Bench Marks

Bench Marks
CLOSE TO THE BONE
Baruch Frenkel's research into the delicate cellular balance that dictates how bone mass is maintained has already significantly impacted patient care.
by Monika Guttman

If he were an actor, people might tell Baruch Frenkel to “break a leg.” But Frenkel, Ph.D., a key scientist in USC’s Institute for Genetic Medicine, is actually building bones. Or, rather, stopping their breakdown on the molecular level.
An assistant professor of orthopaedic surgery and of biochemistry and molecular biology, Frenkel seeks to understand the control of gene expression in bone cells and how that translates to bone formation and destruction.
Frenkel's work has significant clinical impact. When USC orthopaedic surgeons treating patients with bone infections noticed that those patients taking a new class of antibiotics seemed to heal at a slower pace, Frenkel tested the drugs on bone cells in the lab.
"We found the antibiotic to be toxic to bone formation," he says. "We also included a number of derivatives of this drug and found one that was as effective as an antimicrobial agent but had hardly any hazardous effect in terms of bone formation." The findings, published in the Journal of Orthopaedic Research, led to an immediate shift in prescriptions.
The bulk of Frenkel's research concerns the delicate cellular balance that dictates how bone mass is maintained.
On average, close to 10 percent of a person’s bone mass is resorbed, or eaten, and then reformed every year. Two different bone cells work hand in hand to orchestrate the repair: osteoclasts, which resorb the bone, and osteoblasts, which rebuild the bone where it has been resorbed. One cannot work without the other. As a person ages, the processes become unbalanced, usually leading to a net loss of bone.
Frenkel focuses on a form of bone thinning called glucocorticoid-induced osteoporosis. This is a condition that affects the millions who regularly take steroids to help with inflammatory and autoimmune conditions like rheumatoid arthritis, asthma and inflammatory bowel disease. Prolonged steroid use, says Frenkel, especially at higher doses, can lead to osteoporosis that most often manifests as fractured vertebrae.
Only now, says Frenkel, is it becoming evident that the single most important and direct cellular target of the steroids is the osteoblast, or bone rebuilding cell. “It took a long time to understand this because glucocorticoids also have positive effects on the osteoclasts,” he explains. In fact, glucocorticoids are hormones present in blood. "We need certain levels of them for bone formation. It is when we exceed these levels that we start inhibiting the osteoblasts."
Frenkel’s research goal is to find what, exactly, glucocorticoids do that inhibits osteoblast function, and then use a combination of drugs and steroids to overcome the osteoporosis side effect. Currently there are two major groups of drugs prescribed for osteoporosis—one group that blocks resorption by the osteoclasts, and another that stimulates osteoblasts. Since many common drugs for osteoporosis are relatively new, long-term effects are unknown.
There are a few promising drugs in clinical trials, Frenkel says, including parathyroid hormone. The parathyroid glands are positioned close to the thyroid gland and their hormone stimulates bone formation. Other osteoblast stimulators are the bone morphogenetic proteins, which induce bone formation and are now inserted surgically to help repair fractures. Frenkel and his colleagues are interested in whether any of these osteoblast stimulators can fight the adverse effects of steroids on bone formation.
Frenkel is also conducting research on osteogenic growth peptide (OGP), which is present in blood and has been shown to promote bone and blood cell formation. The thought is that OGP may be used in the future to boost immune cells in various situations, such as enhancing immune system recovery after chemotherapy.
Frenkel expects the future will bring many new drugs that will help save the bones of those who take glucocorticoids. "Now that we understand some of the basic mechanisms for how these cells are affected, hopefully we will be able to alleviate the problems." ?

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