Bone is a dynamic tissue that constantly remodels by balancing osteoblast-mediated bone formation and osteoclast-mediated bone resorption. The disruption of this tissue homeostasis causes several devastating human diseases including osteoporosis, arthritis and bone metastasis of cancers, leading to severe pain, fractures, life-threatening hypercalcemia, limited mobility and increased mortality. The nuclear receptor PPAR3 (peroxisome proliferator-activated receptor-3) is a critical regulator of energy metabolism and an important therapeutic target for treating the escalating obesity and diabetes epidemic. Emerging evidence suggests that PPAR3 also modulates bone turnover. We discovered that activation of PPAR3 promotes osteoclast differentiation and bone resorption. It has also been shown to suppress osteoblast differentiation and bone formation. Importantly, these findings unravel a central role for PPAR3 in the connection between mineral and energy metabolism, linking skeletal disorders such as osteoporosis with metabolic syndrome hallmarked by obesity, diabetes and atherosclerosis. Synthetic PPAR3 ligands thiazolidinediones (TZDs) are FDA-approved drugs for insulin resistance and type 2 diabetes. Recent clinical trials have reported that long-term use of TZDs increased fracture rates among diabetic patients. Thus, it is of paramount importance to understand how PPAR3 regulates bone metabolism. In this proposal, we hypothesize that 1) PPAR3 exerts a biphasic regulation of osteoclastogenesis, at both the early stage of osteoclast lineage commitment and the late stage of osteoclast differentiation;2) this regulation is influenced by the metabolic context and represents a critical mechanism for TZD-mediated bone loss.
In Aim 1, we will determine the cellular mechanisms for osteoclast development by identifying its hematopoietic origin.
In Aim 2, we will determine the molecular mechanisms for osteoclast lineage commitment and PPAR3 regulation.
In Aim 3, we will determine how TZDs induce bone loss in the context of diabetes. A combination of tools will be employed, including mouse genetic and disease models, molecular and cell biology, biochemistry and small molecules. The proposed investigation will elucidate how PPAR3 regulates mineral metabolism by controlling osteoclast lineage commitment, differentiation and function, as well as how this regulation is influenced by energy metabolism. It will open exciting new paths to the understanding of skeletal physiology and its connection with metabolic diseases. Importantly, the outcome of these studies will provide fundamental insights for the treatment of diabetes, as well as other diseases associated with increased bone resorption such as osteoporosis, arthritis and cancer metastasis. Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community.
Recent clinical trials have reported that long-term use of the diabetic drug Avandia, an activator of the nuclear receptor PPAR3 (peroxisome proliferator-activated receptor-3), increases fracture rates among diabetic patients. This proposal investigates the mechanisms by which PPAR3 and Avandia regulate bone resorption and explores the potential influence of obesity and diabetes on this regulation. Insights from these studies will significantly advance our understanding of both basic bone biology and Avandia-mediated skeletal fragility in diabetic patients.
Huynh, HoangDinh; Wan, Yihong (2018) mTORC1 impedes osteoclast differentiation via calcineurin and NFATc1. Commun Biol 1:29 |
Yang, Dengbao; Huynh, HoangDinh; Wan, Yihong (2018) Milk lipid regulation at the maternal-offspring interface. Semin Cell Dev Biol 81:141-148 |
Krzeszinski, Jing Y; Schwaid, Adam G; Cheng, Wing Yin et al. (2017) Lipid Osteoclastokines Regulate Breast Cancer Bone Metastasis. Endocrinology 158:477-489 |
Chen, Peiwen; Zuo, Hao; Xiong, Hu et al. (2017) Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. Proc Natl Acad Sci U S A 114:580-585 |
Zuo, Hao; Wan, Yihong (2017) Nuclear Receptors in Skeletal Homeostasis. Curr Top Dev Biol 125:71-107 |
Huynh, HoangDinh; Wei, Wei; Wan, Yihong (2017) mTOR Inhibition Subdues Milk Disorder Caused by Maternal VLDLR Loss. Cell Rep 19:2014-2025 |
Baier, Scott R; Wan, Yihong (2016) MicroRNA Exert Macro Effects on Cancer Bone Metastasis. Curr Osteoporos Rep 14:163-9 |
Wei, Wei; Schwaid, Adam G; Wang, Xueqian et al. (2016) Ligand Activation of ERR? by Cholesterol Mediates Statin and Bisphosphonate Effects. Cell Metab 23:479-91 |
Li, Xiaoxiao; Huynh, HoangDinh; Zuo, Hao et al. (2016) Gata2 Is a Rheostat for Mesenchymal Stem Cell Fate in Male Mice. Endocrinology 157:1021-8 |
Cheng, Wing Yin; Huynh, HoangDinh; Chen, Peiwen et al. (2016) Macrophage PPAR? inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone. Elife 5: |
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