Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9.
OBJECTIVE
Human osteoarthritis (OA) is characterized by a pathologic shift in articular cartilage homeostasis toward the progressive loss of extracellular matrix (ECM). The purpose of this study was to investigate the ability of rAAV-mediated SOX9 overexpression to restore major ECM components in human OA articular cartilage.


METHODS
We monitored the synthesis and content of proteoglycans and type II collagen in 3-dimensional cultures of human normal and OA articular chondrocytes and in explant cultures of human normal and OA articular cartilage following direct application of a recombinant adeno-associated virus (rAAV) SOX9 vector in vitro and in situ. We also analyzed the effects of this treatment on cell proliferation in these systems.


RESULTS
Following SOX9 gene transfer, expression levels of proteoglycans and type II collagen increased over time in normal and OA articular chondrocytes in vitro. In situ, overexpression of SOX9 in normal and OA articular cartilage stimulated proteoglycan and type II collagen synthesis in a dose-dependent manner. These effects were not associated with changes in chondrocyte proliferation. Notably, expression of the 2 principal matrix components could be restored in OA articular cartilage to levels similar to those in normal cartilage.


CONCLUSIONS
These data support the concept of using direct, rAAV-mediated transfer of chondrogenic genes to articular cartilage for the treatment of OA in humans.
Cucchiarini
Magali
M
Saarland University Medical Center, Homburg, Germany. mmcucchiarini@hotmail.com
Thurn
Tanja
T
Weimer
Anja
A
Kohn
Dieter
D
Terwilliger
Ernest F
EF
Madry
Henning
H
D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D024043:Collagen Type II / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D018628:Gene Dosage; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism*; D055758:SOX9 Transcription Factor; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D024043:Collagen Type II; D006609:High Mobility Group Proteins; D011509:Proteoglycans; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D014157:Transcription Factors