Role of Glucose metabolism in Chondrocyte Mechanotransduction

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Ronald Kent June
Organization: MONTANA STATE UNIVERSITY - BOZEMAN
Fiscal Year: 2024
Award: $333,738
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases

All cells are subject to and respond to mechanical forces like compression. However the molecular mechanisms
linking the mechanics to biological responses are not fully understood. The cells of our model system, the
chondrocytes of cartilage, undergo compression in vivo, and these cells can transduce compression into
biological signals. There is evidence that glucose utilization in chondrocytes is regulated by compression and
that physiologic compression stimulates glycolysis, the main pathway chondrocytes use to make ATP. This
phenomenon has been linked to the ability of chondrocytes to maintain cartilage. Thus, the study of glucose
metabolism is relevant to NIH because millions suffer from chondrocyte-driven cartilage deterioration in
osteoarthritis. Current osteoarthritis treatments involve joint motion, which is counterintuitive. We show for the
first time that physiologically relevant culture conditions enable in vitro compression of chondrocytes. This
project tests the hypothesis that physiological compression of both normal and osteoarthritic chondrocytes
results in a specific pattern of metabolites within glucose metabolism that support protein production to maintain
the cellular microenvironment. The premise is that by quantifying glucose metabolism in chondrocytes this
project will develop strategies that use mechanical loading to produce the building blocks for cartilage repair.
Aim 1 - In vitro experiments will examine the source of carbon (glucose or glutamine) and the mechanism of
regulation. Dependent variables include sex, donor age and the level (low or high) of applied compression.
Targeted metabolomics data will be generated from normal and osteoarthritic chondrocytes subjected to
compression under different experimental conditions. Aim 2 - Experiments using mice subjected to voluntary
running will assess in vivo mechanotransduction. Dependent variables include sex and the duration of running.
Readouts will include both targeted metabolites and immunohistological markers examining regulation of
glucose metabolism. Assays will employ highly specific enzyme inhibitors that will allow a step-by-step analysis
of critical metabolic pathways. This project has substantial innovation including a novel systems biology model
and analytical approach that calculate the relative rates of reaction for each step in glucose metabolism. These
modeling results will be used both to refine existing hypotheses and to generate new ones. The goal of this
project is to identify changes in patterns of small metabolites that result from compression for normal and
osteoarthritic chondrocytes. The expected outcome is to identify candidate target reactions that leverage
glucose metabolism to increase mechanically driven production of amino acid precursors to repair cartilage.
Understanding these mechanisms may prove useful in developing translational strategies to heal cartilage by
activating existing mechanosensitive pathways. Insight into how chondrocytes respond to compression will
advance osteoarthritis translation by providing new therapeutic targets for cartilage repair and enabling
substantial clinical progress.

Terms: <Acids><Address><Affect><Age><Aging><Amino Acids><Animals><Arthroplasty><Assay><Basic Research><Basic Science><Bioassay><Biochemical Reaction><Biologic Models><Biological><Biological Assay><Biological Models><Biology><Body Tissues><Body Weight decreased><Carbon><Cartilage><Cartilage Matrix><Cartilaginous Tissue><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Mechanotransduction><Cellular injury><Chondrocytes><Citric Acid Cycle><Clinical><Complex><Cyclicity><D-Glucose><Data><Degenerative Arthritis><Degenerative polyarthritis><Deterioration><Dextrose><Diarthrosis><Drug Targeting><Drugs><Elderly><Energy-Generating Resources><Environment><Enzymatic Reaction><Enzyme Antagonist><Enzyme Inhibitor><Enzyme Inhibitor Agent><Enzyme Inhibitor Drugs><Evaluation><Exercise><Future><Gln><Glucose><Glutamine><Glycolysis><Goals><Health><Hexose Monophosphate Shunt><Histopathology><Human><Impairment><In Vitro><Individual><Inflammatory Response><Injury><Intermediary Metabolism><Intracellular Communication and Signaling><Isotope Labeling><Isotopes><Joint Prosthesis Implantation><Joints><Knowledge><Krebs Cycle><L-Glutamine><Link><Liquid substance><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mechanical Signal Transduction><Mechanical Stimulation><Mechanics><Mechanosensory Transduction><Mediating><Medication><Membrana Synovialis Capsulae Articularis><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Mission><Model System><Modeling><Modern Man><Molecular><Motion><Movement><Murine><Mus><Musculoskeletal System><NIAMS><NIH><National Institute of Arthritis, and Musculoskeletal, and Skin Diseases><National Institutes of Health><Non-Essential Amino Acid><Nonessential Amino Acid><Osteoarthritis><Osteoarthrosis><Outcome><Pain><Painful><Pathogenesis><Pathology><Pathway interactions><Patients><Pattern><Pentose Phosphate Pathway><Pentose Phosphate Shunt><Pentose Shunt><Pentosephosphate Pathway><Pentosephosphate Shunt><Periodicity><Pharmaceutical Preparations><Physiologic><Physiological><Process><Production><Proteins><Q Levoglutamide><Q. Levoglutamide><QOL><Quality of life><Reaction><Reference Ranges><Reference Values><Regulation><Replacement Arthroplasty><Respiration><Rhythmicity><Role><Running><Signal Transduction><Signal Transduction Systems><Signaling><Source><Staining method><Stains><Symptoms><Synovial Membrane><Synovial joint><Synovium><Systems Biology><TCA cycle><Testing><Time><Tissues><Translating><Translations><Tricarboxylic Acid Cycle><United States National Institutes of Health><Walking><Weight Loss><Weight Reduction><advanced age><ages><aminoacid><biologic><biological signal transduction><blood glucose regulation><body movement><body weight loss><bone><bone cell><candidate identification><cartilage repair><cell damage><cell injury><cell type><cellular damage><chemical reaction rate><damage to cells><degenerative joint disease><drug/agent><energy source><experiment><experimental research><experimental study><experiments><fluid><geriatric><glucose control><glucose homeostasis><glucose metabolism><glucose regulation><healing><hypertrophic arthritis><improved><in vivo><inhibitor><injuries><injury to cells><innovate><innovation><innovative><insight><joint arthroplasty><joint damage><joint degeneration><joint degradation><joint destruction><joint function><joint injury><joint loading><joint mobility><joint mobilization><joint movement><joint replacement><joint tissue degeneration><joint trauma><liquid><locomotor system><mechanic><mechanical><mechanical drive><mechanical force><mechanical load><mechanical stimulus><mechanosensing><mechanotransduction><metabolism measurement><metabolomics><metabonomics><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><osteoarthritic><pathway><pre-clinical><pre-clinical research><preclinical><preclinical research><reaction rate><repair><repaired><respiratory><respiratory mechanism><response><senior citizen><sex><small molecular inhibitor><small molecule inhibitor><social role><translation><translation strategy><translational approach><translational strategy><viscoelasticity><wt-loss>