RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes.
Nagesha Guthalu KondegowdaJoanna FilipowskaJeong-Su DoNancy Leon-RiveraRosemary LiRollie HamptonSelassie OgyaaduCamilla LevisterJosef M PenningerHelena ReijonenCarol J LevyRupangi C VasavadaPublished in: Science advances (2023)
Treatment for type 1 diabetes (T1D) requires stimulation of functional β cell regeneration and survival under stress. Previously, we showed that inhibition of the RANKL/RANK [receptor activator of nuclear factor kappa Β (NF-κB) ligand] pathway, by osteoprotegerin and the anti-osteoporotic drug denosumab, induces rodent and human β cell proliferation. We demonstrate that the RANK pathway mediates cytokine-induced rodent and human β cell death through RANK-TRAF6 interaction and induction of NF-κB activation. Osteoprotegerin and denosumab protected β cells against this cytotoxicity. In human immune cells, osteoprotegerin and denosumab reduce proinflammatory cytokines in activated T-cells by inhibiting RANKL-induced activation of monocytes. In vivo, osteoprotegerin reversed recent-onset T1D in nonobese diabetic/Ltj mice, reduced insulitis, improved glucose homeostasis, and increased plasma insulin, β cell proliferation, and mass in these mice. Serum from T1D subjects induced human β cell death and dysfunction, but not α cell death. Osteoprotegerin and denosumab reduced T1D serum-induced β cell cytotoxicity and dysfunction. Inhibiting RANKL/RANK could have therapeutic potential.
Keyphrases
- nuclear factor
- cell death
- toll like receptor
- type diabetes
- endothelial cells
- high glucose
- cell proliferation
- diabetic rats
- cell cycle arrest
- bone mineral density
- oxidative stress
- signaling pathway
- drug induced
- inflammatory response
- stem cells
- emergency department
- pi k akt
- cardiovascular disease
- blood pressure
- bone marrow
- pluripotent stem cells
- postmenopausal women
- skeletal muscle
- body composition
- metabolic syndrome
- weight loss
- peripheral blood
- lps induced