Shuying Yang, MD, PhD

Most adult skeletal diseases are due to excess osteoclastic activity leading to an imbalance in bone remodeling which favors bone resorption. Such diseases would include osteoporosis, periodontal disease, rheumatoid arthritis, multiple myeloma and metastatic cancers. Therefore, understanding the molecular mechanisms of osteoclast differentiation and activation is critical for successful treatment of these diseases. We are attempting to identify key molecules for osteoclastic bone resorption to understand the molecular network of these molecules in bone metabolism. Our major effort focuses on signaling mechanisms in osteoclasts in which Regulator of G proteins (RGS) control calcium signaling and bone resorption.

Molecular mechanism of the action of Regulators of G proteins

RGS proteins play a pivotal role in controlling [Ca2+]i oscillations and cell differentiation. [Ca2+]i oscillations are a biochemical phenomenon emanating from regulation of Ca2+ signaling by RGS proteins. We are investigating how RANKL evokes the [Ca2+]i oscillations that participate in triggering osteoclast differentiation.

By identifying RANKL-induced signaling proteins that regulate [Ca2+]i oscillations, to date, we have found that RGS10 and RGS12 were prominently expressed in human osteoclasts and mouse Osteoclast-Like-Cells (OLCs). RGS10 and RGS12 are essential for terminal differentiation of osteoclasts through effects on different pathways. RGS10 binds to G protein subunits and accelerates GAP activity of Gåq to inactive Ca2+ reuptake and the delay between Ca2+ spikes and regulates Ca2+ oscillations. However, RGS12 may regulate Ca2+ oscillation through interaction with Ca2+ channel or other pathways. In addition, I generated RGS10-deficient mice and found that a null mutation of RGS10 in mice resulted in a severe osteopetrosis due to lack of RGS10-mediated phosphorylation of PLCk and [Ca2+]i oscillations, resulting in reduced osteoclastogenesis. The role and mechanism of RGS12 in vivo in regulating osteoclast differentiation and activation are being evaluated by utilizing genetically engineered gene knockout technology.

The role and mechanism of RGS10 and RGS12’s heterodimerzation partners in regulating [Ca2+]i oscillation and bone resorption

The tissue and stage specific manifestation of RGS10 and RGS12 activity suggests that interaction(s) are necessary with other factors or coactivator(s) for [Ca2+]i oscillations and osteoclast differentiation and activation. In this project, the function and mechanism of the heterodimerzation partners of RGS10 and RGS12 are being characterized using the yeast two-hybrid system, co-immunoprecipitation, RNA interference (RNAi) and genetically engineered gene knockout technologies.

Molecular mechanism of the action of CNBP in bone development and formation

We have found that CNBP plays an important role in early osteoprogenitor cells in vitro and in vivo. By generating CNBP conventional knockout mice, we have found that homozygous mutants exhibit embryonic lethality, whereas heterozygous mice survive to develop postnatal abnormalities associated with altered bone formation, skeletal morphogenesis and osteoporosis. Recently, we have generated bone tissue-specific CNBP conditional knockout mice using Cre/loxP technology. The effect of the mutation on osteoblast proliferation, differentiation and function is being determined.

Selected Publications

Kamolmatyakul S, Chen W, Yang S, Abe Y, Moroi R, Ashique AM, Li Y-P. 2004. IL-1 stimulates Cathepsin K expression in osteoclasts via the tyrosine kinase-NF-kB pathway. J. Dent. Res. 83(10):791–796.

Franceschi RT, Yang S, Rutherford RB, Krebsbach PH, Zhao M, Wang D. 2004. Gene therapy approaches for bone regeneration. Cells Tissues Organs 176(1–3) :95–108.

Yang S, Wei D, Wang D, Phimphilai M, Krebsbalh PH, Franceschi RT. 2003. In vitro and in vivo synergistic interaction between the Runx2/Cbfa1 transcription factors and bone morphogenetic protein-2 in stimulating osteoblast differentiation. J. Bone Miner. Res. 18(4):705–715.

Franceschi RT, Xiao G, Jiang D, Gopalakrishnan R, Yang S, Reith E. 2003. Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation. Connect. Tissue Res. 44 (Suppl.1) :109–116.

Yang SY, Duan FL, Pan W, et. al. 2003. Co-expression of TNF, IFNb gene controlled by HLA-B7 promoter enhances antitumor effect. Chin. J. Microbiol. Immunol. 23(4):275–279.

Yang SY, Duan FL, Lu FM, et. al. 2002. Comparative study on in vivo direct intratumal gene transfer cationic liposome-TK and nude HSV-TK gene in mice. Chin. J. Gastroenter. Hapato. 11 (1):42–45.

Yang SY, Cao GW, Duan FL, et. al. 1999. Construction of adenoviral vector increasing tumor immunogenicity by enhancing gene expression of TNF, IFNb, MHC I. Acad. J. Sec. Med. Univ. 20(9) :608–61 0.

Yang SY, Duan FL. 1998. Killing mechanisms of suicide gene system. Chin. J. Gastroenter. Hepato. 7(2):181–185.

Yang SY, Duan FL, Lu FM, et. al. 1998. The effect of anti-hepatocellular carcinoma of HSV-tk gene therapy mediated by cationic liposome in vitro and in vivo. Chin. J. Cancer Biother. 5(2):112–115.

Yang SY, Duan FL, Cao GW, et. al. 1998. Construction of retroviral vector carry the IRES linked tumor necrosis factor alpha and interferon beta cDNAs under the control of HLA-B7 inducible promoter. Chin. J. Gastroenter. Hepato. 7(4):308– 313.

Yang SY, Duan FL, Lu FM. 1997. Transcriptional regulatory sequences of -fetoprotein. Chin. J. Gastroenter. Heptato. 6(3) :198–200.

Yang SY, Duan FL, Lu FM, et. al. 1997. Primary study on mechanisms of bystander effect caused by expression of suicide gene. Chin. J. Gastroenter. Hepato. 6(4):301–306.

Yang SY, Duan FL, Lu FM. 1997. Effect and mechanism on anti-hepatocellular carcinoma of suicide gene mediated by SA cationic liposome. J. Henan. Med. Univ. 32 (Suppl.):58–59.