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Collaboration Leads to Key Discoveries in Bone Research


 













Charles O'Brien, Ph.D., right, talks to Jinhu Xiong, a postdoctoral research fellow, in O'Brien's lab at the Center for Osteoporosis and Metabolic Bone Diseases.











Maria Almeida, Ph.D., right, visits with UAMS students, Kelly Allison, left, S. Serra Ucer, center, and endocrinology insructor Li Han, in Almeida's lab at the center.










Robert Jilka, Ph.D., second from left, checks in with researchers Annick DeLoose, left, Kanan Vyas and Michaela Palmieri.

July 25, 2013 | UAMS research scientists are working to unlock the secrets of the network of cells in bone, work that may prove central to the more effective treatment of osteoporosis.

Walls and windows separate the laboratories of the UAMS Center for Osteoporosis and Metabolic Bone Diseases, but there are no such barriers between the scientists there engaged in the research.

“That’s a common theme on this floor,” said Charles O’Brien, Ph.D., a professor in the UAMS College of Medicine Department of Internal Medicine. “There’s a lot of complementary work and a lot of team-based work. Results from one project will inform what’s going on with another and both can benefit from a single observation.”

Established in 1994, the Center for Osteoporosis and Metabolic Bone Diseases has a faculty of 10 and a staff of more than 30 with a combined research experience of almost 200 years. The goal of the center is to improve the understanding of osteoporosis, a condition of the skeleton that causes increased risk of fracture.  This knowledge may then be used to develop optimal therapies for its treatment.

“When UAMS first decided to establish the Center, the plan was to tackle big research questions from multiple perspectives,” said Stavros Manolagas, Ph.D., M.D., the Center’s director. “This is not about individual labs. This is a very coordinated effort with multiple principal investigators. It’s funded by several grants from the National Institutes of Health and the Department of Veteran’s Affairs. It’s a mega-operation.”

And one that has produced some mega-discoveries and insights into bone metabolism.

Osteoclasts break down old bone, a process called bone resorption, and osteoblasts lay down new bone in the cavities they create. This sequence of events is known as bone remodeling. Once osteoblasts become embedded in the new bone they’ve made, they become osteocytes that are networked and connected through canals in the bone.

In 2011, work led by O’Brien found that osteocytes are an unexpected source of RANK ligand, a protein that controls the formation of osteoclasts.  He is currently using this discovery to identify key mechanisms that control bone remodeling in bone diseases like osteoporosis.

Robert L. Jilka, Ph.D., the Center’s Associate Director, has capitalized on Dr. O’Brien’s work to show that the prolonged lifespan of osteocytes in aged bone may result in an overproduction of RANK ligand. “It put us on a path we hadn’t seen before, which was one in which osteocytes that become defective with aging make too much RANK ligand and bring in too many osteoclasts,” Jilka said.

Maria Almeida, Ph.D., a center research scientist and associate professor in the UAMS College of Medicine, is looking at how increased oxidative stress acts to prevent the formation of new bone during the aging process. Oxidative stress occurs when the levels of reactive oxygen species produced during respiration rise to levels that damage the cells. This process may be a common mechanism among several diseases of aging, not just osteoporosis. Understanding these common mechanisms may lead to the development of drugs that treat bone and other age-related diseases.

“Teasing apart all these pathways is what we do,” Jilka said.

O’Brien, Jilka and Almeida hope a greater understanding of what goes wrong during aging will lead to more narrowly targeted drug treatments that stop bone loss.

Manolagas’s own work addresses how hormonal changes, like the loss of estrogen at menopause or androgen loss in older men or men undergoing certain treatments for prostate cancer, contribute to the effects of old age on bone loss.

Rob Weinstein, M.D., another member of the team, is studying how steroid hormones prescribed extensively for conditions like rheumatoid arthritis, asthma, Crohn’s Disease, or for patients with organ transplants can also cause osteoporosis and a very debilitating condition called osteonecrosis.

Haibo Zhao, M.D., Ph.D., is the latest addition to the team, arriving at UAMS in 2009. He is trying to understand how osteoclasts destroy bone, in order to develop new ways for stopping them. He is also studying how common diseases of blood, for example anemias or sickle cell disease, can also cause osteoporosis.

“Not only can we stop bone resorption, but we can increase bone formation,” Manolagas said. “That’s why all these research projects are so critical. The contributions of this group have changed the way the world thinks about the causes and treatment of osteoporosis.”

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