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October 17, 2002 - Scientists Turn Early Fat Cells into Bone Cells in the Laboratory

the 1970s, researchers discovered that adult progenitor cells in the bone marrow can differentiate into a variety of different cell tissue types, such as bone, fat, or cartilage. With this finding, scientists also began to wonder: Once a progenitor cell has committed initially to become a fat cell, for instance, is it possible to influence the cell to turn back and become another cell type instead?

In the current issue of the Journal of Cell Biology, scientists report that it can be done. Based on a series of laboratory experiments, the researchers say they succeeded at inducing early, or pre-fat cells to become fully developed bone cells. What's more, they show it can be done by applying two natural compounds externally to these cells, a straightforward approach that is far less laborious than manipulating genes in the cells.

The scientists noted that, with further research and refinement, turning pre-fat cells into bone cells could have important implications in promoting bone regeneration after surgery or thickening brittle bones. "In all people, cells in the bone marrow must make a decision as to whether they will become a bone cell or a fat cell," said Rik Derynck, Ph.D., a scientist at the University of California at San Francisco and the senior author on the paper. "As people get older, however, the number of cells that are available to make this decision decreases and, of those cells, most become fat cells, a contributing factor in the onset of osteoporosis."

"If we could tip the balance in people at risk for osteoporosis and induce more cells in the bone marrow to become bone cells, it could have important therapeutic implications," added Derynck. "Our data indicate that this approach falls within the realm of possibility."

Derynck said the current article is an outgrowth of his laboratory's studies on the abilities of so-called bone morphogenetic proteins, or BMPs, to promote cells to become bone or fat cells depending on where they attach to bone marrow progenitor cells. BMPs, originally identified for their ability to promote bone or cartilage formation, are a family of growth-promoting proteins that play a role in human development, the spatial patterning of tissue formation, and cell proliferation. Scientists currently estimate that the human genome contains 15 to 20 BMP genes.

According to Jeremy Skillington, a post-doctoral fellow in Derynck's laboratory and lead author on the paper, "Despite numerous attempts we were unable to promote bone cell differentiation, just by using BMPs. That, of course, led to several brainstorming sessions to consider possible alternatives."

Skillington said the breakthrough came when, during one of these brainstorming sessions, Lisa Choy, a member of the Derynck laboratory and an author on the paper, suggested combining BMP with retinoic acid. Retinoic acid, a derivative of vitamin A, is known to inhibit fat cell differentiation, while also promoting bone cell growth. Using this two-pronged approach, Skillington et al. soon found in cell culture studies that BMP-2 and retinoic acid seemed to have a synergistic effect in halting the pre-fat cells from differentiating into fat cells. At the same time, the physical characteristics of the cells began to change, and the scientists detected alkaline phosphatase, an enzyme that adult progenitor cells produce as they begin the process of differentiating into bone cells, or osteoblasts. Skillington said this raised the important question of whether the cells were still simply pre-fat cells that happened to express a single protein associated with osteoblasts? Or, did these pre-fat cells still possess the capability to completely switch their developmental program and become fully differentiated osteoblasts?

Skillington said he and his colleagues soon found the latter to be the case. To produce this finding, the scientists studied the same well-characterized pre-fat cell line as in their previous experiments. But they genetically enhanced its BMP signaling, essentially turning up the signal for these cells to differentiate into osteoblasts. The group found the cells responded by expressing a small array of genes associated with osteoblast differentiation and maturation, as well as a gene involved in depositing a calcified matrix, the hallmark of a fully differentiated bone cell.

"These findings now allow us to ask why these two signaling pathways-one activated by retinoic acid, the other by BMP-2-cooperate to make bone?" said Derynck. "They also raise the possibility that retinoic acid and BMP may play a role in converting other progenitor cells down other developmental pathways."

The article is titled, "Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes." Its authors are Jeremy Skillington, Lisa Choy, and Rik Derynck. The article was published online in the Journal of Cell Biology on October 14, 2002. The research was supported by NIH's National Institute of Dental and Craniofacial Research

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This page last updated: February 26, 2014