The researchers discovered that changes or mutations in the Gab2 gene influence the sensitive balance between bone formation and bone breakdown.
As so often in science, this discovery too is down to chance: originally, the researchers had begun working on Gab2 to investigate the function of mast cells in allergies. However, during investigations with so-called "knock-out" mice in which the Gab2 gene was silenced, it was found that a defect in or absence of this gene impaired bone resorption. This indicates that Gab2 plays a key role in breaking down the bone material.
The findings described are the result of a research collaboration between Dr. Penninger and his team of Teiji Wada, Tomoki Nakashima and Hiromitus Hara (IMBA), Antonio J. Oliveira-dos-Santos (Boston), Juerg Gasser (Basel), and Georg Schett (Rheumatology Division, Department of Internal Medicine III, University of Vienna). The work was supported financially by the Oesterreichische Nationalbank (Anniversary Fund), IMBA, the Austrian Academy of Sciences, and the Japanese Society for the Promotion of Science.
The work of the research team was presented in early April in the journal Nature Medicine.
Dynamic bone remodelling
Two types of cell are responsible for the continuous, dynamic bone tissue remodelling process: osteoblasts synthesise bone matrix, and osteoclasts coordinate bone resorption. If the harmonious balance between these two types of cell is impaired, this results in diseases such as osteoporosis, osteopetrosis (where bones become excessively dense) or rheumatoid arthritis. In an earlier study, the group around Josef Penninger succeeded in identifying a gene named RANKL (OPGL) as the most important factor in the development of osteoclasts. Clinical studies aimed at switching off the function of RANKL for therapeutic purposes are already well-advanced. In the meantime, it has been discovered that the bonding of RANKL to the receptor RANK acts as the signal for the cell to develop into a “bone-eating” osteoclast. A team working with Teiji Wada and Tomoki Nakashima, from Josef Penninger’s research group, have now succeeded in identifying a molecule, in Gab2, which plays a key part in communicating this signal. In mice where Gab2 is switched off, RANK signals are interrupted and the cells which break down the bone are defective.
Demand for new concepts in treatment
All current treatment options for osteoporosis, including oestrogens and bisphosphonates, are associated with undesirable side-effects. Since we have now found the key regulators of bone mass in RANK and RANKL, it would enable new treatment concepts to start with these molecules. On the basis of the study which has just been presented, the researchers involved hope that a new route in treating the cause of bone diseases can be pursued.