CBFB is Involved in the Loss of Osteoblasts with Advancing Age

The proximate cause of osteoporosis, the age-related loss of bone strength, is a growing imbalance between the populations of osteoblasts responsible for creating bone and osteoclasts responsible for removing it. Bone tissue is in a constant state of active remodeling, so as the balance leans towards osteoclasts, bone becomes ever more fragile. Why does this balance shift? From the SENS rejuvenation research point of view, it is a downstream consequence of forms of fundamental cellular damage that accumulate over time, but as is the case for near all aspects of aging there is no complete and accurate map of the chain of causes and consequences leading from that damage to a loss of osteoblasts.

The majority of the research community works backwards from the other end of the chain, starting with the end stage of the condition, in search of the next most proximate cause. This is usually some form of change in the circulating levels of specific regulatory proteins, as is the case here. That in turn must be a reaction to an early form of change and damage - but this is usually where research teams stop, and hand off their work for an attempt at commercial development of therapies. This is precisely why most existing approaches to the treatment of age-related conditions are not all that effective in practice; they are tinkering with a comparatively late stage of the altered disease state rather than addressing root causes.

A major health problem in older people is age-associated osteoporosis - the thinning of bone and the loss of bone density that increases the risk of fractures. Often this is accompanied by an increase in fat cells in the bone marrow. Researchers have now detailed an underlying mechanism leading to that osteoporosis. When this mechanism malfunctions, progenitor cells stop creating bone-producing cells, and instead create fat cells. The researchers found that a protein called Cbf-beta, core-binding factor subunit 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. 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. The researchers focused on the molecular mechanism that controls the lineage commitment switch between the osteoblast and adipocyte tracks, and investigated the key role played by Cbf-beta.

The team generated three mouse models by deleting Cbf-beta at various stages of the osteoblast lineage. All three mouse 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 mesenchymal stem cells 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 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.

Link: http://www.uab.edu/news/innovation/item/8714

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