By David N. Leff

Over time, every bone in your body has its skeletal mass renewed by two opposite processes - resorption and new boneformation.

"Bone remodeling has been known for many years," observed skeleton molecular biologist Gerard Karsenty, at Baylor Collegeof Medicine, in Houston. He set out to test the widely held supposition that the two reciprocal processes - bone build-up andbone removal - probably signal each other to maintain constant bone mass.

"Why does a 30-year-old have the same bone mass as a 20-year-old?" he asked rhetorically. "Remodeling destroys X grams ofmass, and replaces it with the same amount, up to menopause, when osteoporosis may alter things."

Why nature should indulge in such an inexplicable exercise "is a very strange phenomenon," Karsenty told BioWorldToday. "One of the questions we discuss in the lab is whether there a reason for it. Or is it rather the remnant of an olderprocess during evolution?

"To tell you the truth," he allowed, "we don't know. My own inclination would be to believe that it is a remnant of an olderprocess. We have no proof, but it is certainly a concept to keep in mind." The reason, he said, is that bone "is the only organ inthe body to self-destruct, to commit suicide every day. It's not apoptotic. It's not programmed cell death. The osteoclast, thebone-resorbing cell, eats bone, and the osteoblast replaces it."

But he also pointed out that the process is necessary. "We need to remodel bone every day to have a healthy skeleton for theweight and all the movements that we have," he said.

Karsenty, who teaches molecular and human genetics at Baylor, has a paper in today's Proceedings of the National Academyof Sciences (PNAS), titled: "Dissociation between bone resorption and bone formation in osteopenic transgenicmice."

Constant Bone Mass Concept Challenged

"The assumption that bone formation and resorption reciprocally regulate each other to maintain a constant bone mass wasthe concept that we challenged in our mice," he observed.

These custom-made rodents, he pointed out, represent "the first animal model that mimics osteoporosis very closely and that isinducible and reversible."

Karsenty went on to observe that other animal models exist, rendered osteoporotic by removing their ovaries. "But that is a one-shot deal," he said. "They become osteoporotic, but you can't reverse the process. Here, we can induce it, reverse, do it again,stop, and so on."

These mice, he said, have both pharmaceutical and scientific utility.

"First," he said, "to test putative new anti-resorptive drugs, because here we have a model of osteoporosis that is due only toosteoclast activity. If you have new anti-osteoclast drugs, it is the best model to test them. That is for the biotechnology, or theapplied, aspect of this approach.

"Second, to study the mechanism," Karsenty said, "the genetic basis of the disease, these mice can be used now to doexperiments, to test the function of some gene products at the onset of osteoporosis. And that's what we are now doing in thelab. We have two projects going on, and should have the results of these experiments within the next six months."

The Baylor scientists' research is partly sponsored by Hoechst Marion Roussel, of Frankfurt, Germany. "They have our mice,and are probably going to test them on kinase-active drugs," Karsenty said.

To construct their transgenic mice, Karsenty and his co-authors did not disable any gene or genes. "What we did was tointroduce into osteoblasts - the bone-forming cell - a gene that expresses a totally innocuous product called thymidine kinase[TK]," he said. "If we treat cells that express TK with a particular drug, these cells die. That drug is the antiviral gancyclovir.

"If we don't give our transgenic mice gancyclovir, they are just happy, content. Once we start treating them with gancyclovir,we kill the osteoblast, and only the osteoblast," he said.

For the yin of gancyclovir there's a yang compound called alendronate, which is a drug that arrests the function of the bone-resorbing osteoclast. This dichotomy harks back to the received wisdom that bone absorption and remodeling trigger eachother.

"That idea," Karsenty explained, "is that bone formation and bone resorption are really cross-regulating each other, at thefunctional level, not only at the differentiation level. Then, if you arrest bone formation with gancyclovir, you should have abone in a frozen state, like a mummy. No more histology, no osteoblasts, no more remodeling.

No Sign That Fluctuating Bone Masses Swap Signals

"If cross-regulation does exist in vivo," Karsenty said, "what we should have seen dosing those mice withgancyclovir alone, was functional regulation between bone formation and bone resorption - and we did not see it. Rather, ourPNAS paper reports that a striking feature of these mice is that we can arrest their bone formation. They stop growing;their bones are completely empty. And then, when we relieve the inhibition, the bone grows back to a normal content of bonematrix, and the mice grow back to their normal size.

"The fact that there is an inner clock, if you will, in these animals, to tell them to go back to exactly where they started from,"Karsenty concluded, "suggests an endocrine regulation, rather than an in situ regulation between an osteoclast and anosteoblast."