Abstract
Mitochondrial reactive oxygen species (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 with deletion of the mitochondrial antioxidant enzyme Sod2 in Osx1-Cre (Sp7-tTA,tetO-EGFP/cre) targeted cells, designated Sod2ΔOsx1. We showed that Sod2 deletion caused 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 Sod2ΔOsx1 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 support the rationale that treatment combinations aimed at decreasing mitochondrial ROS and senescent cells and increasing NAD+ should confer additive effects in delaying age-associated osteoporosis.
Keywords:
NAD+; cellular senescence; mitochondrial dysfunction; nicotinamide riboside; proteostasis; single-cell RNA sequencing; skeletal aging.