The discovery of nuclear receptors provides a molecular approach to the study of regulation by fat-soluble hormones, vitamins and dietary lipids. We investigate how nuclear receptors and their ligands regulate metabolism and cancer. The nuclear receptor PPARγ can be activated by the TZD drugs for type II diabetes, such as rosiglitazone. However, TZD usage has been reported to associate with bone loss and fracture risk. Our research reveal that PPARγ activation not only inhibit osteoblast differentiation and bone formation but also stimulate osteoclast differentiation and bone resorption, unraveling a central role for PPARγ in the emerging connection between mineral and energy metabolism, linking skeletal disorders with metabolic syndrome.
Bone is a dynamic tissue that undergoes constant remodeling, balancing bone formation by osteoblasts and bone resorption by osteoclasts. When resorption outpaces formation, bone degenerative diseases such as osteoporosis occur. We have identified new regulators of bone remodeling including FGF21 and Orexin, establishing rationale for novel treatment of osteoporosis by enhancing bone formation and suppressing bone resorption.
Bone metastasis is a frequent, debilitating and essentially incurable complication of many types of cancers including breast, prostate, lung, kidney tumors, causing severe bone pain, life-threatening hypercalcemia, spinal cord compression, limited mobility and motality. We investigate how tumor cells and bone cells form a vicious cycle to promote bone metastasis, thereby uncovering novel strategies for the prevention and treatment of bone metastasis. To this end, our preclinical study has shown that nanoparticle delivery of microRNA-34a mimetics can suppress osteoporosis and cancer bone metastasis.
Lactation is a metabolically demanding process yet crucial for the development of newborn mammals. Our recent studies reveal that maternal genetic or dietary defects result in production of “toxic milk” that triggers systemic inflammation in the nursing neonates, manifested as alopecia. We use this unique "pup fur loss" phenotype as a visual readout to identify novel regulators of metabolism and inflammation for a better understanding and treatment of infantile disorders and inflammatory diseases.
Our research is funded by: