Bone density is the end result of an interplay between two cell types: bone-forming osteoblasts and bone-chomping osteoclasts.
Over the course of a lifetime (according to U.S. statistics), the osteoclasts appear to win out: The National Osteoporosis Foundation said one in two women and one in four men older than 50 will have an osteoporosis-related fracture in her or his remaining lifetime.
That presents a market opportunity, as well as a public health problem, something that has not escaped the notice of the biotech industry.
Companies working in the space include Salt Lake City-based NPS Pharmaceuticals Inc., which received an approvable letter last month from the FDA for its injectable parathyroid hormone, and Amgen Inc., which published Phase II data in the New England Journal of Medicine in February showing that twice-yearly injections of its antibody denosumab significantly increased bone mineral density compared to placebo.
Meanwhile, basic research into the mechanisms of bone formation also is an active field. In a study published online in the Journal of Experimental Medicine April 10, 2006, researchers from the Medical College of Georgia in Augusta; the Savannah River National Laboratory in Aiken, S.C., Germany's University of Heidelberg; the University of Alabama at Birmingham; and the University of Cincinnati in Ohio, published new data on osteoclast maturation that, in addition to their basic research value, suggested a new pharmaceutical target: the receptor for advanced glycation end products, or RAGE.
Advanced glycation end products are a group of molecules that appear to be responsible for many of the complications of diabetes. Indeed, RAGE receptor function has been tied to any number of illnesses.
"All the known ligands are potentially involved in disease," said senior author Wen-Cheng Xiong, a research professor at the Medical College of Georgia. Those known ligands include the Alzheimer's protein a-beta, inflammatory cytokines and advanced glycation end products themselves.
Overall, the receptor's function appears to be related to immunity, but little is known about its functions outside of the pathological arena. Xiong and her team wanted to know more about such normal function, which spurred the current set of experiments.
The researchers first studied RAGE in a test tube, using bone marrow cell cultures of mice lacking the receptor. They found that fewer and smaller bone-chomping osteoclasts formed in such cultures than in normal controls.
In vivo, 4-week-old mice lacking the RAGE receptor had fewer osteoclasts and denser bones than wild-type controls.
The scientists next studied the molecular details of which step of the differentiation of bone marrow precursors was disrupted when the RAGE receptors were missing. While the early steps of osteoclast maturation proceeded in an essentially normal manner, maturation or terminal differentiation of osteoclasts, as well as their activation to become fully functional, were disrupted. Follow-up studies suggested that the reason for the disruption might be their inability to form actin rings.
Consistent with those findings, deleting the RAGE gene in mice did not appear to have much of an effect on RANK and M-CSF, two known players in early osteoclast maturation. (RANK is the target of Amgen's denosumab.)
Instead, the receptor appears to regulate integrins, which play a role in the later stages of osteoclast maturation.
Xiong said the regulation comes about by both direct and indirect interactions of RAGE and integrins, though she said that she and her colleagues still are confirming that hunch. "Integrin signaling definitely requires this receptor," she said. "We just don't know exactly how."
Despite the fact that Xiong and her team were studying the normal function of RAGE, their findings could yield fruit in bone disease treatment. Xiong, who along with several of her co-authors, is an inventor on "patent applications involving the RAGE technology," said the receptor might be a useful target for the treatment of bone loss diseases.
The field, she said, is open: "So far, no really good inhibitors [of RAGE] have been found," Xiong added. "Or at least, they have not been published."