Osteoporosis is a major public health threat in the United States, with approximately 6 million fractures occurring annually (National Osteoporosis Foundation). Osteoporosis is characterized by two defining features-decreased bone mineral density and microarchitectural deterioration. The loss of bone mass leads to increased bone fragility and, consequently, an increased risk for osteoporotic fracture. Although the development of osteoporosis cannot be pinpointed to a single causative factor, recently there is mounting evidence that oxidative stress poses detrimental effects on bone by depleting antioxidants, activating osteoclasts, inhibiting bone formation, and increasing the incidence of apoptosis. However, the mechanisms that are utilized by cells of osteoblastic and osteoclastic lineage to fight against oxidative stress are poorly understood. Because apoptosis is an important regulatory point in regulating osteoblast cell functions and because increased osteoblast apoptosis caused by age-related increase in oxidative stress is a potential mechanism that may contribute to impaired bone formation seen during aging, our long term goal is to understand the molecular pathways by which oxidative stess regulates osteoblast apoptosis and establish the molecular deficiency that leads to defective osteoblast cell functions with advance in age. Towards this goal, we have proposed studies to investigate the role of a newly identified gene, gluateredoxin 5 (Grx5) in regulating osteoblast apoptosis. The rationale for focusing on this gene is based on the past findings in yeast which indicate that members of the glutaredoxin family play a critical role in regulating apoptosis and our preliminary data that Grx5 is highly expressed in osteoblasts. Based on these findings, we plan to test the hypothesis that Grx5 protects osteoblasts against oxidative stress induced apoptosis via regulating the release of cytochrome c from cardiolipin in mitochondria and decreasing subsequent caspase activation and PARP cleavage. Therefore, the specific aims are: 1) Demonstrate that Grx5 is a modulator of the mitochondrial dependent apoptosis pathway and 2) Demonstrate that Grx5 is a modulator of cytochrome c release, caspase 3, 9 activation and subsequent PARP cleavage. The proposed studies will examine the molecular mechanism by which Grx5 protects osteoblasts against oxidative stress induced apoptosis. Furthermore, these studies will advance our understanding of the components of defense mechanisms to combat oxidative stress and could provide drug targets for osteoporosis therapy.
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| Linares, Gabriel R; Xing, Weirong; Burghardt, Hans et al. (2011) Role of diabetes- and obesity-related protein in the regulation of osteoblast differentiation. Am J Physiol Endocrinol Metab 301:E40-8 |
| Linares, Gabriel R; Xing, Weirong; Govoni, Kristen E et al. (2009) Glutaredoxin 5 regulates osteoblast apoptosis by protecting against oxidative stress. Bone 44:795-804 |
