Polyol Pathway Inhibition by Epalrestat Attenuates Pathological Bone Loss through Redox Homeostasis and Sorbitol-Linked Calcium Signaling.

Abstract

The contribution of polyol metabolism to pathological bone remodeling remains incompletely understood. Here, we examined its role in osteoclastogenesis and evaluated the skeletal effects of epalrestat, a clinically approved aldose reductase inhibitor. Exploratory single-cell analysis of two human femoral-head specimens suggested greater macrophage-associated polyol-pathway activity in the osteoporosis specimen. In primary bone marrow-derived macrophages, silencing of Akr1b3 and Sord produced opposing effects on osteoclast differentiation. Epalrestat suppressed RANKL-induced osteoclastogenesis and attenuated bone loss in diabetic, ovariectomy-induced, and inflammatory mouse models under early-intervention regimens. Mechanistic analyses showed improved NADPH/NADP⁺ and GSH/GSSG balance, reduced oxidative stress, and attenuated cytosolic and mitochondrial Ca²⁺ signals and Ca²⁺ oscillations. Genetic and osmotic-compensation experiments further supported a model in which intracellular sorbitol contributes to the osmotic regulation of Ca²⁺ oscillations. Additional findings included reduced inflammation in osteolysis and arthritis models, altered macrophage polarization, and partial preservation of bone marrow vascular features. Together, these findings connect glucose metabolism with redox and Ca²⁺ regulation during osteoclast differentiation and provide a rationale for further evaluation of epalrestat in skeletal disease.