My Research focus is on therapeutic targets of bone metastases. Transforming growth factor β (TGF-β) is stored in the bone matrix and released due to bone resorption. It has been shown that TGFβ plays an essential role in the process of bone metastases from different cancer, including breast, prostate, and melanoma. We have demonstrated that TGF-β drug inhibition of TGF-β signaling in breast cancer, prostate cancer, and melanoma models of bone metastases model resulted in a reduction of lesion area and tumor burden in this model (Figure 1). We have shown that Overexpressing inhibitory Smad7 in a mouse model of melanoma bone metastases causes a reduction in osteolytic lesions and area on tumor burden.

I am also interested in studying the role of TGF-β in normal bone physiology. TGF-β can affect both bone resorption and formation. We have shown that inhibiting TGF-β in normal bone increases bone mineral density, trabecular bone volume, bone formation rate, and improved mechanical properties. This was the result of increased bone formation and reduced bone resorption.

I am interested in muscle and bone cross-talk. Factors released from bone can influence muscle function and vice versa. We have shown that TGF-β released from bone due to different pathological conditions, such as bone metastases, is a crucial mediator of muscle weakness. TGF-β activates Nox4 in skeletal muscle, causing protein oxidation, and that skeletal muscle RyR1 Ca2+-release channels are a target of the oxidative stress that results from the upregulation of NOX4 by TGF-β (Figure 2). We have shown that inhibition of RyR1-mediated SR Ca2+ leakage, TGF-β activity, TGF-β release from bone, or inhibition of Nox4 improved muscle force production. These results suggest that these processes could be potential therapeutic targets for cancer-associated muscle weakness in the setting of bone destruction due to metastases.