Bone-Specific Metabolism and Mechanism of Action of Curcuminoids in Blocking Osteolysis in Breast Cancer and Other Resorptive Bone Diseases

Abstract

Osteoclast-mediated bone resorptive disorders, including post-menopausal osteoporosis, age-related bone loss, rheumatoid arthritis, and osteolytic bone metastases, affect over 55 million Americans each year. Breast cancer bone metastases, the model of bone resorptive disorders to be used here, causes osteolysis through a “vicious cycle”, whereby osteoclasts release growth factors (e.g., TGFβ) stored in the bone, which can cause bone-metastatic tumor cells to secrete pro-osteolytic factors (e.g., PTHrP), resulting in more osteoclast-mediated bone resorption. Curcuminoids, dietary polyphenols derived from the turmeric rhizome, inhibit progression of osteolytic bone metastases and other resorptive diseases by targeting osteoclasts and – in the case of bone metastases, also blocking tumoral TGFβ signaling – despite circulating as a glucuronide conjugate that is posited to lack bioactivity. These studies demonstrated that curcumin-glucuronide did not inhibit tumoral TGFβ signaling, with confirmation in multiple breast cancer cell lines that form TGFβ-dependent osteolytic lesions, nor did it inhibit osteoclastogenesis, with both TGFβ signaling and osteoclastogenesis being central to this osteolytic feed-forward loop. However, mouse bone marrow β-glucuronidase (GUSB) deconjugated curcumin-glucuronide to the active aglycone, which was maintained across sexual and skeletal development and with bone resorptive disorders, with evidence that human bone marrow also has deconjugation activity. Other bone-protective dietary polyphenols (e.g., quercetin and resveratrol) were also deconjugated by bone marrow, a GUSB-mediated effect that was required for bone-protective bioactivity, suggesting that GUSB-mediated deconjugation of abundantly glucuronidated dietary polyphenols may be a universal requirement to derive benefits. Finally, curcuminoids inhibited tumoral TGFβ signaling by reducing protein levels of TGFβR2 (receptor that binds TGFβ) and Smad2 (phosphorylated by TGFβR1 following activation of TGFβR2 to stimulate genes promoting bone metastasis progression) primarily through effects on gene expression that depended, in part, on oxidative metabolism. In toto, these novel findings answer a long-standing question about curcumin’s apparent lack of bioavailability, with implications for the bioactivity of other dietary polyphenols, and provide a framework for future studies to explore how interindividual GUSB expression in the population may impact both curcumin’s bone-protective bioactivity and its side effects as well as to further provide insight into cellular targets underlying curcumin’s inhibition of signaling pathways important in bone resorption.