2016 年 62 巻 Suppl.1 号 p. 205
Age-related motor organ failure is the major problem in super-aged society because it is leading to care requirements or bedridden. Although locomotive syndrome is recently defined as the individual state with gait disturbance having functional decline of motor organs; bone, cartilage, intervertebral disc, nerve and skeletal muscle, it has been practically difficult to treat it because the cause is complicatedly multifactorial, such as osteoporosis, osteoarthritis, sarcopenia and so on. Superoxide dismutase 2 (SOD2) is the endogenous mitochondrial antioxidant enzyme which converts superoxide anion to hydrogen peroxide to maintain the reduction-oxidation balance in cells. The physiological role of SOD2 and the pathological role of superoxide in degeneration of motor organs have been investigated in our previous study using tissue-specific SOD2-deficient mice. Here we focused on the effect of mitochondrial superoxide and SOD2 imbalance in the development of the locomotive syndrome.
We generated conditional SOD2-deficient mice crossbreeding Sod2 flox mice with dentin matrix acidic phosphoprotein (DMP1) promotor Cre, type2 collagen (Col2) promotor Cre and human skeletal actin (HSA) promotor Cre mice to find tissue-specific phenotypes in osteocyte, chondrocyte and skeletal muscle, respectively. Osteocyte-specific SOD2 deficiency showed both increased expression of sclerostin leading to suppressed bone formation and increased expression of receptor activator of NF-κB ligand (RANKL) causing activated bone resorption. As a result, the mutant mice in vivo showed remarkable bone loss in an age-dependent manner, composing increase of disorganized osteocytic canalicular networks and decrease of live osteocytes number. Chondrocyte-specific deletion of SOD2 promoted mitochondrial superoxide overproduction, mitochondrial dysfunction and impaired extracellular matrix homeostasis, leading to spontaneously accelerated cartilage degeneration both during aging and under mechanical loading. Furthermore skeletal muscle-specific SOD2-deficient mice displayed increased selective loss of enzymatic activity in mitochondrial respiratory chain complexes and reduced ATP content in their muscle, leading to severe disturbances in exercise activity.
These findings demonstrate that mitochondrial superoxide in common plays a pivotal role in the development and progression of osteoporosis, osteoarthritis and muscle weakness, so to speak, age-related locomotive dysfunction, and suggest that the regulation of superoxide balance in the local tissue or in the entire body is a promising target for the treatment of locomotive syndrome.
