My research interest is the regulatory mechanism of bone development and remodeling. The research projects in my laboratory are focused on the following areas:

1. To investigate the signaling mechanism of BMP and Wnt pathways and their cross-talks in osteoblasts and chondrocytes.
We are studying:
a) The interaction of TGF-β signaling molecule Smad3 with β-catenin and the mechanism by which TGF-β regulates β-catenin signaling in chondrocytes.
b) The role of β-catenin signaling proteins Axin and Axin2 in Smad phosphorylation and dephosphorylation.

2. To investigate the ubiquitin-proteasome regulation of key transcription factors in bone cells.
We are investigating:
a) The mechanism of cell cycle proteins cyclin D1/CDK4 in Runx2 and 3 phosphorylation, ubiquitination and degradation.
b) The E3 ligase(s) responsible for the degradation of endogenous Runx2 protein.

3. To create and characterize mouse models and determine functions of key molecules in regulation of bone development and remodeling.
We are characterizing:
a) The role of Axin and Axin2 in bone remodeling using Axin and Axin2 knockout and transgenic mice.
b) The role of WWP1, a Hect domain E3 ligase, in Runx2 degradation and bone formation using Col1a1-WWP1 transgenic mice.
c) The function of β-catenin in the development of osteoarthritis using inducible β-catenin conditional activation and conditional knockout mice targeted by Col2a1-CreERT2 transgenic mice.

1. Chen D, Ji X, Harris MA, Feng JQ, Celeste AJ, Rosen V, Mundy GR, and Harris SE (1998) Differential roles for BMP receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol 142:295-305.

2. Mbalaviele G, Nishimura R, Myoi A, Niewolna M, Reddy SV, Chen D, Feng JQ, Roodman GD, Mundy GR, and Yoneda T (1998) Cadherin-6 mediates the heterotypic interactions between the hemopoietic osteoclast cell lineage and stromal cells in a murine model of osteoclast differentiation. J Cell Biol 141:1467-1476.

3. Nishimura R, Kato Y, Chen D, Harris SE, Mundy GR, and Yoneda T (1998) Samd5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. J Biol Chem 273:1872-1879.

4. Jikko A, Harris SE, Chen D, Mendrick DL, and Damsky CH (1999) Collagen integrin receptors regulate early osteoblast differentiation induced by BMP-2. J Bone Miner Res 14:1075-1083.

5. Shi X, Yang X, Chang Z, Chen D, and Cao X (1999) Smad1 interacts with homeodomain DNA binding proteins in BMP signaling. J Biol Chem 274:13711-13717.

6. Mundy GR, Garrett R, Harris SE, Chan J, Chen D, Rossini G, Boyce B, Zhao M, and Gutierrez G (1999) Stimulation of bone formation in vitro and in rodents by statins. Science 286:1946-1949.

7. Zhao M, Harris SE, Horn D, Geng Z, Nishimura R, Mundy GR, and Chen D (2002) BMP receptor signaling is necessary for normal murine postnatal bone formation. J Cell Biol 157:1049-1060.

8. Garrett IR, Chen D, Gutierrez G, Rossini G, Zhao M, Escobedo A, Kim KB, Hu S, Crews CM, and Mundy GR (2003) Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest 111:1771-1782.

9. Oyajobi BO, Franchin G, Williams PJ, Pulkrabek D, Gupta A, Munoz S, Grubbs B, Zhao M, Chen D, Sherry BA, and Mundy GR (2003) Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease. Blood 102:311-319.

10. Zhao M, Qiao M, Oyajobi B, Mundy GR, and Chen D (2003) E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha 1/Runx2 degradation and plays a specific role in osteoblast differentiation. J Biol Chem 278:27939-27944.

11. Feng JQ, Xing L, Zhang J, Zhao M, Horn D, Chan J, Boyce BF, Harris SE, Mundy GR and Chen D (2003) NF-kB specifically activates BMP-2 gene expression in growth plate chondrocytes in vivo and in a chondrocyte cell line in vitro. J Biol Chem 278:29130-29135.

12. Zhao M, Qiao M, Harris SE, Oyajobi BO, Mundy GR, and Chen D (2004) Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo. J Biol Chem 279:12854-12859.

13. Ye L, Mishina Y, Chen D, Huang H, Dallas SL, Dallas M, Kunieda TW, Tsutsui T, Boskey A, Bonewald LF and Feng JQ (2005) Dentin matrix protein 1 (Dmp1) deficient mice display severe defects in cartilage formation responsible for a chondrodysplasia-like phenotype J Biol Chem 280:6197-6203.

14. Li TF, Darowish M, Zuscik MJ, Chen D, Schwarz EM, Rosier RN, Drissi H, O'keefe RJ (2005) Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation. J Bone Miner Res 21:4-16.

15. Young N, Mikhalkevich N, Yan Y, Chen D, and Zheng WP (2005) Differential regulation of osteoblast activity by Th cell subsets mediated by parathyroid hormone and IFN-gamma. J Immunol 175:8287-8295.

16. Shen R, Chen M, Wang Y, Kaneki H, Xing L, O’Keefe RJ and Chen D (2006) Smad6 interacts with Runx2 and mediates Smurf1-induced Runx2 degradation. J Biol Chem 281:3569-3576.

17. Kaneki H, Gao R, Chen D, Yao Z, Schwarz EM, Zhang YE, Boyce BF, and Xing L (2006) TNF promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 281:4326-4333.

18. Shen R, Wang X, Drissi H, Liu F, O’Keefe RJ, and Chen D (2006) Cyclin D1-Cdk4 induce Runx2 ubiquitination and degradation. J Biol Chem 281:16347-16353.

19. Li T, Chen D, Wu Q, Chen M, Sheu T, Schwarz EM, Drissi H, Zuscik M, and O’Keefe RJ (2006) TGF-beta stimulates cyclin D1 expression through activation of beta-catenin signaling in chondrocytes. J Biol Chem 281:21296-21304.

20. Zhao M, Qiao M, Harris SE, Chen D, Oyajobi BO and Mundy GR (2006) The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling. Mol Cell Biol 26:6197-6208.

21. Chen M, Lichtler AC, Sheu T, Xie C, Zhang X, O’Keefe RJ and Chen D (2007) Generation of a transgenic mouse model with chondrocyte-specific and tamoxifen-inducible expression of Cre recombinase. Genesis 45:44-50.

22. Wang Q, Wei X, Zhu T, Zhang M, Shen R, Xing L, O’Keefe RJ, and Chen D (2007) BMP-2 activates Smad6 gene transcription through bone-specific transcription factor Runx2 J Biol Chem 282:10742-10748.

23. Wang Q, Zhang M, Wang X, Yuan W, Chen D, Royer-Pokora B, and Zhu T (2007) A novel transcript of the LMO2 gene, LMO2-c, is regulated by GATA-1 and PU.1 and encodes an antagonist of LMO2. Leukemia 21:1015-1025.

24. Tan X, Weng T, Zhang J, Wang J, Li W, Wan H, Lan Y, Cheng X, Hou N, Liu H, Ding J, Lin F, Yang R, Gao X, Chen D, and Yang X (2007) Smad4 is required for maintaining normal murine postnatal bone homeostasis J Cell Sci (in press)