Skeletal tissue regulation by catalase overexpression in mitochondria

Abstract

Accumulation of oxidative damage from excess reactive oxygen species (ROS) may contribute to skeletal aging and mediate adverse responses to physiological challenges. Wildtype (WT) and transgenic mice (male, 16 weeks of age) with human catalase targeted to the mitochondria (mCAT) were analyzed for skeletal responses to the remodeling stimuli of combined hindlimb unloading and exposure to ionizing radiation (137Cs, 2 Gy). Treatment for 2wk caused lipid peroxidation in WT bones but not mCAT, showing that transgene expression mitigated oxidative stress. Ex vivo osteoblast colony growth rate was 95% greater in mCAT mice than WT, and correlated with catalase activity levels (P<0.005, r=0.67), although terminal osteoblast and osteoclast differentiation were unaffected. Ambulatory control mCAT animals also displayed reduced cancellous and cortical structural properties compared to control WT. In mCAT but not WT mice, treatment caused an unexpectedly rapid radial expansion (+8% cortical area, +22% moment of inertia), reminiscent of compensatory bone growth during advancing age. In contrast, treatment caused similar structural deficits in cancellous tissue of mCAT and WT mice. In sum, mitochondrial ROS signaling via H2O2 was important for the acquisition of adult bone structure and catalase overexpression failed to protect cancellous tissue from treatment. In contrast, catabolic stimuli caused radial expansion in mCAT not WT mice, suggesting mitochondrial ROS in skeletal cells act to suppress tissue turnover in response to remodeling challenges.

Long Bone Mineral Loss, Bone Microstructural Changes and Oxidative Stress After Eimeria Challenge in Broilers

“…In vitro studies in human and mouse cells have shown that ROS is an important activator for various cell signaling pathways, mediated MSCs differentiation and cell fate ( Yang et al, 2013 ; Atashi et al, 2015 ). Accumulating evidence suggesting the alteration of the redox state causes systemic changes that can coordinate osteoblast differentiation or osteoclast activity that relat to the bone remodeling process in human and animal models ( Domazetovic et al, 2017 ; Schreurs et al, 2020 ; Sheppard et al, 2022 ). The supplementation of trace minerals can alleviate the negative effect of oxidative stress and optimize the bone quality in human and broilers ( Santos et al, 2020 ; Savaram Venkata et al, 2021 ).…”

Effect of high-fructose consumption in pregnancy on the bone growth of offspring rats

“…Increasing numbers of studies have reported that fetal bone is extremely sensitive to environmental influences during pregnancy, such that adverse exposures such as oxidative stress will increase the risk of skeletal disorders. The alteration of the redox state causes systemic changes that can coordinate osteoblast differentiation or osteoclast activity related to the bone remodeling process ( 50 , 51 ). We propose that a maternal high-fructose diet can impair cartilage proliferation and bone homeostasis by increasing fetal oxidative stress and then affecting offspring bone mass and microstructure.…”

Biophysical Modulation of the Mitochondrial Metabolism and Redox in Bone Homeostasis and Osteoporosis: How Biophysics Converts into Bioenergetics

“…Mice overexpressing mitochondrial catalase show less lipid oxidation upon hindlimb unloading by tail suspension than wild type mice. Catalase overexpression fails to mitigate hindlimb unloading-induced cortical bone loss, suggesting that mitochondrial catalase-mediated redox is dispensable in “sensing” mechanical disuse in bone microenvironment [ 92 ]. Low-intensity pulsed ultrasound increases the ROS levels and osteogenic gene expression in MC3T3-E1 osteoblasts.…”