approximately one in two women and up to one in four men in the United States age 50 and older will break a bone due to osteoporosis. Knowledge of the mechanism behind osteoporosis can provide targets in the search for novel bone-loss therapeutics to treat the condition with minimal side effects.
The researchers, from University of Alabama at Birmingham (UAB), found that a protein called Cbf-beta plays a critical role in maintaining the bone-producing cells. Furthermore, examination of aged mice showed dramatically reduced levels of Cbf-beta in bone marrow cells, as compared to younger mice.
Thus, they propose, maintaining Cbf-beta may be essential to preventing human age-associated osteoporosis that is due to elevated creation of fat cells.
Bone is a living tissue that constantly rebuilds. Bones need a constant new creation of cells specific to their tissue, including the bone-producing cells called osteoblasts. Osteoblasts live only about three months and do not divide.
The progenitor cells for osteoblasts are bone marrow mesenchymal stem cells (MSCs). Besides osteoblasts, mesenchymal stem cells can also differentiate into the chondrocyte cells that make cartilage, the myocyte cells that help form muscles and the adipocytes, or fat cells. Thus, the same progenitor cell has four possible tracks of differentiation.
UAB researchers and colleagues focused on the molecular mechanism that controls the lineage commitment switch between the osteoblast and adipocyte tracks. Led by Yi-Ping Li, Ph.D., UAB professor of pathology, and Wei Chen, M.D., UAB associate professor of pathology, they investigated the key role played by Cbf-beta, or core-binding factor subunit beta.
The team led by Drs. Li and Chen generated three mouse models by deleting Cbf-beta at various stages of the osteoblast lineage. All three models showed severe osteoporosis with accumulation of fat cells in the bone marrow, a pathology that resembles aged bone from enhanced adipocyte creation.
Bone marrow MSCs and bone cells from the skulls of Cbf-beta-deficient mice showed increased expression of adipocyte genes.
Looking at the mechanism downstream, the researchers found that the loss of Cbf-beta impeded the canonical Wnt signaling pathway, particularly through decreased Wnt10b expression. In non-mutant mice, they found that the protein complex composed of Cbf-beta and the Runx2 transcription factor binds to the Wnt10b promoter to drive Wnt10b expression. The Cbf-beta/Runx2 complex also inhibited expression of the enhancer protein C/EBP-alpha that promotes differentiation of adipocytes.
In addition, the researchers showed that Cbf-beta maintains the osteoblast lineage commitment in two ways — through the Wnt paracrine pathway to affect nearby cells and through endogenous signaling within the cell to suppress adipogenesis gene expression.
Altogether, this knowledge of the mechanism driven by Cbf-beta can help explain the imbalance in bone maintenance seen in older people.
A protein called Cbf-beta plays a critical role in maintaining bone-producing cells. An examination of aged mice showed dramatically reduced levels of Cbf-beta in bone marrow cells, as compared to younger mice. Image courtesy of University of Alabama at Birmingham.