TNF-family member Receptor Activator of NF-κB (RANK) and RANK-Ligand (RANKL) in bone remodelling

4th International Conference on Agricultural and Biological Sciences

农业科学;生物科学

Quax, W.J.^1 ; Van Assen, A.H.G.^1 ; Wang, Y.Z.^1

Department of Chemical and Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, Groningen

9713 AV, Netherlands^1

关键词: Bone homeostasis;    Bone mineral density;    Computational protein design;    Necrosis factors;    Pathological conditions;    Receptor activator;    Therapeutic strategy;    Therapeutic targets;   

Others  :  https://iopscience.iop.org/article/10.1088/1755-1315/185/1/012001/pdf
DOI  :  10.1088/1755-1315/185/1/012001

来源: IOP

【 摘 要 】

Receptor Activator of NF-κB (RANK) and RANK-Ligand (RANKL) are members of the Tumour Necrosis Factor (TNF)-superfamily involved in bone homeostasis. In a tightly controlled interplay of this receptor and ligand, bone is continuously being remodelled. Several pathological conditions resulting from a misbalance between bone resorption and bone formation have been documented. Most frequently resorption gets the overhand resulting in a lower Bone Mineral Density (BMD), increased fracture risk and reduced mobility of patients. RANKL is expressed on bone producing osteoblasts whereas RANK is expressed on preosteoclasts, which can develop in bone resorbing osteoclasts. The binding of RANKL to RANK functions as a trigger for the formation of these bone resorbing osteoclasts. With the development of a monoclonal antibody directed against RANKL a new therapeutic strategy to interfere with bone remodelling has become available some years ago. In this manuscript we discuss the prospective of interfering with the RANK/RANKL pathway as a therapeutic target for bone diseases. We discuss the role of the soluble receptor osteoprotegerin (OPG) as a therapeutic in bone diseases. Then we focus on the possibility to develop antagonistic and agonistic variants of RANKL based on computational protein design and we discuss the development of antagonistic RANKL variants by changing the stoichiometry of the RANKL molecule.