Master Gene Makes Skeletal Progenitor Cells Differentiate Into Cartilage Cells

Skeletons are made of bone and cartilage cells that are differentiated from the same multipotent stem cell, said Dr. Brendan Lee, associate professor of molecular and human genetics at BCM, director of the Skeletal Dysplasia Clinic at Texas Children's Hospital and a Howard Hughes Medical Institute investigator. This same stem cell gives rise to bone, cartilage, fat and fibroblasts.

"The big question is what are the master genes that make a stem cell go one way versus another," said Lee.

Both SOX9 and RUNX2 are master transcription factors involved in the process of differentiating bone and cartilage.

The master protein SOX9 directs skeletal progenitor cells to become cartilage and another master protein, RUNX2, directs such cells to become bone, However, he said, the primordial skeletal cell has both RUNX2 AND SOX9.

"We then asked a simple question: Could these master transcription factors (that direct the expression of other genes) directly affect one another's function"" he said. After studies in the laboratory, with mice and with humans, the answer was yes.

"SOX9 appears to be the dominant player," said Lee. "When it is present in a progenitor cell, it turns off RUNX2 and allows the cell to become cartilage."

That does not answer the question of how such cells become bone.

"Clearly, something must turn off SOX9," said Lee. "That's the next question we have to answer."

Working in a genetic lab allowed Lee and his colleagues to learn from gene-caused diseases of the skeletal system. Studies of human tissues proved that the protein activity identified in cells in the laboratory and in studies with mice occurred in humans as well.

Others who took part in the research include Drs. Guang Zhou, Qiping Zheng, Feyza Engin, Elda Munivez, and Yuqing Chen of Baylor College of Medicine; Eiman Sebald of Cedars Sinai Medical Center in Los Angeles; and Deborah Krakow of the David Geffen School of Medicine, University of California, Los Angeles.

Funding for this research came from the National Institutes of Health and the Baylor College of Medicine Mental Retardation and Development Disability Research Center.