Turnover of cells and matrix in bone occur through osteonal remodeling, wherein resorption removes and osteoblastic infilling replaces microscopic regions of compact bone that have reached the end of their functional life. Imbalances in this turnover process can lead to impaired bone quality and increased fragility. How bone remodeling targets area of bone has long been unclear. We found that inhibiting osteocyte apoptosis after fatigue prevents activation of osteoclastic resorption, demonstrating for the first time that osteocyte apoptosis is a controlling step in the activation of targeted bone resorption of microdamage. We also discovered that the spatial and temporal relationships between osteocyte apoptosis and osteoclastic bone resorption previously established for remodeling of microdamage in bone hold as well for resorption induced by ovariectomy and disuse. Finally, we found that the surviving osteocytes near areas of microdamage also appear to respond to the focal microinury and may potentially secrete regulatory factors that help coordinate the osteoclastic response. In the current studies, we will use a combination of real-time PCR, immunohistochemical and histomorphometry approaches in the rat ulnar fatigue model in vivo to determine the regulatory processes by which apoptotic and non-apoptotic osteocytes surrounding microdamage signal to osteoclasts and activate bone remodeling. We will also determine which among the osteocyte derived signals is dependent upon osteocyte apoptosis by using a pan-caspase inhibitor to suppress the apoptosis. We will focus on osteocyte expression of major regulators of bone resorption that are a) an established requirements for osteoclastic differentiation and b) have demonstrated expression by, or effects on, osteocytes. Complementary in vitro studies on osteocyte-like cells will be used to test causal relationships using specific blocking approaches to determine roles of individual signaling cytokines within the pathway linking apoptotic and pro-osteoclastogenic cells. In the second series of studies, we will use the rat ulnar fatigue model to establish the importance of osteocyte apoptosis in the activation versus progression of bone resorption around microdamage. Finally, we will test whether osteocyte apoptosis is a 'common final pathway'for initiation of bone resorption in response to diverse remodeling stimuli, by using a pan-caspase inhibitor to suppress osteocyte apoptosis in mouse models for estrogen withdrawal and disuse.

Public Health Relevance

. Maintaining bone quality and preventing bone tissue fragility depends upon bone remodeling, wherein osteoclasts remove and osteoblasts replace microscopic regions of bone that have reached the end of their functional life. Our recent discoveries indicate that this remodeling, as well as the increased turnover and bone loss in postmenopausal and disuse osteoporoses, in turn, depends of the regulated death (apoptosis) of osteocytes within the bone. These findings suggest that osteocyte apoptosis may be a 'common final pathway'controlling bone resorption in response to diverse remodeling stimuli, and also suggest that this apoptosis could represent a novel therapeutic target for modulating osteoclastic activity in aging and osteoporosis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Lester, Gayle E
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City College of New York
Engineering (All Types)
Schools of Engineering
New York
United States
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Smaldone, Silvia; Clayton, Nicholas P; del Solar, Maria et al. (2016) Fibrillin-1 Regulates Skeletal Stem Cell Differentiation by Modulating TGFβ Activity Within the Marrow Niche. J Bone Miner Res 31:86-97
Cheung, Wing Yee; Fritton, J Christopher; Morgan, Stacy Ann et al. (2016) Pannexin-1 and P2X7-Receptor Are Required for Apoptotic Osteocytes in Fatigued Bone to Trigger RANKL Production in Neighboring Bystander Osteocytes. J Bone Miner Res 31:890-9
Frikha-Benayed, Dorra; Basta-Pljakic, Jelena; Majeska, Robert J et al. (2016) Regional differences in oxidative metabolism and mitochondrial activity among cortical bone osteocytes. Bone 90:15-22
Kaya, Serra; Basta-Pljakic, Jelena; Seref-Ferlengez, Zeynep et al. (2016) Lactation-Induced Changes in the Volume of Osteocyte Lacunar-Canalicular Space Alter Mechanical Properties in Cortical Bone Tissue. J Bone Miner Res :
Seref-Ferlengez, Zeynep; Maung, Stephanie; Schaffler, Mitchell B et al. (2016) P2X7R-Panx1 Complex Impairs Bone Mechanosignaling under High Glucose Levels Associated with Type-1 Diabetes. PLoS One 11:e0155107
Cardoso, Luis; Schaffler, Mitchell B (2015) Changes of elastic constants and anisotropy patterns in trabecular bone during disuse-induced bone loss assessed by poroelastic ultrasound. J Biomech Eng 137:
Coughlin, Thomas R; Voisin, Muriel; Schaffler, Mitchell B et al. (2015) Primary cilia exist in a small fraction of cells in trabecular bone and marrow. Calcif Tissue Int 96:65-72
Kennedy, Oran D; Sun, Hui; Wu, Yingjie et al. (2014) Skeletal response of male mice to anabolic hormone therapy in the absence of the Igfals gene. Endocrinology 155:987-99
Seref-Ferlengez, Zeynep; Basta-Pljakic, Jelena; Kennedy, Oran D et al. (2014) Structural and mechanical repair of diffuse damage in cortical bone in vivo. J Bone Miner Res 29:2537-44
Cheung, Wing-Yee; Kennedy, Oran D; Majeska, Robert J et al. (2014) Authors response to letter from Plotkin and Bellido. Calcif Tissue Int 95:384

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