UAMS Researchers Find Critical Clue to Bone Renewal Process

By Jon Parham

Understanding the ongoing cellular processes of bone destruction and renewal, called bone remodeling, could lead to new treatments for diseases such as bone-weakening osteoporosis.

The team, led by Charles O’Brien, Ph.D., a professor in the UAMS College of Medicine and a scientist in the UAMS Center for Osteoporosis and Metabolic Bone Diseases, reported that a unique type of cell in the bone appeared to be the catalyst in the bone renewal process — and not other cell types widely believed to be the trigger.

The results of their work were detailed in the article “Matrix-embedded cells control osteoclast formation,” that appears in the online edition of Nature Medicine, the premier journal for biomedical research. The article is available online at

“Any way that we can more completely understand the bone remodeling process would offer new targets for treatments of several bone disorders,” O’Brien said. “These results suggest a revision to the model for how bone remodeling is controlled and opens up new avenues of research since it seems the process is controlled by cells embedded in the bone itself.”

O’Brien compared the skeleton’s constant process of breaking down old or damaged bone and replacing it with new bone to the process of road repairs. When a section of road needs repairs, the old section is removed and replaced with new road.

In the skeleton, osteoclasts are the cells that break up and remove the old bone. Osteoblasts are the cells that form new bone.

O’Brien said scientists have been seeking the process responsible for signaling the production of osteoclasts. There’s something that signals the road repair crew, he said, but the precise source has been unclear.

The protein known as RANKL is necessary for osteoclast formation and was thought to be supplied by osteoblasts or cells that will eventually become osteoblasts called progenitors. “We have known RANKL was essential for osteoclast formation but that protein is produced by a variety of cell types and it has been unclear which one of them was the source of the RANKL that controls bone remodeling,” O’Brien said.

The researchers used a mouse model with a version of the RANKL gene that could be deleted from different cell types while the cellular activity was monitored. This allowed them to see what cellular source of RANKL triggered osteoclast production.

The study found that osteocytes — former osteoblasts buried within bone – supplied the RANKL protein during bone remodeling. “These cells were known to sense and respond to changes in force placed on bone and know we know that are also an important source of RANKL during bone remodeling,” O’Brien said.

The study also allowed the scientists to rule out osteoblast progenitors as a contributing factor to bone remodeling. O’Brien said that when the RANKL protein was removed from the progenitor cells, it did not change the number of the bone-destroying osteoclasts — as would be expected if the progenitors were using RANKL protein to trigger osteoclast production.

Lead author of the article is Jinhu Xiong, a graduate student in the interdisciplinary biomedical sciences program of the UAMS Graduate School. Other authors include O’Brien, Melda Onal a graduate student in the interdisciplinary biomedical sciences program of the UAMS Graduate School, Robert L. Jilka, Ph.D., a professor in the College of Medicine, Robert S. Weinstein, M.D., a professor in the College of Medicine, and Stavros Manolagas, M.D., Ph.D., director of the Division of Endocrinology and Metabolism in the College of Medicine and founder of the Center for Osteoporosis and Metabolic Bone Diseases.

The UAMS Center for Osteoporosis and Metabolic Bone Diseases, established in 1994, is an academic research facility dedicated to the study of osteoporosis and its treatment. It is one of the largest research units of its kind in the United States, and is nationally and internationally recognized as a center of excellence and a unique resource.

UAMS is the state’s only comprehensive academic health center, with colleges of Medicine, Nursing, Pharmacy, Health Related Professions and Public Health; a graduate school; a hospital; a statewide network of regional centers; and seven institutes: the Winthrop P. Rockefeller Cancer Institute, the Jackson T. Stephens Spine & Neurosciences Institute, the Myeloma Institute for Research and Therapy, the Harvey & Bernice Jones Eye Institute, the Psychiatric Research Institute, the Donald W. Reynolds Institute on Aging and the Translational Research Institute. Named best Little Rock metropolitan area hospital by U.S. News & World Report, it is the only adult Level 1 trauma center in the state. UAMS has 2,836 students and 761 medical residents. It is the state’s largest public employer with more than 10,000 employees, including nearly 1,150 physicians who provide medical care to patients at UAMS, Arkansas Children’s Hospital, the VA Medical Center and UAMS’ Area Health Education Centers throughout the state. Visit or