The bare bones of calcification

The bare bones of calcification

Daniel McCabe | Sometimes, you want your body parts to harden and sometimes you don't.

Professor Marc McKee PHOTO: Owen Egan

When it comes to building bones and teeth, you need material that's durable and tough, almost rock solid.

But when it comes to softer tissues or to particles floating about in blood vessels and kidneys, rock solid is the last thing you desire. Kidney stones, anyone?

Dentistry and anatomy and cell biology professor Marc McKee is a molecular explorer, charting a path through the biological processes that start and stop calcification, the processes that cause certain tissues to crystallize and become hard.

The associate dean of research for the Faculty of Dentistry, McKee is as interested in the calcification that shouldn't be taking place as he is in the normal mechanisms governing the building of teeth and bone.

It's an important area of research, particularly in Quebec, which has the highest rate of toothlessness in the country, atttributable to cavities and loss of jaw bone caused by periodontal disease.

While having a strong set of chompers is clearly an important goal, calcification plays a role in other conditions that relate more directly to life and death issues, such as strokes and heart attacks.

Calcification of blood vessels typically involves the heart's coronary arteries in atherosclerosis, where lipids accumulate in the blood vessel wall. It also occurs in arteries more generally throughout the body in arteriosclerosis, or hardening of the arteries.

In both these conditions, vascular calcification "is a very prognostic risk factor," says McKee. Patients experiencing this form of calcification "are at a much greater risk for heart attacks and strokes."

Kidney stones are a "pathological calcification in tissue fluids," McKee notes. Breast cancer tumours can become calcified, as can brain tissue.

McKee focuses his attention on the role played by proteins in promoting or slowing down calcification. Some proteins seem to flip on the switch, starting the crystallizing process in tissues containing high levels of calcium. Other proteins seem to play a role in controlling the way this hardening takes place, inhibiting the process where necessary and allowing it to occur in a highly regulated manner.

Without these inhibitory proteins, McKee posits that "we could all suffer the fate of Lot's wife and turn to pillars of salt. There is so much calcium and phophate in our bodies, many of our tissues and organs could mineralize spontaneously."

It's pretty much the fate some transgenic mice suffered back in 1997, when McKee's lab, then at Université de Montréal, and collaborators in Texas provided the first hard proof that proteins played such a vital role in subduing the calcification process in animals.

Mice were genetically altered to be without matrix Gla protein, a protein that McKee and his collaborators had thought might play an instrumental role in controlling how calcification takes place.

Without the Gla-containing protein, "their entire vascular tree turned to stone," McKee says. The study, published in Nature, was a turning point for researchers in this field.

"One of the reasons we're seeing such a renewed interest in calcification is the new non-invasive imaging techniques," says McKee.

"CT scans allow calcification to be observed in a way that just wasn't possible before. X-rays didn't have the resolution to show small calcified deposits in coronary arteries. The extent of calcification can be correlated better now with cardiovascular disease." As a result, its role in fostering heart disease and strokes is much better understood.

While matrix Gla protein inhibits calcification in soft tissues, another protein that McKee studies, osteopontin, slows down calcification in hard tissues.

Why would you want to slow down calcification in hard tissues when strong teeth and bones are an essential part of the formula for good health?

Unchecked calcification in bone, occurring in a haphazard way, would be disastrous, notes McKee. "If the process wasn't inhibited, the crystallization would obliterate everything in its path. It would literally tear a path through tissue."

Osteopontin also seems to come into play when things go wrong -- it tries to subdue pathological calcification.

McKee says the original tip-off about which proteins play a role in inhibiting calcification came as a result of finding proteins normally associated with bones and teeth in unexpected places, in kidney stones, for instance.

"That fuelled the idea that crystal growth is controlled by proteins expressed in diseased soft tissue to fight calcification. The same proteins were found in other body sites to shut down uninhibited crystal growth."

McKee has been uncovering a lot of interesting information about osteopontin, which is proving to be a very important protein. Our skeletons are dynamic structures, notes McKee. "The entire skeleton gets turned over every 10 years. It's being remodelled constantly."

Old bones, weakened by the ravages of time, get tunnelled out and refilled with newer material. He likens this never-ending bone regeneration to an inner construction site where activity never ceases.

The interfaces between new and old bone material are critical, says McKee. Osteopontin helps bond the two together to fashion durable, almost seamless connections.

The subject of bonding biological tissues together is another area of McKee' s expertise. Along with other researchers, McKee holds a patent on a novel method for constructing dental and orthopedic implants. Armed with his understanding of how osteopontin provides the "glue" for holding bone tissue together, McKee's implant of the future isn't just a chunk of metal designed to act as a fake tooth, it does much more.

The new generation implants will be "bioactive," coated with proteins that make the dead metal "come alive."

Once the implant is placed in the mouth or in the hip as an artificial joint, surrounding cells "don't see an inert piece of metal, they see a protein and it's a protein they know."

These attached proteins can send off messages to accelerate healing and speed the reconstruction of surrounding tissue. McKee says "designer implants" could carry different types of proteins, one set to spur soft tissue healing, another to encourage hard tissue growth on another front. Given that dental implants are fixed in the jaw bone and inserted through gum tissue, this two-pronged approach would be essential. He believes the customized implants could be on the market in about five years.

McKee's office sports some unusual items -- a skull, which has been his constant lab companion since graduate school, and a collection of teeth from various species, each with unusual and, at times, striking banding patterns caused by calcium dyes. The process uncovers information about the structure of the teeth but it's also strangely attractive. McKee's sister had some banded teeth made into earrings. He also has a chessboard for games he plays via e-mail with another calcification expert at the University of Western Ontario, as they simultaneously exchange tidbits about their field and chess moves.

McKee earned three degrees from McGill before leaving for a postdoctoral fellowship at Harvard and then a faculty position at U de M.

In 1996 he earned the prestigious Young Investigator Award from the International Association for Dental Research. He came back to McGill in 1998 and was recently named a William Dawson Scholar as one of the University's rising young stars.

McKee twice made Québec Science's annual "top ten" discoveries of the year list. The achievement earned McKee the strangest request of his academic career thus far.

"A horse breeder read about my work and asked if I could give him some osteopontin," McKee recalls. A prized racehorse had suffered a fracture.

While his research has uncovered some interesting findings, McKee's expertise doesn't quite yet extend to the repair of future Kentucky Derby winners. But it might one day.