Mechanisms of mitochondrial reactive oxygen species action in bone mesenchymal cells

Abstract

Mitochondrial (mt)ROS, insufficient NAD+, and cellular senescence all contribute to the decrease in bone formation with aging. ROS can cause senescence and decrease NAD+, but it remains unknown whether these mechanisms mediate the effects of ROS in vivo. Here, we generated mice lacking the mitochondrial antioxidant enzyme Sod2 in osteoblast lineage cells targeted by Osx1-Cre and showed that Sod2{Delta}Osx1 mice had low bone mass. Osteoblastic cells from these mice had impaired mitochondrial respiration and attenuated NAD+ levels. Administration of an NAD+ precursor improved mitochondrial function in vitro but failed to rescue the low bone mass of Sod2{Delta}Osx1 mice. Single-cell RNA-sequencing of bone mesenchymal cells indicated that ROS had no significant effects on markers of senescence but disrupted parathyroid hormone signaling, iron metabolism, and proteostasis. Our data supports the rationale that treatment combinations aimed at decreasing mtROS and senescent cells and increasing NAD+ should confer additive effects in delaying age-associated osteoporosis.