A systems view of musculoskeletal health: Roberto Civitelli, MD, and Linda J. Sandell, PhD
BY JIM DRYDEN
The focus of bone health has long been repair. Broken bones, torn ligaments and damaged cartilage either can be put in a cast to heal or surgically repaired to restore normal function. Or, a worn joint can be totally replaced. But that only fixes the mechanical breakdown. It doesn’t address the underlying problems that led to the breakdown of bones, muscles, tendons, ligaments and cartilage.
“If you’re going to have biological solutions,” says Linda J. Sandell, PhD, the Mildred B. Simon Research Professor of Orthopaedic Surgery and professor of cell biology and physiology, “you need to reach back from the structure to the things that are performing the function.”
“Exactly,” echoes Roberto Civitelli, MD, the Sydney M. and Stella H. Schoenberg Professor of Medicine and chief of the Division of Bone and Mineral Diseases. “We must cover the spectrum, from the basic biology to cell biology to the signals between cells that regulate breakdown and healing. It is much cheaper to prevent problems such as fractures than to treat them after they occur.”
At the new Washington University Center for Musculoskeletal Research, researchers are attempting to do just that. By employing a collaborative approach, they hope to better understand the biological underpinnings of problems with bones and connective tissue.
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“The skeleton and its components are part of the organism,” says Civitelli, professor of orthopaedic surgery and of cell biology and physiology and the leader of an NIH-funded training program in skeletal disorders. “Without the skeleton, you don’t have any way for muscles to function. You would have no protection of soft tissues, and you would have no way of regulating many key cellular processes. We’re even learning that bone is necessary for normal glucose metabolism.”
“Roberto’s point is that the bone is doing more than just taking care of itself,” Sandell adds. “We’ve got cells that make bone and cells that resorb bone, the so-called osteoblasts and osteoclasts. Those regulate the bone, but the bone appears to be regulating other things. There are clear connections between diabetes and obesity and inflammation and the skeleton. That’s why we need all of these investigators working together. One specialty just doesn’t bring enough to the table to understand this anymore.”
The Center for Musculoskeletal Research, a joint effort primarily involving investigators from the Department of Orthopaedic Surgery and the Department of Medicine’s Division of Bone and Mineral Diseases, is located in the BJC Institute of Health at Washington University School of Medicine. In all, the center includes investigators from 54 laboratories. Not all of those laboratories are housed in the new space, and not all of those investigators work mainly with the muscles of the skeleton, but all are contributing in some way to an interdisciplinary effort to better understand the biologic causes that underlie skeletal problems.
“We have a historic interaction because most of us used to be housed in the Yalem Research Building,” says Sandell, who directs the NIH-funded program that supports the center’s core activities. “We had collaborations between investigators that allowed us to put together a center grant, and that greatly facilitated the creation of a center on this floor. Now we hope to launch a number of major projects that will help us diagnose and treat bone and connective tissue problems earlier so that we can prevent more serious problems later on.”
Like other floors in the Institute, workspace in the new musculoskeletal center is organized with cores in the center and laboratories surrounding those cores. Investigators’ offices line a hallway along the north side of the building.
It’s designed, says Civitelli, so that investigators in the center will see each other…a lot. “All of this didn’t just come out of the blue,” he explains. “This is the end of a long process of nurturing trainees, attracting investigators to this field, and building infrastructure. And the way the space is designed — with open labs and open administrative suites — it’s natural to bump into one another on a daily basis, which we believe will spur new collaborations across disciplines and foster creativity within the research base.”
Intricate computer scans offer inside views of bone and joint health in animal models.
Other key members of the center include associate directors Matthew J. Silva, PhD, and Steven L. Teitelbaum, MD. Deborah V. Novack, MD, PhD, directs a core devoted to microscopic and jmolecular analysis of bone, muscle, cartilage, tendons and ligaments, while David M. Ornitz, MD, PhD, and Fanxin Long, PhD, lead a mouse genetic core. One of the center’s investigators produces mice with genetic traits that mimic various bone and connective tissue diseases, while other researchers are developing animal models to find better ways to regenerate bone, cartilage and muscle.
Ultimately, all of the studies will provide not only a better understanding of the biology of skeletal problems, but more insight into multiple disorders and how they interact. But it all starts with individual investigations.
Civitelli’s primary research focus is osteoporosis. As with other problems, he says it once was true that many cases of osteoporosis were discovered only after a fracture. Now it’s possible to screen for weakening of bones long before they break. Doctors can use a machine called a DXA scanner (Dual-energy X-ray Absorptiometry) to measure bone mineral density and determine who is at risk for fractures. The center also has a small DXA scanner and other more sensitive techniques to study bone structure and strength in mice. By studying how bone cells work, investigators are developing new approaches by which weak bones can be made stronger.
Sandell focuses on osteoarthritis. For the most part, early diagnosis of osteoarthritis isn’t yet possible. Patients don’t go to the doctor until they’re already having pain and stiffness. But there are some known risk groups.
“Half a million people have arthroscopic knee surgery each year to treat torn meniscus cartilage,” she says. “When those injuries occur in young people, they’re likely to develop arthritis later in life. So we have to find some way to repair these injuries, other than just treating the structural problem in the knee with surgery. We need to understand what’s going to happen to that person 10 or 20 years later.”
That expanded understanding is the center’s reason for existence. Although not all associated investigators are pulling in a single direction, working together will allow the researchers to better understand what goes wrong not only in osteoporosis and osteoarthritis, but in other musculoskeletal problems.
Balancing act ▼
Painful legacy ▶
A body tears down and rebuilds its skeleton every 10 years or so. This natural cycle is key to skeletal health — that is, as long as the resorption and formation processes remain balanced. Once bone formation slows later in adulthood, however, excess resorption can weaken bones, increasing the risk of fractures. Drug therapies that rebalance the cycle can mitigate the disease known as osteoporosis.
Osteoblasts (green) build up bone tissue. Healthy bone equalizes the processes of resorption and formation.
Osteoclasts (red) break down bone tissue. An excess of this process, known as resorption, leads to osteoporosis.
Ten million people in the United States have osteoporosis, and 24 million more have low bone mass that puts them at increased risk
About 1.5 million osteoporotic, or fragility, fractures occur each year (mostly in the vertebrae and hips), leaving individuals with chronic pain and disability
The cost of treating these fractures could reach $25 billion annually by the year 2025
Why doesn’t everyone get osteoarthritis (OA)? The disease affects skeletal joints and cartilage, the “cushion” between the bones. Research shows that some animals inherit the ability to repair damaged cartilage. Understanding and possibly enhancing this repair process in humans is one goal of OA research.
‘Repair genes’ heal injured cartilage, restored and shown here in dark blue
Without the repair genes, an injured area does not heal, shown here as a gap in the red cartilage
The most common form of arthritis and the leading cause of chronic disability in the United States, affecting 27 million people
Causes vary: hereditary, developmental, metabolic and mechanical
Lifestyle modification (weight loss and exercise) and analgesics are the recommended treatments; surgical joint replacement or resurfacing may be necessary
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