Project Summary/Abstract Substantial efforts have been expended to elucidate the biological effects of curcuminoids, polyphenolic compounds from the turmeric rhizome. This plant has been used as traditional medicine for millennia to treat inflammatory conditions, such as arthritis, and has become the best-selling herbal supplement in US health food stores. Our laboratory elucidated the in vivo bone-protective effects of curcuminoids in the pre-clinical treatment of rheumatoid arthritis, which led us to discover that curcuminoids behaved similarly in other osteoclast-mediated bone resorptive disorders, including postmenopausal osteoporosis and osteolytic breast cancer bone metastases. Despite this traditional use and increased public interest, the veracity of curcuminoid health claims have been called into question by others in the field. One such concern deals with the bioavailability of curcuminoids. In humans, as in mice, nearly all curcuminoids (>90%) in circulation exist as curcumin-glucuronide, which preliminary evidence suggests is biologically inactive. Despite this, numerous reports exist of turmeric having biological effects including the prevention of bone resorption. This naturally led to an untested hypothesis in the field that curcumin-glucuronide is a pro-drug that is deconjugated at sites of action, which in the context of bone-resorptive diseases presupposes that local deconjugation is occurring in the bone. Preliminary data from our laboratory has confirmed this basic principle; while curcumin circulates primarily (>90%) as the glucuronide conjugate, most curcumin found in bone exists as the free, aglycone. Since bone marrow is the primary site of hematopoiesis, and hematopoietic cells highly express ?- glucuronidase (GUSB), an enzyme capable of deglucuronidating compounds, we hypothesize that curcumin- glucuronide, and indeed other bone-active glucuronidated polyphenols, are converted to the active aglycone by the action of hematopoietic GUSB in the bone marrow. However, other enzymes, such as klotho and heparanase, have reported glucuronide deconjugation activity and may contribute to deconjugation of curcuminoids in vivo. Results from this proposed study will examine the relative bioactivity of curcumin vs. curcumin-glucuronide in the context of osteolysis inhibition and identify the mechanism by which circulating polyphenols are converted into their original aglycone form in the bone microenvironment. While public interest and use of turmeric and curcumin-containing supplements are at an all-time high, the scientific community?s confidence in curcuminoids as a bioactive botanical is wavering. Therefore, the identification of a mechanism for curcuminoid biotransformation and its relationship to bioactivity is both relevant to public health and timely in terms of advancing our understanding of the biological underpinning of curcumins? in vivo effects.