Dem Bones

by James Martin

Investigators at the Centre for Bone and Periodontal Research are decoding the mysteries of musculoskeletal disorders

You have rocks in your head. And your arms. And your legs. Good thing, too.

These rocks—more specifically, calcium-phosphate nanocrystals—collect in the protein scaffolding of select tissues. “There are billions of these nano-rocks inside your body, binding and hardening like a cement,” says Marc McKee, a researcher at McGill’s Centre for Bone and Periodontal Research (CBPR) and professor in Dentistry and the Department of Anatomy and Cell Biology. It’s these rocks that distinguish mineralized tissues—bones, cartilage, teeth and otoconia (minute particles in the inner ear, crucial to maintaining balance)—from other, softer tissues, like skin or tendons. “Most people don’t stop to think that the same rock they might pick up on the ground is what makes them stand upright,” adds McKee.

When all goes well, our bodies’ “rocks” are tough stuff. But things don’t always go well. In fact, musculoskeletal conditions are the most common causes of severe long-term pain and physical disability, spurring the World Health Organization to declare the 2000s the “Bone and Joint Decade.” Back problems and joint diseases, such as arthritis, afflict hundreds of millions of people. Advanced cancers frequently spread to bones, thinning them and causing pain and fractures. Between 30 and 40 per cent of women over the age of 60, and approximately 15 per cent of men, will develop fractures related to osteoporosis (brittle bones caused by decreased amounts of mineralized bone), a problem that is increasing as throngs of baby boomers enter their golden years. Teeth are a problem, too, as this aging population becomes a prime target for bone and tooth loss associated with periodontal disease. Some rare diseases even result in too much bone: osteopetrosis (overly dense bones) can lead to blindness, deafness or strokes; fibrodysplasia ossificans progressiva can actually cause muscles to mineralize, effectively turning people into human statues.

McGill researchers have long been concerned with what causes good bones to go bad. From Charles Leblond and Léonard Bélanger’s invention of radioautography (which employed newly discovered radioactive isotopes to investigate the workings of cellular renewal) to Charles Scriver’s description of the molecular genetics of bone diseases, the University has earned its place at the vanguard of mineralized tissue research. The CBPR continues this long tradition of working to improve the quality of life for people living with musculo-skeletal disorders.

A co-initiative of the Faculties of Medicine and Dentistry, the centre unites several sites (including various labs in Dentistry, Medicine, the McGill Institute for Advanced Materials and the Jewish General Hospital, as well as the Jamson T.N. Wong Laboratories for Bone and Periodontal Research), creating one of the world’s highest critical masses of bone and periodontal researchers. In addition to skeletal, dental and molecular cell biologists, the CBPR encompasses clinical investigators exploring new therapies for bone diseases such as osteoporosis and osteogenesis imperfecta—and works closely with the Canadian Multicentre Osteoporosis Study (CaMos), a major pan-Canadian epidemiologic study headquartered at McGill. “The diseases we explore at the centre cripple people and cost a tremendous sum of money to the health care system,” says CBPR director Dr. David Goltzman, who worked with McKee and Janet Henderson, the Faculty of Medicine’s Associate Dean of Research, to establish the centre in 2000. “As the population is aging, it’s becoming a huge problem across the world, for just about every ethnic group in every nation.”

A run-of-the-mill X-ray machine only detects calcium phosphate crystals en masse (e.g., as a bone or tooth), so it takes specialized equipment to decipher the nano-sized mechanisms that can cause mineralized tissues to misbehave. This machinery isn’t cheap, though. “The centre doesn’t only afford investigators the opportunity to meet and collaborate,” explains Goltzman, who himself has partnered with Dr. Francis Glorieux on seminal research into how vitamin D and bisphosphonate drugs can maintain healthy skeletons. “It also gives them access to state-of-the-art equipment that no one researcher would be able to afford.” The centre’s most prized possession is its $350,000 micro-computed tomography scanner, which allows researchers to non-invasively, non-destructively section a sample. Unlike an instantaneous X-ray snapshot, a micro-CT scan is really a series of scans, each one no more than a 10-micrometre slice. These slices are then amalgamated into a 3D image, a virtual bone or tooth that can be rotated,

spun and even stripped of its many layers. A micro-CT scan isn’t just a pretty picture: It also quantifies the amount of calcified material in a tissue sample; the technology has been essential to studying mechanisms—and potential treatments—in models of osteoporosis, genetic bone disease and bone cancer.

Micro-CT scanning, along with electron microscopy (used to view individual nano-crystals), proved crucial for a recent CBPR breakthrough, led by McKee, into the calcification process. It’s no secret that a small molecule called pyrophosphate (PPi) blocks calcification by directly binding to mineral crystals—but CBPR researchers now know that PPi also induces the body’s natural defence mechanism, increasing calcification-inhibiting proteins and decreasing calcification-friendly enzymes. “What this tells us is that PPi and other molecules work together to control mineralization,” says McKee. “So, in the right balance, they could be used therapeutically to block unwanted calcification in arteries, joints and other soft tissues.

“Understanding the mechanisms that control how calcium and phosphate combine to harden body tissues,” he adds, “opens the door to the development of new drug therapies to treat skeletal and dental diseases, kidney stones, coronary arteries, atherosclerosis and cardiovascular disease.”

The Centre for Bone and Periodontal Research is funded by the Canadian Institutes of Health Research, the Canada Foundation for Innovation and Valorisation-Recherche Québec, with additional research support from Mrs. Pierrette Wong.