Osteoprotegerin: a double-edged sword in osteoarthritis development

Rodriguez Ruiz, A. (2022)

Doctoral Thesis

To advance development of effective disease modifying OA treatments, a better understanding of its pathophysiological mechanisms is necessary. By studying
a 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.

• Osteoarthritis
• Disease mode
• l Osteoprotegerin
• Induced pluripotent stem cell
• Lentiviral overexpression
• Cartilage
• Mineralization
• Bone
• Rare mutation

• All authors: Rodriguez Ruiz, A.
• Supervisor: Meulenbelt, I.
• Co-supervisor: Ramos, Y.F.M.
• Committee: Mummery, C.L.; Osch, G.J.V.M. van; Vries, T.J. de; Geurts, J.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2022-10-19
• ISBN (print): 9789464585278