Osteoarthritis (OA) is a degenerative joint disease and the mechanism of this disease is poorly understood. The articular chondrocyte is the only cell type in articular cartilage and these cells are responsible for maintaining the appropriate structure and function of the articular cartilage tissue. The function of articular chondrocytes is regulated by a variety of growth factors, including Wnt family members. Recent human genetic studies demonstrate that patients with a mutation (Arg324Gly substitution) in the secreted frizzled-related protein 3 (sFRP3), a Wnt signaling inhibitor, have a predisposition for the development of OA. It is also known that the mutation of sFRP3 causes activation of ?-catenin signaling. These findings suggest that the canonical Wnt/?-catenin signaling pathway may play a critical role during the development of OA. However, direct genetic and molecular evidence for the role of ?-catenin in the development of OA has not been reported before. In preliminary studies, we demonstrated that ?-catenin conditional activation (cAct) mice developed a severe OA-like phenotype. We also found that meniscus injury and mechanical injury, which often lead to the development of OA, activate canonical Wnt/?-catenin signaling in articular chondrocytes. The underlying hypotheses of this proposal are that 1) canonical Wnt/?-catenin signaling plays a key role and is required for sensing changes in meniscus injury and mechanical injury in articular chondrocytes and its abnormal activation will lead to the development of an OA-like phenotype;and 2) Bmp2 and Mmp13 are key downstream target genes of ?-catenin signaling in articular chondrocytes and deletion of these genes will significantly reverse the OA-like phenotype observed in ?-catenin cAct mice.
In Specific Aim 1, we will analyze ?-catenin cAct mice and determine the age-dependent OA-like phenotype in adult ?-catenin cAct mice. Changes in articular cartilage structure and morphology and articular chondrocyte function will be examined in 3-, 6-, 9-, and 12-month-old ?-catenin cAct mice. In addition, we will also determine if adult ?-catenin cAct mice are more susceptible to chemically- or joint injury-induced OA.
In Specific Aim 2, we will determine the role of meniscus injury or mechanical injury in activation of ?-catenin signaling and the development of OA. We will determine if activation of the canonical Wnt/?-catenin signaling is required for the meniscus injury- or mechanical injury-induced OA-like phenotype in articular chondrocytes.
In Specific Aim 3, we will determine if Bmp2 and Mmp-13 are key downstream mediators of ?-catenin signaling during the development of OA in adult ?-catenin cAct mice. We will delete the Bmp2 or Mmp-13 gene in articular chondrocytes where the ?-catenin gene is over expressed and determine if their deletion will significantly reverse the OA-like phenotype observed in ?-catenin cAct mice. Our proposed studies will provide novel and definitive evidence about the role of ?-catenin signaling in articular chondrocyte function and OA pathogenesis.

Public Health Relevance

Osteoarthritis (OA) is a degenerative joint disease and the mechanism of this disease is poorly understood. Recent human genetic studies demonstrated that ?-catenin signaling may play a key role in OA development. In the proposed studies, we will use molecular genetic approach and different mouse OA models to investigate the role of ?-catenin in OA pathogenesis. The ?-catenin gene will be specifically activated or deleted in articular chondrocytes in adult mice. Our studies will provide direct genetic evidence on the function of ?-catenin in OA development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055915-05
Application #
8286054
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$327,175
Indirect Cost
$113,335
Name
Rush University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
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