Development and characterisation of novel models for studying osteoclasts
The bones in the human body are continuously rebuilt in order to repair damage to the skeleton and to maintain the mineral balance in the body. This process is called bone remodeling. Two cell types; the osteoclasts, which resorb bone, and the osteoblasts, which form bone, are involved in bone remodeling.
The resorption and formation are under normal circumstances tightly balanced, with resorption always followed by the same amount of formation, a process referred to as coupling. Imbalances in the coupling lead to pathological situations, such as too little bone (osteoporosis) and too much bone (osteopetrosis).
Studies of patients with osteopetrosis, a disease with too much bone mass often caused by defective bone resorption by the osteoclasts, have however indicated that bone formation is not only correlated to bone resorption. It is also likely that the osteoclasts, even if they are inactive as seen in osteopetrosis, can stimulate osteoblasts to form more bone. These studies indicate that osteoclasts produce a so far unknown factor leading to bone formation by the osteoblasts.
One difficulty with the studies of osteopetrosis is that the disease is initiated during embryonal development, and thus the bones are not correctly developed. This has led to several less well-understood findings, of which reduced bone strength is the most interesting.
To address this difficulty we are now developing novel mouse models, the adult osteopetrotic mice, for studying the interplay between osteoclasts and osteoblasts. These mice are obtained by transplanting haematopoietic stem cells derived from osteopetrotic mice (and wild type mice as control), which have defective resorption, into adult normal mice.
This current project is focused on a detailed characterisation of these models, and secondly manipulation of the models using treatments known to affect osteoclasts. Furthermore, the project focuses on using protein chemistry and proteomic analyses for identification of the unknown factor(s) secreted by the osteoclasts.
These factors are potential drug candidates, and therefore are highly relevant both from a scientific and a pharmacological point of view, for example for treatment of osteoporosis.
The project also focuses on developing a novel tool for studying human osteoclasts, namely gene transfer to osteoclasts and the cells that osteoclasts are formed from. Gene transfer will be then used to introduce siRNA into these cells, leading to silencing of the osteoclast factor(s) identified in the project.
The effect of this gene silencing on osteoclast function will be studied. Furthermore, this approach can be used to study the function of other genes of interest in the osteoclasts, i.e. genes potentially involved in the bone resorption process, and thus detect new targets for pharmacological modulation of the bone remodelling process potentially important for treatment of osteoporosis.