The endoplasmic reticulum (ER) orchestrates protein folding and secretion and the unfolded protein response (UPR) maintains ER homeostasis. The UPR is mediated by three signal transduction pathways, controlled by the proteins PERK, IRE1?, and ATF6, that act to clear unfolded proteins from the ER. Sustained elevation of the UPR, or its insufficient activation, contributes to the pathology of diseases such as diabetes, obesity, atherosclerosis, and cancer. Osteoblasts are bone forming cells that secrete large amounts of collagen and have extensive ER. Moreover, humans and mice lacking a functional version of the PERK gene display several metabolic defects and have low bone mass. However, it is not clear whether the reduced bone mass is due to a decrease in the UPR in osteoblasts or in other cell types. Some osteoblasts become buried in new bone matrix and become osteocytes, which produce factors that control bone remodeling. Osteocyte death can induce factors that stimulate production of bone resorbing osteoclasts. In preliminary studies, we found that induction of ER stress in mice and osteocyte-containing bone cultures increased osteoclastogenic cytokine production, osteoclast number, and bone resorption. Conversely, in a mouse model of glucocorticoid excess, which causes bone loss in humans, we observed reduced expression of downstream mediators of the UPR. This evidence suggests that either excessive or insufficient UPR activation can lead to bone loss. Based on this, we propose the central hypothesis that components of the UPR play an essential role in osteoblast differentiation and function, and dysregulation of the UPR in cells of the osteoblast lineage contributes to pathological bone loss. To test this hypothesis, we will determine whether Perk plays an essential role in osteoblast physiology by conditionally deleting this gene from cells of the osteoblast lineage using Osx1-Cre transgenic mice (Aim 1). We will also determine the skeletal consequences of sustained elevation of the UPR in cells of the osteoblast-lineage by deleting the protein-folding co-chaperone ERdj4 specifically in these cells followed by a comprehensive analysis of the skeleton and osteoblast gene expression (Aim 2). Lastly, we will determine whether glucocorticoid excess inhibits bone formation in mice, in part, by suppressing UPR activation using UPR reporter mice treated with exogenous glucocorticoids and biochemical analyses of UPR pathways (Aim 3). The scientific theme of the proposed Center for Musculoskeletal Disease Research is that genetic analysis of musculoskeletal diseases will support development of novel therapies for such conditions. The proposed studies are aligned with this theme and their successful completion may identify new therapeutic targets for common causes of osteoporosis. These studies will be supported by all three proposed COBRE research cores and the Project Leader will be mentored by a two-member team and other members of Center. Results produced during the first 2 years of the project will lead to the submission of an R01 grant application by the end of the second year of COBRE support.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM125503-01
Application #
9415549
Study Section
Special Emphasis Panel (ZGM1)
Project Start
2018-02-16
Project End
2023-01-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Rasche, L; Alapat, D; Kumar, M et al. (2018) Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma. Leukemia :
Jenkins, Samir V; Vang, Kieng B; Gies, Allen et al. (2018) Sample storage conditions induce post-collection biases in microbiome profiles. BMC Microbiol 18:227
O'Brien, Charles A; Morello, Roy (2018) Modeling Rare Bone Diseases in Animals. Curr Osteoporos Rep 16:458-465
Ambrogini, Elena; Que, Xuchu; Wang, Shuling et al. (2018) Oxidation-specific epitopes restrain bone formation. Nat Commun 9:2193
Went, Molly; Sud, Amit; Försti, Asta et al. (2018) Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nat Commun 9:3707
Piccolo, Brian D; Graham, James L; Stanhope, Kimber L et al. (2018) Diabetes-Associated Alterations in the Cecal Microbiome and Metabolome are Independent of Diet or Environment in the UC Davis Type 2-Diabetes Mellitus Rat Model. Am J Physiol Endocrinol Metab :
Rasche, Leo; Angtuaco, Edgardo J; Alpe, Terri L et al. (2018) The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma. Blood 132:59-66
Xiong, Jinhu; Almeida, Maria; O'Brien, Charles A (2018) The YAP/TAZ transcriptional co-activators have opposing effects at different stages of osteoblast differentiation. Bone 112:1-9
Wongsurawat, Thidathip; Athipanyasilp, Niracha; Jenjaroenpun, Piroon et al. (2018) Case of Microcephaly after Congenital Infection with Asian Lineage Zika Virus, Thailand. Emerg Infect Dis 24:
Xiong, Jinhu; Cawley, Keisha; Piemontese, Marilina et al. (2018) Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss. Nat Commun 9:2909

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