The Journal of Bone and Joint Surgery (American) 83:S15-S22 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.
Smad-Runx Interactions During Chondrocyte Maturation
Phoebe S. Leboy, PhD,
Giovi Grasso-Knight, PhD,
Marina D'Angelo, PhD,
Susan W. Volk, PhD,
Jane B. Lian, PhD,
Hicham Drissi, PhD,
Gary S. Stein, PhD and
Sherrill L. Adams, PhD
Department of Biochemistry, School of Dental Medicine, University
of Pennsylvania, Philadelphia, Pennsylvania, and *Department of
Cell Biology, University of Massachusetts Medical Center, Worcester,
Massachusetts
Phoebe S. Leboy, PhD
Giovi Grasso-Knight, PhD
Marina D'Angelo, PhD
Susan W. Volk, PhD
Sherrill L. Adams, PhD
Dental Biochemistry, University of Pennsylvania, 4001 Spruce Street,
Philadelphia, PA 19104-6003, U.S.A. E-mail address for P.S. Leboy: phoebe{at}biochem.dental.upenn.edu
Jane B. Lian, PhD
Hicham Drissi, PhD
Gary S. Stein, PhD
Department of Cell Biology, University of Massachusetts Medical
Center, 55 Lake Avenue North, Worcester, MA 01655-0106, U.S.A.
In support of their research or preparation of this manuscript,
one or more of the authors received grants or outside funding from
NIH AR39588(GSS). None of the authors received payments or other
benefits or a commitment or agreement to provide such benefits from
a commercial entity. No commercial entity paid or directed, or agreed
to pay or direct, any benefits to any research fund, foundation,
educational institution, or other charitable or nonprofit organization
with which the authors are affiliated or associated.
Background:Intracellular signaling triggered by bone morphogenetic proteins
(BMPs) results in activated Smad complexes that regulate transcription
of BMP-responsive genes. However, the low specificity of Smad binding
to regulatory sequences implies that additional tissue-specific
transcription factors are also needed. Runx2 (Cbfa1) is a transcription
factor required for bone formation. We have examined the role of
Smads and Runx2 in BMP induction of type X collagen, which is a
marker of chondrocyte hypertrophy leading to endochondral bone formation.
Methods:Pre-hypertrophic chondrocytes from the cephalic portion of the
chick embryo sternum were placed in culture in the presence or absence
of rhBMP-2. Cultures were transiently transfected with DNA containing
the BMP-responsive type X collagen promoter upstream of the luciferase
gene. The cultures were also transfected with plasmids, causing over-expression
of Smads or Runx2, or both. After 24-48 hours, cell extracts were
examined for levels of luciferase expression.
Results:In the presence of BMP-2, chondrocytes over-expressing BMP-activated
Smad1 or Smad5 showed significant enhancement of luciferase production
compared with that seen with BMP alone. This enhancement was not
observed with over-expression of Smad2, a transforming growth factor beta
(TGF-ß)-activated Smad. Over-expression of Runx2 in BMP-treated
cultures increased transcriptional activity to levels similar to
those seen with Smads 1 or 5. When chondrocytes were simultaneously
transfected with both Runx2 and Smad 1 or 5, promoter activity was
further increased, indicating that BMP-stimulated Smad activity
can be augmented by increasing the levels of Runx2.
Conclusions:These results implicate the skeletal tissue transcription factor
Runx2 in regulation of chondrocyte hypertrophy and suggest that
maximal transcription of the type X collagen gene in pre-hypertrophic chondrocytes
involves interaction of BMP-stimulated Smads with Runx2.
Clinical Relevance:Many skeletal abnormalities are associated with impaired regulation
of chondrocyte hypertrophy in growth plates. These studies demonstrate
that both BMP-activated Smads and Runx2 levels can modulate chondrocyte
transition to hypertrophy.
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