ABSTRACT
An exponential increase in sales of curcumin-containing turmeric dietary supplements (DS), now the top selling
botanical DS in the United States, has been associated with a marked increase in turmeric DS usage by
Americans for the treatment of chronic musculoskeletal conditions, such as rheumatoid arthritis (30%
prevalence). Scientifically, however, it has been difficult to reconcile in vivo evidence of bone protective effects
of curcumin in humans and rodents with pharmacokinetic data demonstrating barely detectable circulating levels
of aglycone curcumin following curcumin ingestion, due to its rapid conjugation by intestine and liver to form
curcumin glucuronide, a major circulating metabolite shown to be largely inactive. Recent work by our laboratory
has shed light on this process, demonstrating high activity levels of enzymatic deconjugation of curcumin
glucuronide within bone to form bioactive aglycone in concentrations similar to those required in vitro to inhibit
bone-resorbing osteoclast formation, a key driver of bone loss in all major bone diseases, including osteoporosis.
Because glucuronidation is a common metabolic fate for many bone-protective dietary polyphenols, the primary
goal of this project is to determine whether bone-protective polyphenol bioactivity is similarly dependent on ß-
glucuronidase (GUSB), the enzyme required for the deconjugation of glucuronides of curcumin and other bone
protective dietary polyphenols, such as quercetin, within bone. This question has great clinical relevance since
GUSB expression is highly variable in human populations. Experiments will utilize a model of post-menopausal
bone loss (ovariectomized [OVX] mice), mice with defects in GUSB activity and/or processing, and
supplementation with a FDA-approved GUSB enzyme to assess the GUSB-dependence of bone preservation
in OVX mice in response to curcumin or quercetin treatment. An investigation of the relative importance of
extracellular (e.g. secreted) vs. intracellular GUSB-mediated deconjugation of dietary polyphenol glucuronides,
a key question when assessing relevant enzyme phenotypes and replacement therapies in humans, will also be
addressed. Given recent clinical reports of turmeric dietary supplement-associated hepatotoxicity, effects of
GUSB phenotypes on liver function in curcumin-treated mice will be a secondary outcome. Our collaborative
investigative team is well poised to address these research questions. Proof of concept data obtained here will
be impactful, challenging our understanding and supporting new research regarding the role of enzyme
phenotypes in maintaining bone health in response to dietary polyphenols, and opening new avenues for
personalized approaches to promote the healthspan of our aging US population.