Browsing by Author "Alliston, Tamara"

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    Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling
    (Elsevier, 2017-11-28) Dole, Neha S.; Mazur, Courtney M.; Acevedo, Claire; Lopez, Justin P.; Monteiro, David A.; Fowler, Tristan W.; Gludovatz, Bernd; Walsh, Flynn; Regan, Jenna N.; Messina, Sara; Evans, Daniel S.; Lang, Thomas F.; Zhang, Bin; Ritchie, Robert O.; Mohammad, Khalid S.; Alliston, Tamara; Medicine, School of Medicine
    Summary Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRIIocy−/−), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility.
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    Pharmacologic or genetic interference with atrogene signaling protects against glucocorticoid-induced musculoskeletal and cardiac disease
    (American Society for Clinical Investigation, 2024-11-08) Sato, Amy Y.; Cregor, Meloney; McAndrews, Kevin; Schurman, Charles A.; Schaible, Eric; Shutter, Jennifer; Vyas, Punit; Adhikari, Bhawana; Willis, Monte S.; Boerma, Marjan; Alliston, Tamara; Bellido, Teresita; Anatomy, Cell Biology and Physiology, School of Medicine
    Despite their beneficial actions as immunosuppressants, glucocorticoids (GC) have devastating effects on the musculoskeletal and cardiac systems, as long-term treated patients exhibit high incidence of falls, bone fractures, and cardiovascular events. Herein, we show that GC upregulate simultaneously in bone, skeletal muscle, and the heart the expression of E3 ubiquitin ligases (atrogenes), known to stimulate the proteasomal degradation of proteins. Activation of vitamin D receptor (VDR) signaling with the VDR ligands calcitriol or eldecalcitol prevented GC-induced atrogene upregulation in vivo and ex vivo in bone/muscle organ cultures and preserved tissue structure/mass and function of the 3 tissues in vivo. Direct pharmacologic inhibition of the proteasome with carfilzomib also conferred musculoskeletal protection. Genetic loss of the atrogene MuRF1-mediated protein ubiquitination in ΔRING mice afforded temporary or sustained protection from GC excess in bone or skeletal and heart muscle. We concluded that the atrogene pathway downstream of MuRF1 underlies GC action in bone, muscle, and the heart, and it can be pharmacologically or genetically targeted to confer protection against the damaging actions of GC simultaneously in the 3 tissues.
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    The tissue diagnostic instrument
    (2009-05) Hansma, Paul; Yu, Hongmei; Schultz, David; Rodriguez, Azucena; Yurtsev, Eugene A.; Orr, Jessica; Tang, Simon; Miller, Jon; Wallace, Joseph M.; Zok, Frank; Li, Cheng; Souza, Richard; Proctor, Alexander; Brimer, Davis; Nogues-Solan, Xavier; Mellbovsky, Leonardo; Peña, M Jesus; Diez-Ferrer, Oriol; Mathews, Phillip; Randall, Connor; Kuo, Alfred; Chen, Carol; Peters, Mathilde; Kohn, David; Buckley, Jenni; Li, Xiaojuan; Pruitt, Lisa; Diez-Perez, Adolfo; Alliston, Tamara; Weaver, Valerie; Lotz, Jeffrey
    Tissuemechanical properties reflect extracellular matrix composition and organization, and as such, their changes can be a signature of disease. Examples of such diseases include intervertebral disk degeneration, cancer, atherosclerosis, osteoarthritis, osteoporosis, and tooth decay. Here we introduce the tissue diagnostic instrument (TDI), a device designed to probe the mechanical properties of normal and diseased soft and hard tissues not only in the laboratory but also in patients. The TDI can distinguish between the nucleus and the annulus of spinal disks, between young and degenerated cartilage, and between normal and cancerous mammary glands. It can quantify the elastic modulus and hardness of the wet dentin left in a cavity after excavation. It can perform an indentation test of bone tissue, quantifying the indentation depth increase and other mechanical parameters. With local anesthesia and disposable, sterile, probe assemblies, there has been neither pain nor complications in tests on patients. We anticipate that this unique device will facilitate research on many tissue systems in living organisms, including plants, leading to new insights into disease mechanisms and methods for their early detection.