This re-entry supplement will support postdoctoral studies of Dr. Priyanka Brahmachary. All cells are subject to and respond to mechanical forces like compression, and the aims of this project are (1) to study glucose metabolism by chondrocytes in vivo and (2) to delineate the effects of a High Fat Diet on synovial joint mechanotransduction in mice. However, the molecular mechanisms linking the mechanics to biological responses are not fully understood. The cells of our model system, the chondrocytes of articular 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 currently accepted pathway chondrocytes use to make ATP. This phenomenon has been linked to the ability of chondrocytes to maintain cartilage. 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 these studies will advance strategies that use mechanical loading to produce the building blocks for cartilage repair.
Aim 1 - 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.
Aim 2 - Obesity is one of the important risk factors associated with OA and is associated with chronic and systemic inflammation that precedes OA pathology. Studies show that changes in blood metabolite levels, as a result of change in tissue and body composition also play a role in the pathogenesis of OA. Experiments using mice fed a high fat diet and exposed to voluntary exercise will help understand glucose metabolism in chondrocytes as well as the relation of mechanotransduction to OA pathogenesis. Using a multidisciplinary approach involving specific immunohistochemical markers and targeted metabolites, we will analyze the effects and underlying molecular mechanisms of obesity related progression of OA and its effects on chondrocytes. 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.
Everyone uses the cartilage in their joints for daily activities like walking. Understanding how cartilage responds to the compressions caused by movement will advance basic understanding of the musculoskeletal system. The project will provide a basic understanding of how chondrocytes respond to mechanical compression and compression affects chondrocyte energy utilization. The project will also expand our understanding of the role of obesity in the progression of OA. These advances are likely to identify candidate biochemical reactions for drugs to repair and grow cartilage.
