TORONTO - Living bone is in a constant state of flux. On the one hand, there is synthesis of bone matrix by osteoblasts; on the other, the corresponding resorption of bone by osteoclasts. While these processes are normally in harmony, imbalances between the numbers of the two types of cells can arise from hormonal changes or other factors, causing the body to absorb more of its own bone cells than it creates, in effect cannibalizing its own bone and causing skeletal abnormalities like osteoporosis.
The loss of bone mass leads to brittle bones and fractures in this crippling disease, which affects more than 1.4 million Canadians and more than 14 million in the U.S.
New therapies that can reverse or prevent osteoporosis may be on the horizon, according to a Canadian research team that has identified the key gene that regulates osteoporosis. Josef Penninger, an immunologist at Toronto's Princess Margaret Hospital/Ontario Cancer Institute and the Amgen Research Institute, and a member of the departments of medical biophysics and immunology at the University of Toronto, said the team is the first in the world to accomplish this research breakthrough. Penninger is the lead author of a paper on the findings, published in the Jan. 28 edition of Nature.
The research was a collaborative effort between Penninger and his colleague, Young-Yun Kong, in Toronto, and Bill Boyle, at Amgen Inc., of Thousand Oaks, Calif.
Using knockout mice, the researchers found clear evidence that damage or changes to the gene, osteoprotegerin ligand (OPGL), trigger the body's cells to cannibalize its own bone, leading to severe bone deterioration. Penninger said that mice with a disrupted OPGL gene appeared normal until three weeks of age, after which time their physical growth was severely stunted due to underdeveloped bones, bone deterioration, altered bone structure and a lack of teeth. At the molecular level, the mice completely lacked osteoclasts, because osteoblasts could not support osteoclastogenesis.
The study proves that OPGL is the gene that regulates the critical balance between bone growth and bone absorption, Penninger said. A mutated OPGL triggers cells to begin absorbing bone at random and at a much higher rate than normal, causing cells to indiscriminately consume healthy bone as well as damaged bone.
The team also discovered that the same molecule that regulates bone growth also regulates the development of lymph nodes and white blood cells. Mice missing OPGL completely lacked lymph nodes, a finding that may lead to critical discoveries in the fields of arthritis, infectious diseases and cancer.
The discovery will be central to Amgen's ongoing research to discover a drug that can prevent and perhaps reverse bone deterioration. Amgen has already begun a Phase I trial of osteoprotegerin (OPG), a recombinant version of a naturally occurring protein that, based upon extensive preclinical studies, appears to be a critical regulator of bone mass. OPG is a secreted protein identified by Amgen's Genomic Drug Discovery Group. It neutralizes OPGL-induced osteoclastogenesis, suggesting that OPG is a secreted "decoy" receptor that blocks initiation of a critical signal transduction pathway within osteoclast precursors.
In earlier studies at Amgen, it was found that mice that have too much OPG have decreased numbers of osteoclasts and develop abnormally dense bones, which results in the rare disease osteopetrosis.
In preclinical studies, OPG was shown to inhibit bone destruction. When osteoporotic mice were injected with the OPGL inhibitor, bone deterioration stopped instantly, said Penninger.
The genes encoding human OPG and mouse OPG are highly conserved, making it likely that the mode of action of human and mouse OPG is similar. The parallels between human osteoporosis and the OPG-deficient mice emphasize the importance of this discovery and suggest a future therapy using OPG in the treatment of osteoporosis, as well as other diseases characterized by bone loss.
The next project for the scientists at Princess Margaret Hospital/Ontario Cancer Institute and Amgen is to determine how OPGL triggers cells to eat bone mass, and develop a way to block that response. Now that researchers know what triggers a cell to eat away bone, they can find a way to stop it, maybe in the next several years, Penninger said.