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.
|Cheng, Wing Yin; Huynh, HoangDinh; Chen, Peiwen et al. (2016) Macrophage PPARÎ³ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone. Elife 5:|
|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|
|Wei, Wei; Schwaid, Adam G; Wang, Xueqian et al. (2016) Ligand Activation of ERRÎ± by Cholesterol Mediates Statin and Bisphosphonate Effects. Cell Metab 23:479-91|
|Jin, Zixue; Wei, Wei; Huynh, HoangDinh et al. (2015) HDAC9 Inhibits Osteoclastogenesis via Mutual Suppression of PPARÎ³/RANKL Signaling. Mol Endocrinol 29:730-8|
|Li, Xiaoxiao; Wei, Wei; Huynh, HoangDinh et al. (2015) Nur77 prevents excessive osteoclastogenesis by inducing ubiquitin ligase Cbl-b to mediate NFATc1 self-limitation. Elife 4:e07217|
|Wang, Xunde; Wei, Wei; Zinn, Andrew R et al. (2015) Sim1 inhibits bone formation by enhancing the sympathetic tone in male mice. Endocrinology 156:1408-15|
|Jin, Zixue; Li, Xiaoxiao; Wan, Yihong (2015) Minireview: nuclear receptor regulation of osteoclast and bone remodeling. Mol Endocrinol 29:172-86|
|Krzeszinski, Jing Y; Wan, Yihong (2015) New therapeutic targets for cancer bone metastasis. Trends Pharmacol Sci 36:360-73|
|Wang, Xunde; Wei, Wei; Krzeszinski, Jing Y et al. (2015) A Liver-Bone Endocrine Relay by IGFBP1 Promotes Osteoclastogenesis and Mediates FGF21-Induced Bone Resorption. Cell Metab 22:811-24|
|Bornstein, Sheila; Brown, Sue A; Le, Phuong T et al. (2014) FGF-21 and skeletal remodeling during and after lactation in C57BL/6J mice. Endocrinology 155:3516-26|
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