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