Age-associated osteoporosis is a major health problem, which is characterized by an imbalance in bone remodeling and metabolism due to the increase of osteoclastogenesis and activity with age. The current treatment options have been constrained with lower response rates or side-effects and ineffectively tackle the burden and heterogeneity of osteoporosis. Further progress in establishing successful treatment urgently requires a clearer understanding of the mechanisms of osteoclast (OC) differentiation and bone remodeling with age. Evidences have documented that RANKL -evoked Ca2+ oscillations play a switch-on role in the activation of PLC? and NFATc1, and OC differentiation. Further study showed that FcR? and DAP 12 regulate the phosphorylation of PLC?, which is the critical component involved in the RANKL-induced Ca2+ oscillations- NFATc1 pathway. Despite these new insights, it remains unclear how RANKL evokes the essential Ca2+ oscillations that triggers NFATc1 activation and OC differentiation, and it is unknown whether and how this mechanism is involved in age-associated bone loss. Our recent research demonstrated that Regulator of G protein signaling protein 12 (RGS12) was prominently expressed during OC differentiation and that RGS12 expression was significantly increased with increasing age. Knockdown of RGS12 expression inhibited Ca2+ oscillations, NFATc1 expression and OC differentiation. Deletion of RGS12 from hematopoietic/early OC lineage cells (RGS12 / /cre) led to a significantly increase of bone mass, and this increase of bone mass was protected from age-associated bone loss in RGS12 / /cre mice. We also found that loss of RGS12 in mice decreased OC number and levels of marrow adipogenesis with age. Based on these results, we hypothesize that age-associated bone remodeling and metabolism requires RGS12 expression and function, and RGS12 is a critical regulator in controlling Ca2+ oscillation and OC differentiation during aging. We will test the hypothesis through the following two specific aims.
In Aim 1, we will reveal the function of RGS12 in OC differentiation and function during aging through characterization of the phenotypes and pathomechanism of RGS12 conditional knockout mice. We will analyze bone phenotypes in young (6 months (m)), mid-aged (14m) and aged (24m) mice to determine how deletion of RGS12 in early and late OC lineage cells affect postnatal age-associated bone metabolism by using Mx1-cre and Cathepsin K-Cre mice. We will further characterize in vitro of OCs derived from aging RGS12 / /cre mice and determine the contribution of mesenchymal lineage cells to the OCs and skeletal phenotype in aging RGS12 / /cre mice.
In Aim 2, we will elucidate the mechanism of RGS12 interactions that confer specificity of Ca2+ oscillation and OCs with age by characterizing pathomechanism and pathways, RGS12 domain functions and its heterodimerization partners. The goal of this project is to discover the role and mechanism of RGS12 in OC differentiation and activation in pathologic age condition, and provide new and more effective therapeutic targets to age-associated osteoporosis and other bone diseases.

Public Health Relevance

Age-related osteoporosis is a major public health threat affecting approximately 44 million women and men aged 50 and older in the US and results in 1.5 million fractures annually. The current treatment options such as parathyroid hormone have been constrained with lower response rates or side effects and ineffectively tackle the quantitative burden and heterogeneity of osteoporosis. Identifying new proteins which target bone resorbing osteoclasts has potential to provide a significant impact on patients.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Williams, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University of New York at Buffalo
Schools of Dentistry
United States
Zip Code
Ng, Andrew Yh; Tu, Chengjian; Shen, Shichen et al. (2018) Comparative Characterization of Osteoclasts Derived From Murine Bone Marrow Macrophages and RAW 264.7 Cells Using Quantitative Proteomics. JBMR Plus 2:328-340
Liu, Zunpeng; Yuan, Xue; Liu, Min et al. (2018) Antimicrobial Peptide Combined with BMP2-Modified Mesenchymal Stem Cells Promotes Calvarial Repair in an Osteolytic Model. Mol Ther 26:199-207
Liu, Zunpeng; Yuan, Xue; Fernandes, Gabriela et al. (2017) The combination of nano-calcium sulfate/platelet rich plasma gel scaffold with BMP2 gene-modified mesenchymal stem cells promotes bone regeneration in rat critical-sized calvarial defects. Stem Cell Res Ther 8:122
Carpio, Lomeli R; Bradley, Elizabeth W; McGee-Lawrence, Meghan E et al. (2016) Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling. Sci Signal 9:ra79
Yuan, Xue; Cao, Jay; He, Xiaoning et al. (2016) Ciliary IFT80 balances canonical versus non-canonical hedgehog signalling for osteoblast differentiation. Nat Commun 7:11024
Fernandes, Gabriela; Wang, Changdong; Yuan, Xue et al. (2016) Combination of Controlled Release Platelet-Rich Plasma Alginate Beads and Bone Morphogenetic Protein-2 Genetically Modified Mesenchymal Stem Cells for Bone Regeneration. J Periodontol 87:470-80
Yuan, Xue; Smith Jr, Randall J; Guan, Huiyan et al. (2016) Hybrid Biomaterial with Conjugated Growth Factors and Mesenchymal Stem Cells for Ectopic Bone Formation. Tissue Eng Part A 22:928-39
Yuan, X; Yang, S (2016) Primary Cilia and Intraflagellar Transport Proteins in Bone and Cartilage. J Dent Res 95:1341-1349
Fernandes, Gabriela; Yang, Shuying (2016) Application of platelet-rich plasma with stem cells in bone and periodontal tissue engineering. Bone Res 4:16036
Brooks, Emily K; Tobias, Menachem E; Yang, Shuying et al. (2016) Influence of MC3T3-E1 preosteoblast culture on the corrosion of a T6-treated AZ91 alloy. J Biomed Mater Res B Appl Biomater 104:253-62

Showing the most recent 10 out of 24 publications