Research
Specific
Clinical/Research Interest:
Gene regulation and signal
transduction of joint tissue homeostasis; mechanotransduction pathway and its
potential use for disease prevention and treatment; effects of chemo-factors
and mechano-factors on MSC renewal, commitment, and differentiation; role of
MSCs in wound healing and tissue engineering
Current Students: Melissa
Ramcharan, Daniel Leong, Jonathan Lee, Edward Maharam
Postdoctoral Fellows: Zhengzhe
Li, MD, Ph.D
Summary of Research
Studies:
The focus of our integrated systems-based research is to elucidate the
molecular mechanism of signal transduction in skeletal tissue. The goal of the
research is to provide molecular and signaling base for preventing and for
therapeutic treatment of skeletal breakdown diseases such as arthritis,
osteoporosis, tendonopathy. Three specific interests are: Role of mechanical
stimuli in preventing cartilage/tendon breakdown: Our research project has
provided strong evidence that gentle mechanical load exerts a role in
preventing skeleton tissue degeneration; and that CITED2 (CBP/p300-Interacting
Transactivator with ED-rich tail 2), a cytokine and stress inducible gene that
I cloned previously, plays a critical role in tissue-breakdown. Based on
computational analysis for biological experiment data, the current project is
focusing on CITED2 mediated novel signaling pathway in modulation of matrix
homeostasis. Mechanism of load-induced bone formation: Mechanical loading is a
potent stimulator of bone growth. Using a novel 3-dimensional osteoblasts
culture-piezoelectric mechanical loader, our laboratory is now able to induce
osteo-mineralization in vitro. We are currently using this novel in vitro model
to identify key signaling pathways and critical biological and mechanical
environment factors for osteo-mineralization and bone formation. In our in vivo
study, we have recently demonstrated that sinusoidal loads to an elbow joint
stimulate bone formation in cortical bone without bone deformation. Using
pathway-specific cDNA-array, trans-signal protein-array and other molecular
technologies, this in vivo study is focusing on identifying the critical
signaling pathway in bone formation induced by neighboring joint deformation.
Identification of cellular signaling pathway by genome-wide transcription
analysis: We have developed a novel approach in integrating the experimental
data and genomic DNA sequences. This computational and biochemical tool
demonstrated in the model of chondrocyte cellular response to interleukine-1,
can be used for any biological process including molecular and cellular
mechanism of mechanotransduction of joint, tendon, and bone. Using
biotin-avidin affinity binding and protein fingerprints technologies, the
current project is aiming at cloning novel transactivators that binds to the
identified DNA binding motifs. Accomplishment of this project will result in
not only cloning new signal molecules in tissue-breakdown but also proving our
experiment-based genome-wide cloning strategy.
Sun HB, Zhu YX, Yin T, Sledge G, Yang YC. MRG1, the production of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity. Proc. Natl. Acad. Sci. USA 1998; 95: 13555-13560.
Sun HB, Yokota H. Messenger RNA levels of matrix metalloproteinases, tissue inhibitors of metalloproteinases, and transcription factors in rheumatic synovial cells under mechanical stimuli. Bone 2001; 28: 303-309.
Sun HB, Yokota H. Altered mRNA levels of matrix metalloproteinase 13 in MH7A synovial cells by mechanical loading. Bone 2001; 28: 399-403.
Sun HB, Malacinski GM, Yokota H. Promoter competition assay for analyzing gene regulation in joint tissue engineering. Frontiers in Bioscience 2002; 7: 169-174.
Sun HB, Yokota H. Reduction of cytokine-induced expression and activities of MMP-1 and MMP-13 by mechanical strain in MH7A rheumatoid synovial cells. Matrix Biol 2002; 21: 263-270.
Sun HB, Liu Y, Qian L, Yokota H. Model-based analysis of matrix metalloproteinases expression under mechanical shear. Ann. Biomed. Eng 2003; 31: 171-180.
Sun HB, Nalim R, Yokota H. Expression and activities of matrix metalloproteinases under oscillatory shear in IL-1 stimulated rheumatic synovial cells. Connective Tissue Res 2003; 44: 42-49.
Yokota H, Goldring MB, Sun HB. CITED2 mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear. J. Biol. Chem 2003; 278: 47275-47280.