To advance development of effective disease modifying OA treatments, a better understanding of its pathophysiological mechanisms is necessary. By studyinga family with early onset OA and high... Show moreTo advance development of effective disease modifying OA treatments, a better understanding of its pathophysiological mechanisms is necessary. By studyinga family with early onset OA and high cartilage mineralization, a likely causal mutation in the TNF receptor superfamily member 11b (TNFRSF11B) encoding for osteoprotegerin (OPG) was identified. This mutation causes a 19 amino acid extension in the C-terminal domain of OPG (OPG-XL). OPG is a decoy receptor that competes with receptor activator of the nuclear KB factor (RANK) for the binding of nuclear factor KB ligand (RANKL). This triad is known for regulating the formation of osteoclasts, hence playing a critical role in bone remodeling. Given that TNFRSF11B is also one of the highest upregulated genes in OA lesioned cartilage as compared to preserved, this gene is likely underlying OA development and progression but its implication in cartilage homeostasis is as of yet unknown.Altogether, this thesis highlights the role of OPG in OA development by generating an OPG overexpression system in primary chondrocytes and by studying a rare mutation in TNFRSF11B. By further generating neo-cartilage, neo-bone and osteoclasts from the OPG-XL family members, we showed a bidirectional interplay of OPG-XL characterized by higher bone resorption and higher cartilage mineralization. Novel treatments for this family and extrapolation to common OA could be addressed on highly differentially expressed genes such as MGP and DIO2. Finally, the pleiotropy that OPG-XL showed indicates a beneficial or detrimental stage depending on the tissue, making OPG-XL, and likely OPG, a double-edged sword in OA development. Show less
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... Show moreIn 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. Show less
