ESPE Yearbook of Paediatric Endocrinology

Brief Summary: Through a series of experiments in the nonobese diabetic/Ltj mouse model and human β-cells, the authors show that the RANK pathway mediates cytokine-induced β-cell death through RANK-TRAF6 interaction and induction of NF-KB activation. Inhibition of the RANKL/RANK pathway following treatment with osteoprotegerin and denosumab protected β-cells against this cytotoxicity, reduced proinflammatory cytokines in activated T-cells, and reversed T1D in the mouse model.

Growing evidence supports a link between glucose and bone metabolism, mediated by the key bone regulator, the receptor activator of nuclear factor-kB ligand (RANKL)/the receptor activator of NF-κB (RANK)/osteoprotegerin axis (1). RANKL and RANK are present not only in bone, but also in the liver, muscle, adipose tissue, pancreas. Previous studies showed that the RANKL/RANK pathway can inhibit β-cell replication, and inhibition of this pathway (using osteoprotegerin which binds to RANKL, and the anti-osteoporotic drug denosumab) induces rodent and human β-cell proliferation, and prevents diabetes (1,2).

This study further explored the role of RANKL/RANK in glucose regulation and immune function. A critical role of the RANKL/RANK pathway for cytokine-induced mouse and human β-cell death was identified using 3 separate approaches: i) genetic deletion of the transmembrane receptor RANK in mouse islet cells; ii) use of osteoprotegerin as a competitor of RANKL for the RANK, and iii) the RANKL antibody denosumab in human islet cells. A key intracellular pathway was identified, represented by the interaction of RANK with its intracellular signaling adaptor molecule tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), which support the role of RANK-TRAF6 interaction in cytokine-mediated cytotoxicity. The role of the RANKL/RANK in β-cell death was confirmed by the protection of β-cells by osteoprotegerin and denosumab against cell death and dysfunction, induced by cytokines and serum from individuals with T1D. In addition, osteoprotegerin reversed recent-onset T1D in female NOD/Ltj mice. The study also confirmed the involvement of RANKL/RANK in the immune response, through the induction of inflammatory cytokines by RANKL in monocytes and reduction by OPG and DMB in activated human T cells.

These findings support the clinical and therapeutic potential of targeting the RANKL/RANK pathway in T1D, and the potential use of osteoprotegerin and/or denosumab, either alone or in combination with other immunotherapies, for the treatment of T1D.

References: 1. Kondegowda NG, Fenutria R, Pollack IR, Orthofer M, Garcia-Ocaña A, Penninger JM, Vasavada RC. Osteoprotegerin and Denosumab Stimulate Human Beta Cell Proliferation through Inhibition of the Receptor Activator of NF-κB Ligand Pathway. Cell Metab. 2015;22(1):77-85.2. Xing B, Yu J, Zhang H, Li Y. RANKL inhibition: a new target of treating diabetes mellitus? Ther Adv Endocrinol Metab. 2023;14:20420188231170754.