Metzger, Corinne Elizabeth (2018-05). Inflammatory Bowel Disease and Bone: Mechanisms and Interventions for Inflammation-Induced Bone Alterations. Doctoral Dissertation. Thesis uri icon

abstract

  • Inflammatory bowel disease (IBD) effects approximately 1.6 million people in the United States with the incidence and prevalence increasing worldwide. All current treatments for IBD aim to simply mitigate the disease symptoms and come with negative consequences. A common comorbidity of IBD is inflammation-induced bone loss, which is characterized by increased bone resorption and decreased bone formation. Osteocytes, cells embedded in the bone matrix, are considered the primary regulatory cell type in bone; however, the role of osteocytes in inflammation-induced alterations in bone is unknown. The goals of the current project are to examine the role of osteocyte signaling proteins in inflammation-induced changes in bone turnover during chronic IBD and secondly, to explore lifestyle changes and therapeutic targets for IBD-induced alterations in bone. Male Sprague-Dawley rats (2 months old) were given gut inflammation via rectal instillations of 2,4,6-trinitrobenzenesulfonic acid (TNBS) dissolved in 30% ethanol while vehicle-treated rats received only 30% ethanol for four weeks. Osteoclast surfaces of cancellous bone were increased after TNBS while bone formation rate was decreased. These changes in bone turnover were coincident with higher osteocytes positive for pro-inflammatory markers, osteoclastogenesis regulators, and bone formation inhibitors. In a second experiment, TNBS and vehicle-treated rats were fed a moderately elevated soy protein diet during the experimental period. TNBS-treated animals fed the moderately elevated soy protein diet had reductions in osteoclast surfaces and increased bone formation rates corresponding with declines in osteocytes positive for pro-inflammatory factors. Finally, a third group of TNBS and vehicle-treated rats received exogenous administration of irisin, a protein released during exercise. TNBS-treated rats receiving irisin had significantly higher bone formation rates and lower osteoclast surfaces than those receiving TNBS alone. Additionally, irisin-treated rats had lower osteocytes positive for pro-inflammatory factors. These results indicate that osteocytes respond to inflammatory signals and may orchestrate changes in bone turnover. Secondly, a moderately elevated soy protein diet reduced the inflammatory alterations in bone during chronic IBD. Additionally, designing methods to increase endogenous irisin, possibly through exercise, could potentially reduce inflammatory changes in bone during IBD. Finally, exogenous irisin administration is a potential novel therapeutic target for inflammation-induced bone loss.
  • Inflammatory bowel disease (IBD) effects approximately 1.6 million people in the United States with the incidence and prevalence increasing worldwide. All current treatments for IBD aim to simply mitigate the disease symptoms and come with negative consequences. A common comorbidity of IBD is inflammation-induced bone loss, which is characterized by increased bone resorption and decreased bone formation. Osteocytes, cells embedded in the bone matrix, are considered the primary regulatory cell type in bone; however, the role of osteocytes in inflammation-induced alterations in bone is unknown. The goals of the current project are to examine the role of osteocyte signaling proteins in inflammation-induced changes in bone turnover during chronic IBD and secondly, to explore lifestyle changes and therapeutic targets for IBD-induced alterations in bone.

    Male Sprague-Dawley rats (2 months old) were given gut inflammation via rectal instillations of 2,4,6-trinitrobenzenesulfonic acid (TNBS) dissolved in 30% ethanol while vehicle-treated rats received only 30% ethanol for four weeks. Osteoclast surfaces of cancellous bone were increased after TNBS while bone formation rate was decreased. These changes in bone turnover were coincident with higher osteocytes positive for pro-inflammatory markers, osteoclastogenesis regulators, and bone formation inhibitors. In a second experiment, TNBS and vehicle-treated rats were fed a moderately elevated soy protein diet during the experimental period. TNBS-treated animals fed the moderately elevated soy protein diet had reductions in osteoclast surfaces and increased bone formation rates corresponding with declines in osteocytes positive for pro-inflammatory factors. Finally, a third group of TNBS and vehicle-treated rats received exogenous administration of irisin, a protein released during exercise. TNBS-treated rats receiving irisin had significantly higher bone formation rates and lower osteoclast surfaces than those receiving TNBS alone. Additionally, irisin-treated rats had lower osteocytes positive for pro-inflammatory factors.

    These results indicate that osteocytes respond to inflammatory signals and may orchestrate changes in bone turnover. Secondly, a moderately elevated soy protein diet reduced the inflammatory alterations in bone during chronic IBD. Additionally, designing methods to increase endogenous irisin, possibly through exercise, could potentially reduce inflammatory changes in bone during IBD. Finally, exogenous irisin administration is a potential novel therapeutic target for inflammation-induced bone loss.

publication date

  • May 2018