Bone is a living organ that is maintained through continuous formation of new bone by osteoblasts and resorption 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 funding period, we found that caspase-2 is an important regulator of bone mass in aging animals. Our critical observation was that aging-associated bone loss in old (24-26 month) caspase-2 null mice was more severe than that in the same age wild type mice. The objective of this proposal is to further study the role of caspase-2 in aging skeleton. Our hypothesis is that caspase-2 mediates mitochondrial-dependent apoptosis of aging osteoclasts, which is induced by oxidative stress in vivo. Lack of caspase-2 activity results in reduced 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 to show that caspase-2 affects bone resorption. Next, we will compare the apoptosis rate in aging osteoclasts that have increased/decreased antioxidant capacity to show that oxidative stress is a cause of spontaneous apoptosis of aging osteoclasts. Then, we will compare the apoptosis rate of caspase-2 (-/-)and (+/+) aging osteoclasts to show that caspase-2 plays an important role in the spontaneous apoptosis of aging osteoclasts. Finally, we will compare the apoptosis rate in aging osteoclasts that have both altered antioxidant activity and caspase-2 activity to show that caspase-2 is a mediator of oxidative stress-induced apoptosis. Calmodulin (CaM) dependent kinase II (CaMK II) can phosphorylate procaspase-2 and prevent its activation. NADPH, which provides reducing equivalent for various biochemical reactions to scavenge oxidants, also inhibits the activation of procaspase-2 by enhancing CaMK II function. Based on these findings, we will test the hypothesis that oxidative stress activates caspase-2 in aging osteoclasts through down-regulation of NADPH/CaMK II activity by examining the level of NAPDH and oxidation of CaM and CaMK II. Osteoporosis is a serious disease that affects the elderly. The main strategy and mechanism of action of current anti-osteoporosis therapy is to induce osteoclast apoptosis. Therefore, this study will shed the light on the mechanism of apoptosis in osteoclasts and open new avenues for new anti-osteoporosis therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG019316-10
Application #
8222864
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
10
Fiscal Year
2011
Total Cost
$214,421
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Wu, Junjie; Sun, Yun; Block, Travis J et al. (2016) Umbilical cord blood-derived non-hematopoietic stem cells retrieved and expanded on bone marrow-derived extracellular matrix display pluripotent characteristics. Stem Cell Res Ther 7:176
Doiron, Bruno; Hu, Wenchao; DeFronzo, Ralph A (2016) Beta Cell Formation in vivo Through Cellular Networking, Integration and Processing (CNIP) in Wild Type Adult Mice. Curr Pharm Biotechnol 17:376-88
Solano Fonseca, Rene; Mahesula, Swetha; Apple, Deana M et al. (2016) Neurogenic Niche Microglia Undergo Positional Remodeling and Progressive Activation Contributing to Age-Associated Reductions in Neurogenesis. Stem Cells Dev 25:542-55
Callaway, Danielle A; Riquelme, Manuel A; Sharma, Ramaswamy et al. (2015) Caspase-2 modulates osteoclastogenesis through down-regulating oxidative stress. Bone 76:40-8
Lee, Hak Joo; Feliers, Denis; Mariappan, Meenalakshmi M et al. (2015) Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes. J Biol Chem 290:12014-26
Talley Watts, Lora; Zheng, Wei; Garling, R Justin et al. (2015) Rose Bengal Photothrombosis by Confocal Optical Imaging In Vivo: A Model of Single Vessel Stroke. J Vis Exp :e52794
Choveau, Frank S; Zhang, Jie; Bierbower, Sonya M et al. (2015) The Role of the Carboxyl Terminus Helix C-D Linker in Regulating KCNQ3 K+ Current Amplitudes by Controlling Channel Trafficking. PLoS One 10:e0145367
Souto Padron de Figueiredo, Alvaro; Salmon, Adam B; Bruno, Francesca et al. (2015) Nox2 mediates skeletal muscle insulin resistance induced by a high fat diet. J Biol Chem 290:13427-39
Talley Watts, Lora; Long, Justin Alexander; Manga, Venkata Hemanth et al. (2015) Normobaric oxygen worsens outcome after a moderate traumatic brain injury. J Cereb Blood Flow Metab 35:1137-44
Segovia, Jesus A; Tsai, Su-Yu; Chang, Te-Hung et al. (2015) Nedd8 regulates inflammasome-dependent caspase-1 activation. Mol Cell Biol 35:582-97

Showing the most recent 10 out of 115 publications