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J. Biol. Chem., Vol. 277, Issue 33, 30177-30182, August 16, 2002
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From the The healing of skeletal fractures is essentially
a replay of bone development, involving the closely regulated,
interdependent processes of chondrogenesis and osteogenesis. Using a
rat femur model of bone healing to determine the degree of
transcriptional complexity of these processes, suppressive subtractive
hybridization (SSH) was performed between RNA isolated from intact bone
to that of callus from post-fracture (PF) days 3, 5, 7, and 10 as a
means of identifying up-regulated genes in the regenerative process. Analysis of 3,635 cDNA clones revealed 588 known genes (65.8%, 2392 clones) and 821 expressed sequence tags (ESTs) (31%, 1,127). The
remaining 116 cDNAs (3.2%) yielded no homology and presumably represent novel genes. Microarrays were then constructed to confirm induction of expression and determine the temporal profile of all
isolated cDNAs during fracture healing. These experiments confirmed
that ~90 and ~80% of the subtracted known genes and ESTs are
up-regulated (
Transcriptional Profiling of Bone Regeneration
INSIGHT INTO THE MOLECULAR COMPLEXITY OF WOUND
REPAIR*,
§,,,
,,**
Department of Biomedical Engineering,
Department of Applied Mathematics and Statistics,
** Center for Biotechnology, State University of New York,
Stony Brook, New York 11794 and the ¶ Department of Metabolic
Disease, Millennium Pharmaceuticals,
Cambridge, Massachusetts 02139
2.5-fold) during the repair process, respectively. Clustering analysis revealed subsets of genes, both known and unknown,
that exhibited distinct expression patterns over 21 days (PF),
indicating distinct roles in the healing process. Additionally, this
transcriptional profiling of bone repair revealed a host of activated
signaling molecules and even pathways (i.e. Wnt). In
summary, the data demonstrate, for the fist time, that the healing
process is exceedingly complex, involves thousands of activated genes,
and indicates that groups of genes rather than individual molecules
should be considered if the regeneration of bone is to be accelerated exogenously.
*
This work was supported by Grant 317X from the Center for
Biotechnology (New York State Center for Advanced Technology), by Aircast Foundation Grant F600 (to M. H.), and by Millennium
Pharmaceuticals (to C. T. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The on-line version of this article (available at
http://www.jbc.org) contains Supplemental Tables 1-3.
§
To whom correspondence should be addressed: Dept. of Biomedical
Engineering, Psychology-A Bldg, 3rd Floor, SUNY, Stony
Brook, NY 11794-2580. Tel.: 631-632-1480; Fax: 631-632-8577; E-mail:
michael.hadjiargyrou@sunysb.edu.
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