Unbalanced osteoclast mediated bone resorption is major cause of osteoporosis. Significant progress has been made recently in studies of the mechanism by which RANKL induces osteoclast terminal differentiation. However, how RANKL signal evokes [Ca2+]i oscillation that lead osteoclast differentiation thought NFAT2 pathway still remain unclear. It has been reported that Regulator of G-protein Signaling Protein (RGS) is responsible to [Ca2+]i oscillation regulation in many other tissues and cells. Using differential screening, we found that Regulator of G-protein Signaling Protein 10 gene (RGS10) was predominately expressed in RANKL-induced osteoclast-like cells (OLCs). This result was further confirmed at both mRNA and protein level in both mouse and human osteocalsts. Knockdown of RGS10 expression using RNA interference (RNAi) nhibited osteoclast terminal differentiation induced by RANKL. Our data demonstrated that the failure of osteoclast terminal differentiation resulted from the absence of [Ca2+]i oscillations and silence of NFAT2 expression. Based our results, We hypothesize that RGS10 is essential and sufficient to induce the calcium oscillations for terminal differentiation of osteoclasts. We will test this hypothesis through three specific aims. First, We will examine the spatial and temporal expression of RGS10 and determine whether RGS10 itself directly cause the calcium oscillations for osteoclast differentiation and the functional role of RGS10 in mature osteoclast survival and activation.
In Aim 2, we will define the RGS10 role in bone remodeling and osteoclast differentiation by targeted disruption of RGS10 gene and characterization of the phenotypes of RGS10 knockout mice. The effect of the null mutation on pre-osteoclast proliferation, prosteoclast calcium oscillations, osteoclast differentiation, activation and gene regulation in vivo will be determined. Finally, we will identify the mechanism of RGS10 acting in osteoclast differentiation by characterization of RGS10 heterodimerzation partners and the partners functions. The heterodimerzation partners will be characterized by the approaches of yeast two-hybrid system and co-immunoperticipation. The function of the heterodimerzation partners will be characterized using RNAi approach. RGS10 role in G-protein singling will be characterized. The overall goal of these studies is to establish the roles of RGS10 in osteoclast differentiation and function and discover the mechanism underlying how RANKL signal evokes [Ca2+]i oscillation that lead osteoclast differentiation, and to ultimately apply this knowledge to the control of osteolytic diseases.
|Chen, Wei; Zhu, Guochun; Tang, Jun et al. (2018) C/ebp? controls osteoclast terminal differentiation, activation, function, and postnatal bone homeostasis through direct regulation of Nfatc1. J Pathol 244:271-282|
|Chen, Wei; Zhu, Guochun; Jules, Joel et al. (2018) Monocyte-Specific Knockout of C/ebp? Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebp? in Osteoclast Differentiation and Function. J Bone Miner Res 33:691-703|
|Huang, Hong; Wang, Jue; Zhang, Yan et al. (2018) Bone resorption deficiency affects tooth root development in RANKL mutant mice due to attenuated IGF-1 signaling in radicular odontoblasts. Bone 114:161-171|
|Jules, Joel; Li, Yi-Ping; Chen, Wei (2018) C/EBP? and PU.1 exhibit different responses to RANK signaling for osteoclastogenesis. Bone 107:104-114|
|Jules, Joel; Chen, Wei; Feng, Xu et al. (2018) C/EBP? transcription factor is regulated by the RANK cytoplasmic 535IVVY538 motif and stimulates osteoclastogenesis more strongly than c-Fos. J Biol Chem 293:1480-1492|
|Pan, Jie; Wang, Jue; Hao, Liang et al. (2017) The Triple Functions of D2 Silencing in Treatment of Periapical Disease. J Endod 43:272-278|
|McConnell, Matthew; Feng, Shengmei; Chen, Wei et al. (2017) Osteoclast proton pump regulator Atp6v1c1 enhances breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity. Oncotarget 8:47675-47690|
|Wu, Mengrui; Wang, Yiping; Shao, Jian-Zhong et al. (2017) Cbf? governs osteoblast-adipocyte lineage commitment through enhancing ?-catenin signaling and suppressing adipogenesis gene expression. Proc Natl Acad Sci U S A 114:10119-10124|
|Wu, Mengrui; Chen, Wei; Lu, Yun et al. (2017) G?13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3?-NFATc1 signalling pathway. Nat Commun 8:13700|
|Jules, Joel; Chen, Wei; Feng, Xu et al. (2016) CCAAT/Enhancer-binding Protein ? (C/EBP?) Is Important for Osteoclast Differentiation and Activity. J Biol Chem 291:16390-403|
Showing the most recent 10 out of 52 publications