Grant: Discovery Grants Program - Individual

This research program has focused on correcting or attenuating the dysregulation of bone turnover that occurs during aging using food-drug synergy. We hypothesize that food bioactives (flavonoids from tea) in combination with drug interventions (low dose estrogen) can provide a safe and effective strategy to normalize bone turnover. Habitual consumption of tea is strongly associated with higher bone mineral density (BMD) in women with less data in men. Flavonoids in tea may be the active component mediating these benefits and through multiple mechanisms, including estrogen-like effects, antioxidant activity and anti-inflammatory activity. We have promising data that luteolin and orientin, flavonoids unique to rooibos tea - and that providing green, black and rooibos tea - stimulate osteoblast activity. These data provide a strong rationale for the proposed studies investigating tea and its ability to promote regulation of bone turnover in rodent models of age-mediated declines in sex steroids (ovariectomized (Ovx) and orchidectomized (Orch) rats). ******The overall objective is to elucidate the mechanisms by which food bioactives (i.e. flavonoids from green, black and rooibos tea) alone or in combination with low dose estrogen modulate bone cell metabolism. The overall hypothesis is that providing flavonoids from tea with low dose estrogen will stimulate osteoblast activity and downregulate osteoclastic activity to a greater extent than flavonoids or low dose estrogen alone. ******The scientific approach involves using the well-established Ovx or Orch rat model to simulate changes in bone cell metabolism that occur during normal aging and result in elevated levels of oxidative stress and low-grade inflammation that uncouples bone cell metabolism (formation,resorption). Analysis of bone tissue from Ovx and Orch rats can determine mechanisms by which dietary strategies alone, or with low dose estrogen, modulate oxidant stress and low-grade inflammation by determining the levels and activity of key mediators of five main aspects of osteoblast activity. These aspects include regulation of i. cell numbers; ii. matrix production; iii. growth factor expression and responsiveness; iv. factors that modulate bone resorption; and v. receptor expression and signal transduction. To understand how these mechanisms relate to whole bone, in vivo functional measures of bone such as BMD, bone strength and 3-dimensional bone structure will be measured in the same rat throughout the study. Fat and lean mass will also be measured as they may be altered by an intervention and modulate bone outcomes.******Expected significance: This research will elucidate the mechanisms by which flavonoids from tea may favourably regulate bone cell metabolism, and also, augment or lessen the ability of estrogen therapy to attenuate dysregulation of bone metabolism.**