Molecular Orthopaedic Research
Under the direction of T.-C. He, M.D.,
Ph.D., the
Molecular
Oncology Laboratory has focused on the molecular aspects of
bone and musculoskeletal diseases. Specifically, the current
research interests of the Molecular Oncology Laboratory include
the following areas:
Molecular Genetics Of Bone And Soft
Tissue Tumors
To understand the molecular basis of
osteosarcoma, the He, Haydon & Luu group found that B-catenin
signaling is activated in approximately 70% of the analyzed 40
cases of human osteosarcoma, suggesting that deregulation of B-catenin
may play a role in the development of human osteosarcoma. These
findings have been published in International Journal of Cancer.
The He & Haydon group has also carried out
a study to determine if tyrosine kinase inhibitors down-regulate
the beta-catenin signaling activity. They found that STI-571/Gleveec
effectively inhibited the constitutive activity of B-catenin
signaling in human colon cancer cells as well as the
Wnt1-induced activation of B-catenin signaling in HOS, HTB-94,
and HEK 293 cells. Furthermore, STI-571 was shown to effectively
suppress the proliferation of human colon cancer cells. Finally,
the He & Haydon group demonstrated that the Wnt1-mediated
activation of a GAL4-B-catenin heterologous transcription system
was effectively inhibited by STI-571. Thus, their findings
suggest that tyrosine phosphorylation may play an important role
in regulating B-catenin signaling activity, and inhibition of
this signaling pathway by STI-571 may be further explored as an
important target for alternative/ adjuvant treatments for a
broader range of human cancer. These findings have been
published in Cancer Letters.
To further explore other molecular and
genetic changes that may be responsible for osteosarcoma
development, the He & Haydon group has recently investigated the
possible role of S100 proteins in human osteosarcoma. Several
recent cytogenetic studies suggest that chromosome 1q21.1-1q21.2
region is frequently altered in osteosarcoma and other soft
tissue tumors. One large group of gene family (~20 members)
clustering in this region is the EF-hand calcium binding S100
proteins. The He & Haydon group examined the expression of the
S100A6 in human osteosarcoma, and found that approximately 83%
(57 of 69) of the analyzed osteosarcomas stained positive for
S100A6. The expression level of S100A6 did not correlate with
overall survival (p = 0.13). However, of the 22 patients who did
not have metastatic disease at both diagnosis and follow-up, all
but two stained positively for S100A6. There is a trend towards
decreased clinically evident metastasis in patients whose tumors
positively stained for S100A6 (p = 0.013). Of the 39 patients
who had no metastases at diagnosis, the risk of developing
metastases decreased as S100A6 staining intensity increased (p =
0.043). Thus, these findings suggest that S100A6 may be
associated with the pathogenesis of osteosarcoma. These studies
have been supported by research grants from The Brinson
Foundation, The Schweppe Foundation, and the OREF, as well as an
OREF Resident Research Fellowship awarded to Dr. Hue L. Luu.
Molecular Basis Of Bone Formation
Identification of BMP-9 as one of the most
osteogenic BMPs Understanding the molecular mechanisms
underlying bone formation is pivotal for understanding the
pathogenesis of bone diseases, as well as for develop effective
approaches to bone regeneration. Although several BMPs (mostly
BMP-2 and BMP-7) have been shown to induce bone formation, it is
unclear whether the currently used ones represent the most
osteogenic BMPs. Until recently, comprehensive analysis of
osteogenic activity of all BMPs has been hampered by the fact
recombinant proteins are either not biologically active or not
available for all BMPs. The He & Haydon group has recently
constructed a panel of recombinant adenoviral vectors expressing
the 14 types of human BMPs. Through a comprehensive analysis,
they found that BMP-2, 6, and 9 emerge as the most potent
osteogenic BMPs in osteoblastic progenitor cells in vitro. These
findings have been published in the August 2003 issue of Journal
of Bone and Joint Surgery with Introductory Comments.
Furthermore, the He & Haydon group has recently concluded
several rounds of in vivo studies and found that BMP-9 is
reproducibly demonstrated as one of the most osteogenic BMPs to
induce orthotopic bone formation in an orthotopic ossification
animal model. These findings strongly suggest that, in addition
to BMP-2 and BMP-7 that are currently used in clinical trails,
BMP-6 and BMP-9 could represent equally, if not more effective
osteogenic factors for bone regeneration in a clinical setting.
Molecular Mechanisms behind
BMP-Induced Osteogenic Signaling
To identify potentially important
mediators of BMP-induced osteogenic signaling, the He & Haydon
group has recently determined the gene expression differences
between three osteogenic BMPs (i.e., BMP-2, 6, and 9) and two
inhibitory/non-osteogenic BMPs (i.e., BMP-3 and 12). Through the
microarray analysis of ~12,000 genes in pre-osteoblast
progenitor cells, they found that expression level of 203 genes
(105 up-regulated and 98 down-regulated) was altered >2-fold
upon osteogenic BMP stimulation. BMP-regulated expression of the
selected target genes was confirmed by RT-PCR and CodeLink
microarray analysis. Gene ontology analysis revealed that
osteogenic BMPs, but not inhibitory/non-osteogenic BMPs,
activate genes involved in the proliferation of pre-osteoblast
progenitor cells towards osteoblastic differentiation, and
simultaneously inhibit myoblast-specific gene expression. These
findings are consistent with the notion that osteogenesis and
myogenesis are two divergent processes. The He & Haydon group is
currently elucidating the functional importance of these
downstream mediators in BMP-induced osteogenic signaling. These
functional studies could uncover the missing links between
disruption of normal osteoblast differentiation and osteosarcoma
development. These studies have been supported by a research
grant from The Aircast Foundation, as well as the OREF Career
Development Award to Dr. Rex. C. Haydon.
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Last update:
January 10, 2010
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