Chondroitin sulfate (CS), a sulfated glycosaminoglycan, is one of the most abundant components of cartilage, comprising as much as 30% of the tissue. Because of its highly negative charge and sheer abundance, CS has long been assumed to be a key component to determine the unique biomechanical property of articular cartilage. Nevertheless, our understanding of the physiological role of CS in vivo and it involvement in human diseases is limited, mainly due to the lack of versatile mouse genetic models. To advance CS research to the next level, we have created a conditional null allele of Chsy1, the gene encoding chondroitin sulfate synthase 1. Remarkably, conditional Chsy1 knockout mice targeted to the limb skeletal system using Prx1-Cre exhibit joint pathologies strikingly similar to those of classical human osteoarthritis (OA). These observations, together with the previous in vitro observation that CS is protective to chondrocytes, led us to hypothesize that a decreased capability in CS synthesis underlie the pathogenesis of human OA. To examine this hypothesis, we propose the following studies:
In Aim 1, we will determine the signaling basis of the degeneration of CS-deficient cartilage, focusing on the canonical Notch pathway.
In Aim 2, we will employ an in vitro mechanical stress model to characterize cell death and antioxidant responses of CS-deficient chondrocytes to mechanical stress.
In Aim 3, we will turn to additional conditional knockout experiments to further dissect chondrocyte-specific and osteoblast-specific roles of CS in the context of OA development.
In Aim 4, collaborating with an expert in human association study, we will search for OA-associated, functional SNPs in human CHSY1 and other CS synthesizing genes. By these studies, we wish to gain novel insight into the molecular mechanisms of cartilage degeneration in OA, and to translate our observations in mice into the identification of novel susceptibility genes for human OA.

Public Health Relevance

Osteoarthritis is a chronic debilitating disease that affects more than 20 million people in the US. This research will investigate the molecular mechanisms of cartilage damage seen in osteoarthritis using a novel genetic mouse model, and then translate the observation into human osteoarthritis by association study. Thus this project is considered directly as well as highly relevant to public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR062692-03
Application #
8716529
Study Section
Intercellular Interactions (ICI)
Program Officer
Tyree, Bernadette
Project Start
2012-09-15
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$429,975
Indirect Cost
$209,475
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037