Turnover of cells and matrix occurs in a wide spectrum of organs and tissues and is essential to maintenance of tissue integrity. In bone, numerous investigators have suggested that a major function of osteonal remodeling is to maintain tissue, wherein remodeling serves to remove and replace microscopic regions of compact bone, which have become microdamaged due to fatigue. Left undetected and unrepaired, microdamage in bone leads to compromised mechanical properties and bone fragility. How bone remodeling units """"""""target"""""""" microscopically damaged areas of bone remains a mystery. Previously, we found that osteocytes undergo apoptosis in bone areas immediately surrounding bone fatigue microdamage. This apoptosis precedes the onset of osteoclastic resorption. The resulting areas of osteocyte apoptosis co-localize exactly with the areas of bone, which subsequently undergo resorption by osteoclasts. These observations are the first demonstration of a potential cellular mechanism to explain how microdamage can initiate focal bone remodeling. In the current studies, we will determine whether osteocyte apoptosis is also highly associated with bone resorption stimulated by metabolic challenge (i.e. ovariectomy in rats) and mechanical challenge (i.e. immobilization in rats). Osteocyte apoptosis will be assessed by TUNEL and Bax expression in situ, and quantitated by histomorphometry. In the second series of studies, osteocyte apoptosis and targeted remodeling will be activated using ulnar bending to fatigue long bones in adult rats. Osteocyte apoptosis will then be pharmacologically modulated in vivo using a caspase inhibitor, in order to determine whether the extent of osteocyte apoptosis directly influences the activation, targeting and/or progression of osteoclastic resorption. In the third series of studies, we will examine changes in bone lining cells overlying regions of osteocyte apoptosis. We will determine whether lining cells also change their integrity in concert with underlying osteocytes, and thereby potentially present phagocytic markers to responding osteoclasts and precursors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR041210-14
Application #
7106623
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Lester, Gayle E
Project Start
1992-09-15
Project End
2008-03-31
Budget Start
2006-08-01
Budget End
2008-03-31
Support Year
14
Fiscal Year
2006
Total Cost
$370,344
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Orthopedics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Cabahug-Zuckerman, Pamela; Stout Jr, Randy F; Majeska, Robert J et al. (2018) Potential role for a specialized ?3 integrin-based structure on osteocyte processes in bone mechanosensation. J Orthop Res 36:642-652
Liu, Zhongbo; Han, Tianzhen; Werner, Haim et al. (2018) Reduced Serum IGF-1 Associated With Hepatic Osteodystrophy Is a Main Determinant of Low Cortical but Not Trabecular Bone Mass. J Bone Miner Res 33:123-136
Kennedy, Oran D; Lendhey, Matin; Mauer, Peter et al. (2017) Microdamage induced by in vivo Reference Point Indentation in mice is repaired by osteocyte-apoptosis mediated remodeling. Bone 95:192-198
Kaya, Serra; Basta-Pljakic, Jelena; Seref-Ferlengez, Zeynep et al. (2017) Lactation-Induced Changes in the Volume of Osteocyte Lacunar-Canalicular Space Alter Mechanical Properties in Cortical Bone Tissue. J Bone Miner Res 32:688-697
Liu, Zhongbo; Han, Tianzhen; Fishman, Shannon et al. (2017) Ablation of Hepatic Production of the Acid-Labile Subunit in Bovine-GH Transgenic Mice: Effects on Organ and Skeletal Growth. Endocrinology 158:2556-2571
McCutcheon, Sean; Majeska, Robert; Schaffler, Mitchell et al. (2017) A multiscale fluidic device for the study of dendrite-mediated cell to cell communication. Biomed Microdevices 19:71
Lewis, Karl J; Frikha-Benayed, Dorra; Louie, Joyce et al. (2017) Osteocyte calcium signals encode strain magnitude and loading frequency in vivo. Proc Natl Acad Sci U S A 114:11775-11780
Liu, Zhongbo; Kennedy, Oran D; Cardoso, Luis et al. (2016) DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH. FASEB J 30:635-52
Smaldone, Silvia; Clayton, Nicholas P; del Solar, Maria et al. (2016) Fibrillin-1 Regulates Skeletal Stem Cell Differentiation by Modulating TGF? 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

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