Orchestration of bone remodeling

Abstract

In healthy individuals, a balance exists between bone formation and resorption. Disruption of this balance can lead to higher or lower bone mass, and disease such as osteoporosis. Treatment for osteoporosis generally inhibits bone resorption, but does not rebuild bone to a healthy strength. More knowledge on bone metabolism and new therapeutic strategies is therefore needed. Sclerostin is a protein that inhibits bone formation and is produced by osteocytes in mineralized bone matrix. Due to this specific localization and function it is viewed as one of the most interesting targets for new osteoporosis therapies. The first part of this thesis is focused on the effect of sclerostin in patients. People with inactivating mutations in sclerostin have a strongly increased bone mass. They show the effect of decreased production, and investigating these patients therefore increases knowledge on sclerostin__s mechanism of action. The regulation of sclerostin has been investigated in the second part of this thesis. In addition, antisense oligonucleotides have been used in exon skipping to decrease sclerostin expression. Finally, a new method for quantification of in vitro mineralization of bone cells was developed. This method is easy and scalable and can therefore contribute to future research into new osteoporosis therapies.