Abstract
Osteoarthritis is a debilitating disease likely involving altered metabolism of the chondrocytes in articular cartilage. Chondrocytes can respond metabolically to mechanical loads via cellular mechanotransduction, and metabolic changes are significant because they produce the precursors to the tissue matrix necessary for cartilage health. However, a comprehensive understanding of how energy metabolism changes with loading remains elusive. To improve our understanding of chondrocyte mechanotransduction, we developed a computational model to calculate the rate of reactions (i.e. flux) across multiple components of central energy metabolism based on experimental data. We calculated average reaction flux profiles of central metabolism for SW1353 human chondrocytes subjected to dynamic compression for 30 minutes. The profiles were obtained solving a bounded variable linear least squares problem, representing the stoichiometry of human central energy metabolism. Compression synchronized chondrocyte energy metabolism. These data are consistent with dynamic compression inducing early time changes in central energy metabolism geared towards more active protein synthesis. Furthermore, this analysis demonstrates the utility of combining targeted metabolomic data with a computational model to enable rapid analysis of cellular energy utilization.
Highlights
Osteoarthritis (OA) is the most common joint disorder worldwide and involves the metabolic dysfunction of chondrocytes found in articular cartilage [1,2,3,4,5]
Varying product synthesis reactions did not change the observed trends, even when using the lipid synthesis reaction [S5 Table]. This is especially true for the fluxes of the second 15 minute period, where the maximum distance between two vectors computed with differing synthesis reactions was less than 1% of the norm of the smaller vector. This may be due to a number of factors, such as the precursor metabolites receiving lower weight, or it may be indicative that no single profile dominated metabolism
While compressed chondrocytes showed some of these features, negative fluxes evinced metabolic shifts not accounted for by our hypotheses
Summary
Osteoarthritis (OA) is the most common joint disorder worldwide and involves the metabolic dysfunction of chondrocytes found in articular cartilage [1,2,3,4,5]. The National Health and Nutrition Examination Survey I found that 12.1% of the US population aged 25–74 years had OA in some joint [6]. While joint trauma increases the risk of OA, moderate exercise and associated mechanical loading are linked to improved joint health [7, 8]. For these reasons, understanding chondrocyte responses to mechanical stimulation can yield insight into the initiation, progression, and treatment of osteoarthritis.
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