Bone is a living organ that is maintained through continuous formation of new bone by osteoblasts andresorption of exiting bone by osteoclasts. Loss of bone mass at advanced ages causes osteoporosis.Caspase-2 is a protease that is involved in programmed cell death (apoptosis). During the last fundingperiod, we found that caspase-2 is an important regulator of bone mass in aging animals. Our criticalobservation was that aging-associated bone loss in old (24-26 month) caspase-2 null mice was more severethan that in the same age wild type mice. The objective of this proposal is to further study the role ofcaspase-2 in aging skeleton. Our hypothesis is that caspase-2 mediates mitochondrial-dependent apoptosisof aging osteoclasts, which is induced by oxidative stress in vivo. Lack of caspase-2 activity results inreduced apoptosis of aging osteoclasts, leading to increased bone resorption. To test this hypothesis, first,we will compare the rate of bone formation and bone resorption in old caspase-2 null and wild type mice toshow that caspase-2 affects bone resorption. Next, we will compare the apoptosis rate in aging osteoclaststhat have increased/decreased antioxidant capacity to show that oxidative stress is a cause of spontaneousapoptosis of aging osteoclasts. Then, we will compare the apoptosis rate of caspase-2 (-/-)and (+/+) agingosteoclasts to show that caspase-2 plays an important role in the spontaneous apoptosis of agingosteoclasts. Finally, we will compare the apoptosis rate in aging osteoclasts that have both alteredantioxidant activity and caspase-2 activity to show that caspase-2 is a mediator of oxidative stress-inducedapoptosis. Calmodulin (CaM) dependent kinase II (CaMK II) can phosphorylate procaspase-2 and preventits activation. NADPH, which provides reducing equivalent for various biochemical reactions to scavengeoxidants, also inhibits the activation of procaspase-2 by enhancing CaMK II function. Based on thesefindings, we will test the hypothesis that oxidative stress activates caspase-2 in aging osteoclasts throughdown-regulation of NADPH/CaMK II activity by examining the level of NAPDH and oxidation of CaM andCaMK II. Osteoporosis is a serious disease that affects the elderly. The main strategy and mechanism ofaction of current anti-osteoporosis therapy is to induce osteoclast apoptosis. Therefore, this study will shedthe light on the mechanism of apoptosis in osteoclasts and open new avenues for new anti-osteoporosistherapies.
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