Tissue cells that are destined to become fat cells can be converted to true bone cells in response to signals sent from outside the cell, according to a study at the University of California, San Francisco. The finding lays the groundwork for future research to enable scientists to help replenish lost bone cells, for instance, from osteoporosis, and to help repair bone defects.
This is the first study to find that cells that are destined to turn into muscle, bone, and connective tissue can be transformed from one type into another-so-called transdifferentiation.
UCSF scientists used a vitamin A derivative, retinoic acid, to inhibit fat conversion and, in concert with a substance known to promote bone growth—-so-called bone morphogenic protein (BMP)—- converted pre-fat type cells into true bone cells that deposit bone matrix.
“We used preadipocytes, which are pre-fat cells,” said Rik Derynck, PhD, UCSF professor in the School of Dentistry’s department of growth and development “and explored whether treatments directed from outside the cell itself could redirect their fate from future fat cells to future bone cells.” Derynck is the director of the new UCSF Center for Craniofacial and Mesenchymal Biology.
The results of the study will be published in the October 14 issue of The Journal of Cell Biology. For a cell to convert from one cell type to another there must be suppression of the conversion into the original cell type with promotion of differentiation to the new type, Derynck said. The scientists found that the particular pre-fat cells used (a cell line known as 3T3-F442A cells) had special receptors as well as specific genes known to be involved in signal transduction (called Smads) that are needed for BMP to work. A particular BMP (BMP-2) increased proliferation of the cells, and caused a very mild effect suggesting that these cells could be converted into bone cells. However, it was only after the researchers combined BMP with retinoic acid that the cells were no longer able to develop into fat cells and, instead, converted into mature bone cells.
The new bone cells have all the hallmarks associated with bone formation, including production of bone proteins (like osteocalcin) and calcification (mineralization), as happens whenever true bone forms, Derynck said. Further, this happened at the expense of fat formation that would have occurred without the induction of special additives.
The researchers believe that under the right conditions, retinoids could cooperate with BMP to redirect pre-fat cells into true bone cells, provided the levels of BMP receptors are sufficiently high.
“With the use of these two signaling systems,” Derynck said, “one can do things that one has not thought of before. In effect, the life of these fat cells has been changed from fat to bone. Now we can begin to think about therapeutic applications,” he added.
In addition, the study results indicate that other related substances can exert similar effects in fat and bone formation by these cells. The UCSF scientists plan future studies to characterize the molecular mechanisms of the cooperation of retinoic acid with BMP.
The study was funded by grants from the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the Arthritis Foundation, and a fellowship from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Co-authors on the study are Jeremy Skillington, PhD, UCSF postdoctoral fellow, and Lisa Choy, PhD, UCSF assistant adjunct professor.