This proposal is from Dr. Linda Sandell, a cartilage biologist in the Department of Orthopaedic Surgery and Dr. Jim Cheverud, a population geneticist in the Department of Anatomy and Neurobiology. We propose to identify genetically defined mouse models of cartilage healing. Recently, a direct correlation between articular cartilage healing and protection from osteoarthritis (OA) has been demonstrated. This will be a large-scale project that creates a unique resource for the study of the genes that contribute to cartilage healing and thus to OA. Dr. Cheverud currently uses """"""""super-healing"""""""" mice for studies on genes that contribute to body size and has developed 12 inbred strains of mice containing portions of the genome and an advanced intercross between large (healing) and small (non-healing) mice of 40 generations. It has been demonstrated that the parental """"""""super-healing"""""""" mice are able to regenerate cartilage significantly better than control mice. In the Department of Orthopaedic Surgery, we have established mouse models of fracture healing, cartilage healing and ligament healing and will perform full thickness cartilage wounds in the test animals. The collaboration between the Departments of Anatomy and Neurobiology and Orthopaedic Surgery would provide a unique multi-disciplinary team approach to the problem of cartilage repair. We are in a unique position to carry out these studies provided substantial special funding can be obtained. These studies will provide a completely new resource to investigators in the field and provide the resources to understand the genetics of cartilage repair. These animal models with defined genetics would be made available to investigators to study the mechanism of how a specific gene, or group of genes, contribute to cartilage repair and thus to OA. An investment in this area will catapult the field to allow for the understanding of cartilage repair, a field that, without this Grand Opportunity, will otherwise remain dormant in that funding for the """"""""one strain at a time"""""""" approach will not be available. The results found in mice, a species that is amenable to genetic studies, will be immediately applicable to the human disease as many of the genes are likely to be the same or affect the same pathway. Long term, understanding of the genes that contribute to cartilage healing may allow for the """"""""intrinsic"""""""" repair of cartilage long before OA develops to the point of cartilage degeneration. Knowledge of the players involved in sustaining a cartilage repair response will allow us to determine which individuals will be more susceptible to OA. This could have a huge public health impact as the pain and disability from OA is estimated to effect 40 million people and cost 3 billion dollars per year in work loss and special care.

Public Health Relevance

Osteoarthritis (OA) affects 35 million people in the USA alone with an expected doubling in the number of affected individuals over the next 20 years. Emerging evidence indicates that 50-75% of variation in OA is genetic, however, little evidence is available on the genes that cause OA or protect from OA. It has been suspected that humans differ in their ability to repair cartilage over time and to withstand cartilage degeneration due to OA. While correlating genes with human OA has been difficult, it has recently been demonstrated by three laboratories that certain strains of mice (MRL/MpJ and DBA) are better able to repair cartilage and are protected from post-traumatic arthritis in young animals and age-related osteoarthritis in older animals. We propose to use the intercross of genetic strains also known to vary dramatically in their wound healing capacity, as models of genetic variation in cartilage repair and osteoarthritis. We predict that the animals that are better able to heal a wound in their ear, the classic test for wound healing, are also better able to repair damaged articular cartilage and, therefore, more resistant to osteoarthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
High Impact Research and Research Infrastructure Programs (RC2)
Project #
5RC2AR058978-02
Application #
7941043
Study Section
Special Emphasis Panel (ZAR1-CHW-G (M2))
Program Officer
Tyree, Bernadette
Project Start
2009-09-25
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$1,036,778
Indirect Cost
Name
Washington University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Chinzei, Nobuaki; Rai, Muhammad Farooq; Hashimoto, Shingo et al. (2018) Evidence for Genetic Contribution to Variation in Post-Traumatic Osteoarthritis in Mice. Arthritis Rheumatol :
Rai, Muhammad Farooq; Sandell, Linda J (2014) Regeneration of articular cartilage in healer and non-healer mice. Matrix Biol 39:50-5
Wu, P; Holguin, N; Silva, M J et al. (2014) Early response of mouse joint tissue to noninvasive knee injury suggests treatment targets. Arthritis Rheumatol 66:1256-65
Rai, Muhammad Farooq; Schmidt, Eric J; McAlinden, Audrey et al. (2013) Molecular insight into the association between cartilage regeneration and ear wound healing in genetic mouse models: targeting new genes in regeneration. G3 (Bethesda) 3:1881-91
Hashimoto, S; Rai, M F; Janiszak, K L et al. (2012) Cartilage and bone changes during development of post-traumatic osteoarthritis in selected LGXSM recombinant inbred mice. Osteoarthritis Cartilage 20:562-71
Rai, Muhammad Farooq; Hashimoto, Shingo; Johnson, Eric E et al. (2012) Heritability of articular cartilage regeneration and its association with ear wound healing in mice. Arthritis Rheum 64:2300-10